title: Dred Scott v. Sandford

text: In the late 1810s, a major political dispute arose over the creation of new American states from the vast territory the United States had acquired from France in 1803 through the Louisiana Purchase. The dispute centered on whether the new states would be "free" states, like the Northern states, in which slavery would be illegal, or whether they would be "slave" states, like the Southern states, in which slavery would be legal. The Southern states wanted the new states to be slave states in order to enhance their own political and economic power. The Northern states wanted the new states to be free states for their own political and economic reasons, as well as their moral concerns over allowing the institution of slavery to expand.


title: Dred Scott v. Sandford

text: In 1820, the U.S. Congress passed legislation known as the "Missouri Compromise" that was intended to resolve the dispute. The Compromise first admitted Maine into the Union as a free state, then created Missouri out of a portion of the Louisiana Purchase territory and admitted it as a slave state; at the same time it prohibited slavery in the area north of the Parallel 36°30′ north, where most of the territory lay. The legal effects of a slaveowner taking his slaves from Missouri into the free territory north of the 36°30′ north parallel, as well as the constitutionality of the Missouri Compromise itself, eventually came to a head in the "Dred Scott" case.


title: Dred Scott v. Sandford

text: Dred Scott was born a slave in Virginia around 1799. Little is known of his early years. His owner, Peter Blow, moved to Alabama in 1818, taking his six slaves along to work a farm near Huntsville. In 1830, Blow gave up farming and settled in St. Louis, Missouri, where he sold Scott to U.S. Army surgeon Dr. John Emerson. After purchasing Scott, Emerson took him to Fort Armstrong in Illinois. A free state, Illinois had been free as a territory under the Northwest Ordinance of 1787, and had prohibited slavery in its constitution in 1819 when it was admitted as a state.


title: Dred Scott v. Sandford

text: In 1836, Emerson moved with Scott from Illinois to Fort Snelling in the Wisconsin territory in what has become the state of Minnesota. Slavery in the Wisconsin Territory (some of which, including Fort Snelling, was part of the Louisiana Purchase) was prohibited by the U.S. Congress under the Missouri Compromise. During his stay at Fort Snelling, Scott married Harriet Robinson in a civil ceremony by Harriet's owner, Major Lawrence Taliaferro, a justice of the peace who was also an Indian agent. The ceremony would have been unnecessary had Dred Scott been a slave, as slave marriages had no recognition in the law.


title: Dred Scott v. Sandford

text: In 1837, the army ordered Emerson to Jefferson Barracks Military Post, south of St. Louis. Emerson left Scott and his wife at Fort Snelling, where he leased their services out for profit. By hiring Scott out in a free state, Emerson was effectively bringing the institution of slavery into a free state, which was a direct violation of the Missouri Compromise, the Northwest Ordinance, and the Wisconsin Enabling Act.


title: Dred Scott v. Sandford

text: Before the end of the year, the army reassigned Emerson to Fort Jesup in Louisiana, where Emerson married Eliza Irene Sanford in February 1838. Emerson sent for Scott and Harriet, who proceeded to Louisiana to serve their master and his wife. Within months, Emerson was transferred back to Fort Snelling. While en route to Fort Snelling, Scott's daughter Eliza was born on a steamboat under way on the Mississippi River between Illinois and what would become Iowa. Because Eliza was born in free territory, she was technically born as a free person under both federal and state laws. Upon entering Louisiana, the Scotts could have sued for their freedom, but did not. One scholar suggests that, in all likelihood, the Scotts would have been granted their freedom by a Louisiana court, as it had respected laws of free states that slaveholders forfeited their right to slaves if they brought them in for extended periods. This had been the holding in Louisiana state courts for more than 20 years.


title: Dred Scott v. Sandford

text: Toward the end of 1838, the army reassigned Emerson back to Fort Snelling. By 1840, Emerson's wife Irene returned to St. Louis with their slaves, while Dr. Emerson served in the Seminole War. While in St. Louis, she hired them out. In 1842, Emerson left the army. After he died in the Iowa Territory in 1843, his widow Irene inherited his estate, including the Scotts. For three years after John Emerson's death, she continued to lease out the Scotts as hired slaves. In 1846, Scott attempted to purchase his and his family's freedom, but Irene Emerson refused, prompting Scott to resort to legal recourse.


title: Dred Scott v. Sandford

text: Having been unsuccessful in his attempt to purchase his freedom, Dred Scott, with the help of his legal advisers, sued Emerson for his freedom in the Circuit Court of St. Louis County on April 6, 1846. A separate petition was filed for his wife Harriet, making them the first married couple to file freedom suits in tandem in its 50-year history. They received financial assistance from the family of Dred's previous owner, Peter Blow. Blow's daughter Charlotte was married to Joseph Charless, an officer at the Bank of Missouri. Charless signed legal documents as security for the Scotts and later secured the services of the bank's attorney, Samuel Mansfield Bay, for the trial.


title: Dred Scott v. Sandford

text: It was expected that the Scotts would win their freedom with relative ease. By 1846, dozens of freedom suits had been won in Missouri by former slaves. Most had claimed their legal right to freedom on the basis that they, or their mothers, had previously lived in free states or territories. Among the most important legal precedents were "Winny v. Whitesides" and "Rachel v. Walker." In "Winny v. Whitesides", the Missouri Supreme Court had ruled in 1824 that a person who had been held as a slave in Illinois, where slavery was illegal, and then brought to Missouri, was free by virtue of residence in a free state. In "Rachel v. Walker", the state supreme court had ruled that a U.S. Army officer who took a slave to a military post in a territory where slavery was prohibited and retained her there for several years, had thereby "forfeit[ed] his property". Rachel, like Dred Scott, had accompanied her enslaver to Fort Snelling.


title: Dred Scott v. Sandford

text: Scott was represented by three different lawyers from the filing of the original petition to the time of the actual trial, over one year later. The first was Francis B. Murdoch, a prolific freedom suit attorney who abruptly left St. Louis. Murdoch was replaced by Charles D. Drake, an in-law of the Blow family. When Drake also left the state, Samuel M. Bay took over as the Scotts' lawyer. Irene Emerson was represented by George W. Goode, a proslavery lawyer from Virginia. By the time the case went to trial, it had been reassigned from Judge John M. Krum, who was proslavery, to Judge Alexander Hamilton, who was known to be sympathetic to freedom suits.


title: Dred Scott v. Sandford

text: "Dred Scott v. Irene Emerson" finally went to trial for the first time on June 30, 1847. Henry Peter Blow testified in court that his father had owned Dred and sold him to John Emerson. The fact that Scott had been taken to live on free soil was clearly established through depositions from witnesses who had known Scott and Dr. Emerson at Fort Armstrong and Fort Snelling. Grocer Samuel Russell testified that he had hired the Scotts from Irene Emerson and paid her father, Alexander Sanford, for their services. Upon cross examination, however, Russell admitted that the leasing arrangements had actually been made by his wife, Adeline.


title: Dred Scott v. Sandford

text: Thus, Russell's testimony was ruled hearsay, and the jury returned a verdict for Emerson. This created a seemingly contradictory outcome in which Scott was ordered by the court to remain Irene Emerson's slave, because he had been unable to prove that he was previously Irene Emerson's slave.


title: Dred Scott v. Sandford

text: Bay moved immediately for a new trial on the basis that Scott's case had been lost due to a technicality which could be rectified, rather than the facts. Judge Hamilton finally issued the order for a new trial on December 2, 1847. Two days later, Emerson's lawyer objected to a new trial by filing a bill of exceptions. The case was then taken on writ of error to the Supreme Court of Missouri. Scott's new lawyers, Alexander P. Field and David N. Hall, argued that the writ of error was inappropriate because the lower court had not yet issued a final judgment. The state supreme court agreed unanimously with their position and dismissed Emerson's appeal on June 30, 1848. The main issue before the court at this stage was procedural and no substantive issues were discussed.


title: Dred Scott v. Sandford

text: Before the state supreme court had convened, Goode had presented a motion on behalf of Emerson to have Scott taken into custody and hired out. On March 17, 1848, Judge Hamilton issued the order to the St. Louis County sheriff. Anyone hiring Scott had to post a bond of six-hundred dollars. Wages he earned during that time were placed in escrow, to be paid to the party that prevailed in the lawsuit. Scott would remain in the sheriff's custody or hired out by him until March 18, 1857. One of Scott's lawyers, David N. Hall, hired him starting March 17, 1849.


title: Dred Scott v. Sandford

text: The St. Louis Fire of 1849, a cholera epidemic, and two continuances delayed the retrial in the St. Louis Circuit Court until January 12, 1850. Irene Emerson was now defended by Hugh A. Garland and Lyman D. Norris, while Scott was represented by Field and Hall. Judge Alexander Hamilton was presiding. The proceedings were similar to the first trial. The same depositions from Catherine A. Anderson and Miles H. Clark were used to establish that Dr. Emerson had taken Scott to free territory.


title: Dred Scott v. Sandford

text: This time, the hearsay problem was surmounted by a deposition from Adeline Russell stating that she had hired the Scotts from Irene Emerson, thereby proving that Emerson claimed them as her slaves. Samuel Russell testified in court once again that he had paid for their services. The defense then changed strategy and argued in their summation that Mrs. Emerson had every right to hire out Dred Scott, because he had lived with Dr. Emerson at Fort Armstrong and Fort Snelling under military jurisdiction, not under civil law. In doing so, the defense ignored the precedent set by "Rachel v. Walker." In his rebuttal, Hall stated that the fact that they were military posts did not matter, and pointed out that Dr. Emerson had left Scott behind at Fort Snelling, hired out to others, after being reassigned to a new post.


title: Dred Scott v. Sandford

text: The jury quickly returned a verdict in favor of Dred Scott, nominally making him a free man. Judge Hamilton declared Harriet, Eliza and Lizzie Scott to be free as well. Garland moved immediately for a new trial, and was overruled. On February 13, 1850, Emerson's defense filed a bill of exceptions, which was certified by Judge Hamilton, setting into motion another appeal to the Missouri Supreme Court. Counsel for the opposing sides signed an agreement that moving forward, only "Dred Scott v. Irene Emerson" would be advanced, and that any decision made by the high court would apply to Harriet's suit, also. In 1849 or 1850, Irene Emerson left St. Louis and moved to Springfield, Massachusetts. Her brother, John F. A. Sanford, continued looking after her business interests when she left, and her departure had no impact on the case.


title: Dred Scott v. Sandford

text: Both parties filed briefs with the Supreme Court of Missouri on March 8, 1850. A busy docket delayed consideration of the case until the October term. By then, the issue of slavery had become politically charged, even within the judiciary. Although the Missouri Supreme Court had not yet overturned precedent in freedom suits, in the 1840s, the court's proslavery justices had explicitly stated their opposition to freeing slaves. After the court convened on October 25, 1850, the two justices who were proslavery anti-Benton Democrats – William Barclay Napton and James Harvey Birch – persuaded John Ferguson Ryland, a Benton Democrat, to join them in a unanimous decision that Dred Scott remained a slave under Missouri law. However, Judge Napton delayed writing the court's opinion for months. Then in August 1851, both Napton and Birch lost their seats in the Missouri Supreme Court, following the state's first supreme court election, with only Ryland remaining as an incumbent. The case thus needed to be considered again by the newly elected court. The reorganized Missouri Supreme Court now included two "moderates" – Hamilton Gamble and John Ryland – and one staunch proslavery justice, William Scott.


title: Dred Scott v. Sandford

text: David N. Hall had prepared the brief for Dred Scott, but died in March 1851. Alexander P. Field continued alone as counsel for Dred Scott, and resubmitted the same briefs from 1850 for both sides. On November 29, 1851, the case was taken under consideration, on written briefs alone, and a decision was reached. However, before Judge Scott could write the court's opinion, Lyman Norris, co-counsel for Irene Emerson, obtained permission to submit a new brief he had been preparing, to replace the original one submitted by Garland.


title: Dred Scott v. Sandford

text: Norris's brief has been characterized as "a sweeping denunciation of the authority of both the [Northwest] Ordinance of 1787 and the Missouri Compromise." Although he stopped short of questioning their constitutionality, Norris questioned their applicability and criticized the early Missouri Supreme Court, ridiculing former Justice George Tompkins as "the great apostle of freedom at that day." Reviewing the court's past decisions on freedom suits, Norris acknowledged that if "Rachel v. Walker" was allowed to stand, his client would lose. Norris then challenged the concept of "once free, always free", and asserted that the court under Tompkins had been wrong to rule that the Ordinance of 1787 remained in force after the ratification of the U.S. Constitution in 1788. Finally, he argued that the Missouri Compromise should be disregarded whenever it interfered with Missouri law, and that the laws of other states should not be enforced, if their enforcement would cause Missouri citizens to lose their property. In support of his argument, he cited Chief Justice Roger B. Taney's opinion in the United States Supreme Court case "Strader v. Graham", which argued that the status of a slave returning from a free state must be determined by the slave state itself. According to historian Walter Ehrlich, the closing of Norris's brief was "a racist harangue that not only revealed the prejudices of its author, but also indicated how the "Dred Scott" case had become a vehicle for the expression of such views". Noting that Norris's proslavery "doctrines" were later incorporated into the court's final decision, Ehrlich writes (emphasis his):"From this point on, the" Dred Scott "case clearly changed from a genuine freedom suit to the controversial political issue for which it became infamous in American history."On March 22, 1852, Judge William Scott announced the decision of the Missouri Supreme Court that Dred Scott remained a slave, and ordered the trial court's judgment to be reversed. Judge Ryland concurred, while Chief Justice Hamilton Gamble dissented. The majority opinion written by Judge Scott focused on the issue of comity or conflict of laws, and relied on "states' rights" rhetoric:Every State has the right of determining how far, in a spirit of comity, it will respect the laws of other States. Those laws have no intrinsic right to be enforced beyond the limits of the State for which they were enacted. The respect allowed them will depend altogether on their conformity to the policy of our institutions. No State is bound to carry into effect enactments conceived in a spirit hostile to that which pervades her own laws.Judge Scott did not deny the constitutionality of the Missouri Compromise, and acknowledged that its prohibition of slavery was "absolute", but only within the specified territory. Thus, a slave crossing the border could obtain his freedom, but only within the court of the free state. Rejecting the court's own precedent, Scott argued that Once free' did not necessarily mean 'always free. He cited the Kentucky Court of Appeals decision in "Graham v. Strader", which had held that a Kentucky slaveowner who permitted a slave to go to Ohio temporarily, did not forfeit ownership of the slave. To justify overturning three decades of precedent, Judge Scott argued that circumstances had changed:Times now are not as they were when the former decisions on this subject were made. Since then not only individuals but States have been possessed with a dark and fell spirit in relation to slavery, whose gratification is sought in the pursuit of measures, whose inevitable consequence must be the overthrow and destruction of our government. Under such circumstances it does not behoove the State of Missouri to show the least countenance to any measure which might gratify this spirit. She is willing to assume her full responsibility for the existence of slavery within her limits, nor does she seek to share or divide it with others.On March 23, 1852, the day after the Missouri Supreme Court decision had been announced, Irene Emerson's lawyers filed an order in the St. Louis Circuit Court for the bonds signed by the Blow family to cover the Scotts' court costs; return of the slaves themselves; and transfer of their wages earned over four years, plus 6 percent interest. On June 29, 1852, Judge Hamilton overruled the order.


title: Dred Scott v. Sandford

text: The case looked hopeless, and the Blow family could no longer pay for Scott's legal costs. Scott also lost both of his lawyers when Alexander Field moved to Louisiana and David Hall died. The case was undertaken "pro bono" by Roswell Field, who employed Scott as a janitor. Field also discussed the case with LaBeaume, who had taken over the lease on the Scotts in 1851. After the Missouri Supreme Court decision, Judge Hamilton turned down a request by Emerson's lawyers to release the rent payments from escrow and to deliver the slaves into their owner's custody.


title: Dred Scott v. Sandford

text: In 1853, Dred Scott again sued his current owner John Sanford, but this time in federal court. Sanford returned to New York and the federal courts had diversity jurisdiction under Article III, Section 2 of the U.S. Constitution. In addition to the existing complaints, Scott alleged that Sanford had assaulted his family and held them captive for six hours on January 1, 1853.


title: Dred Scott v. Sandford

text: At trial in 1854, Judge Robert William Wells directed the jury to rely on Missouri law on the question of Scott's freedom. Since the Missouri Supreme Court had held that Scott remained a slave, the jury found in favor of Sanford. Scott then appealed to the U.S. Supreme Court, where the clerk misspelled the defendant’s name, and the case was recorded as "Dred Scott" v. "Sandford", with an ever-erroneous title. Scott was represented before the Supreme Court by Montgomery Blair and George Ticknor Curtis, whose brother Benjamin was a Supreme Court Justice. Sanford was represented by Reverdy Johnson and Henry S. Geyer.


title: Dred Scott v. Sandford

text: When the case was filed, the two sides agreed on a statement of facts that claimed Scott had been sold by Dr. Emerson to John Sanford, though this was a legal fiction. Dr. Emerson had died in 1843, and Dred Scott had filed his 1847 suit against Irene Emerson. There is no record of Dred Scott's transfer to Sanford or of his transfer back to Irene. John Sanford died shortly before Scott's manumission, and Scott was not listed in the probate records of Sanford's estate. Also, Sanford was not acting as Dr. Emerson's executor, as he was never appointed by a probate court, and the Emerson estate had been settled when the federal case was filed.


title: Dred Scott v. Sandford

text: The murky circumstances of ownership led many to conclude the parties to "Dred Scott" v. "Sandford" contrived to create a test case. Mrs. Emerson's remarriage to abolitionist U.S. Representative Calvin C. Chaffee seemed suspicious to contemporaries, and Sanford was thought to be a front and to have allowed himself to be sued, despite not actually being Scott's owner. Nevertheless, Sanford had been involved in the case since 1847, before his sister married Chaffee. He had secured counsel for his sister in the state case, and he engaged the same lawyer for his own defense in the federal case. Sanford also consented to be represented by genuine pro-slavery advocates before the Supreme Court, rather than to put up a token defense.


title: Dred Scott v. Sandford

text: Historians discovered that after the Supreme Court heard arguments in the case but before it issued a ruling, President-elect James Buchanan wrote to his friend, Supreme Court Associate Justice John Catron, to ask whether the case would be decided by the Court before his inauguration in March 1857. Buchanan hoped that the decision would quell unrest in the country over the slavery issue by issuing a ruling to take it out of political debate. He later successfully pressured Associate Justice Robert Cooper Grier, a Northerner, to join the Southern majority in "Dred Scott" to prevent the appearance that the decision was made along sectional lines.


title: Dred Scott v. Sandford

text: Biographer Jean H. Baker articulates the view that Buchanan's use of political pressure on a member of a sitting court was regarded then, as now, to be highly improper. Republicans fueled speculation as to Buchanan's influence by publicizing that Taney had secretly informed Buchanan of the decision. Buchanan declared in his inaugural address that the slavery question would "be speedily and finally settled" by the Supreme Court.


title: Dred Scott v. Sandford

text: On March 6, 1857, the U.S. Supreme Court ruled against Dred Scott in a 7–2 decision that fills over 200 pages in the "United States Reports". The decision contains opinions from all nine justices, but the "majority opinion" has always been the focus of the controversy.


title: Dred Scott v. Sandford

text: Seven justices formed the majority and joined an opinion written by chief justice Roger Taney. Taney began the Court's opinion with what he saw as the core issue in the case: whether or not black people could possess federal citizenship under the U.S. Constitution.


title: Dred Scott v. Sandford

text: In answer, the Court ruled that they could not. It held that black people could not be American citizens, and therefore a lawsuit to which they were a party could never qualify for the "diversity of citizenship" that Article III of the Constitution requires for American federal courts to have jurisdiction over cases that do not involve federal questions.


title: Dred Scott v. Sandford

text: The primary rationale for the Court's ruling was Taney's assertion that black African slaves and their descendants were never intended to be part of the American social and political landscape.


title: Dred Scott v. Sandford

text: Taney then extensively reviewed laws from the original American states that involved the status of black Americans at the time of the Constitution's drafting in 1787. He concluded that these laws showed that a "perpetual and impassable barrier was intended to be erected between the white race and the one which they had reduced to slavery". Thus, he concluded, black people were not American citizens, and could not sue as citizens in federal courts. This meant that U.S. states lacked the power to alter the legal status of black people by granting them state citizenship.


title: Dred Scott v. Sandford

text: This holding normally would have ended the decision, since it disposed of Dred Scott's case, but Taney did not conclude the matter before the Court in the normal manner. He went on to assess the constitutionality of the Missouri Compromise itself, writing that the Compromise's legal provisions intended to free slaves who were living north of the 36°N latitude line in the western territories. In the Court's judgment, this would constitute the government depriving slaveowners of their propertysince slaves were legally the property of their ownerswithout due process of law, which is forbidden under the Fifth Amendment to the Constitution. Taney also reasoned that the Constitution and the Bill of Rights implicitly precluded any possibility of constitutional rights for black African slaves and their descendants. Thus, Taney concluded:


title: Dred Scott v. Sandford

text: Taney held that the Missouri Compromise was unconstitutional, marking the first time since the 1803 case "Marbury v. Madison" that the Supreme Court had struck down a federal law, although the Missouri Compromise had already been effectively overridden by the Kansas–Nebraska Act. Taney made this argument on a narrow definition of the Property Clause of Section 3 of Article 4 of the Constitution. The Property Clause states, "The Congress shall have Power to dispose of and make all needful Rules and Regulations respecting the Territory or other Property belonging to the United States..." Taney made the argument that the Property Clause "applied only to the property which the States held in common at that time, and has no reference whatever to any territory or other property which the new sovereignty might afterwards itself acquire." Taney asserted that because the Northwest Territory was not part of the United States at the time of the Constitution's ratification, Congress did not have the authority to ban slavery in the territory. According to Taney, the Missouri Compromise exceeded the scope of Congress powers and was unconstitutional, and thus Dred Scott was still a slave regardless of his time spent in the parts of the Northwest Territory that were north of 36°N, and he was still a slave under Missouri law, and the Court had to follow Missouri law in the matter. For all these reasons, the Court concluded that Scott could not bring suit in U.S. federal court.


title: Dred Scott v. Sandford

text: Justices Benjamin Robbins Curtis and John McLean were the only two dissenters from the Court's decision, and both filed dissenting opinions.


title: Dred Scott v. Sandford

text: Curtis's 67-page dissent argued that the Court's conclusion that black people could not possess federal U.S. citizenship was legally and historically baseless. Curtis pointed out that at the time of the Constitution's adoption in 1789, black men could vote in five of the 13 states. Legally, that made them citizens of both their individual states and the United States federally. Curtis cited many state statutes and state court decisions supporting his position. His dissent was "extremely persuasive", and it prompted Taney to add 18 additional pages to his opinion in an attempt to rebut Curtis's arguments.


title: Dred Scott v. Sandford

text: McLean's dissent deemed the argument that black people could not be citizens "more a matter of taste than of law". He attacked much of the Court's decision as "obiter dicta" that was not legally authoritative on the ground that once the court determined that it did not have jurisdiction to hear Scott's case, it should have simply dismissed the action, rather than passing judgment on the merits of the claims.


title: Dred Scott v. Sandford

text: Curtis and McLean both attacked the Court's overturning of the Missouri Compromise on its merits. They noted that it was not necessary to decide the question and that none of the authors of the Constitution had ever objected on constitutional grounds to the Congress's adoption of the antislavery provisions of the Northwest Ordinance passed by the Continental Congress or the subsequent acts that barred slavery north of 36°30' N, or the prohibition on importing slaves from overseas passed in 1808. Curtis said slavery was not listed in the constitution as a "natural right", but rather a creation of municipal law. He pointed out the constitution said "The Congress shall have Power to dispose of and make all needful Rules and Regulations respecting the Territory or other Property belonging to the United States; and nothing in this Constitution shall be so construed as to Prejudice any Claims of the United States, or of any particular State." Since slavery was not mentioned as an exception, he felt a prohibition of it fell within the scope of needed rules and regulations Congress was free to pass.


title: Dred Scott v. Sandford

text: The Supreme Court's decision in "Dred Scott" was "greeted with unmitigated wrath from every segment of the United States except the slave holding states." The American political historian Robert G. McCloskey described:


title: Dred Scott v. Sandford

text: Many Republicans, including Abraham Lincoln, who was rapidly becoming the leading Republican in Illinois, regarded the decision as part of a plot to expand and eventually impose the legalization of slavery throughout all of the states. Some southern extremists wanted all states to recognize slavery as a constitutional right. Lincoln rejected the court's majority opinion that "the right of property in a slave is distinctly and expressly affirmed in the Constitution," pointing out that the constitution did not ever mention property in reference to slaves and in fact explicitly referred to them as "persons". Southern Democrats considered Republicans to be lawless rebels who were provoking disunion by their refusal to accept the Supreme Court's decision as the law of the land. Many northern opponents of slavery offered a legal argument for refusing to recognize the "Dred Scott" decision on the Missouri Compromise as binding. They argued that the Court's determination that the federal courts had no jurisdiction to hear the case rendered the remainder of the decision "obiter dictum"—a non binding passing remark rather than an authoritative interpretation of the law. Douglas attacked that position in the Lincoln-Douglas debates:


title: Dred Scott v. Sandford

text: In a speech at Springfield, Illinois, Lincoln responded that the Republican Party was not seeking to defy the Supreme Court, but he hoped they could convince it to reverse its ruling.


title: Dred Scott v. Sandford

text: Democrats had refused to accept the court's interpretation of the U.S. Constitution as permanently binding. During the Andrew Jackson administration, Taney, then Attorney General, had written:


title: Dred Scott v. Sandford

text: Frederick Douglass, a prominent black abolitionist who considered the decision to be unconstitutional and Taney's reasoning contrary to the Founding Fathers' vision, predicted that political conflict could not be avoided:


title: Dred Scott v. Sandford

text: According to Jefferson Davis, then a U.S. Senator from Mississippi, and future President of the Confederate States of America, the case merely "presented the question whether Cuffee [a derogatory term for a black person] should be kept in his normal condition or not . . . [and] whether the Congress of the United States could decide what might or might not be property in a Territory–the case being that of an officer of the army sent into a Territory to perform his public duty, having taken with him his negro slave".


title: Dred Scott v. Sandford

text: Irene Emerson moved to Massachusetts in 1850 and married Calvin C. Chaffee, a doctor and abolitionist who was elected to Congress on the Know Nothing and Republican tickets. Following the Supreme Court ruling, pro-slavery newspapers attacked Chaffee as a hypocrite. Chaffee protested that Dred Scott belonged to his brother-in-law and that he had nothing to do with Scott's enslavement. Nevertheless, the Chaffees executed a deed transferring the Scott family to Henry Taylor Blow, the son of Scott's former owner, Peter Blow. Chaffee’s lawyer suggested the transfer as the most convenient way of freeing Scott since Missouri law required manumitters to appear in person before the court.


title: Dred Scott v. Sandford

text: Taylor Blow filed the manumission papers with Judge Hamilton on May 26, 1857. The emancipation of Dred Scott and his family was national news and was celebrated in northern cities. Scott worked as a porter in a hotel in St. Louis, where he was a minor celebrity. His wife took in laundry. Dred Scott died of tuberculosis on November 7, 1858. Harriet died on June 17, 1876.


title: Dred Scott v. Sandford

text: Economist Charles Calomiris and historian Larry Schweikart discovered that uncertainty about whether the entire West would suddenly become slave territory or engulfed in combat like


title: Dred Scott v. Sandford

text: "Bleeding Kansas" gripped the markets immediately. The east–west railroads collapsed immediately (although north–south lines were unaffected), causing, in turn, the near-collapse of several large banks and the runs that ensued. What followed the runs has been called the Panic of 1857.


title: Dred Scott v. Sandford

text: The Panic of 1857, unlike the Panic of 1837, almost exclusively impacted the North, a fact that Calomiris and Schweikart attribute to the South's system of branch banking, as opposed to the North's system of unit banking. In the South's branch banking system, information moved reliably among the branch banks and transmission of the panic was minor. Northern unit banks, in contrast, were competitors and seldom shared such vital information.


title: Dred Scott v. Sandford

text: Southerners, who had grown uncomfortable with the Kansas-Nebraska Act, argued that they had a constitutional right to bring slaves into the territories, regardless of any decision by a territorial legislature on the subject. The "Dred Scott" decision seemed to endorse that view.


title: Dred Scott v. Sandford

text: Although Taney believed that the decision represented a compromise that would be a final settlement of the slavery question by transforming a contested political issue into a matter of settled law, the decision produced the opposite result. It strengthened Northern opposition to slavery, divided the Democratic Party on sectional lines, encouraged secessionist elements among Southern supporters of slavery to make bolder demands, and strengthened the Republican Party.


title: Dred Scott v. Sandford

text: In 1860, the Republican Party explicitly rejected the "Dred Scott" verdict in their official platform, stating "the new dogma that the Constitution, of its own force, carries slavery into any or all of the territories of the United States, is a dangerous political heresy, at variance with the explicit provisions of that instrument itself, with contemporaneous exposition, and with legislative and judicial precedent; is revolutionary in its tendency, and subversive of the peace and harmony of the country."


title: Dred Scott v. Sandford

text: In 1859, when defending John Anthony Copeland and Shields Green from the charge of treason, following their participation in John Brown's raid on Harpers Ferry, their attorney, George Sennott, cited the "Dred Scott" decision in arguing successfully that since they were not citizens according to that Supreme Court ruling, they could not commit treason. The charge of treason was dropped, but they were found guilty and executed on other charges.


title: Dred Scott v. Sandford

text: Justice John Marshall Harlan was the lone dissenting vote in "Plessy v. Ferguson" (1896), which declared racial segregation constitutional and created the concept of "separate but equal". In his dissent, Harlan wrote that the majority's opinion would "prove to be quite as pernicious as the decision made by this tribunal in the "Dred Scott" case".


title: Dred Scott v. Sandford

text: Charles Evans Hughes, writing in 1927 on the Supreme Court's history, described "Dred Scott v. Sandford" as a "self-inflicted wound" from which the court would not recover for many years.


title: Dred Scott v. Sandford

text: In a memo to Justice Robert H. Jackson in 1952, for whom he was clerking, on the subject of "Brown v. Board of Education", the future Chief Justice William H. Rehnquist wrote that ""Scott v. Sandford" was the result of Taney's effort to protect slaveholders from legislative interference."


title: Dred Scott v. Sandford

text: Justice Antonin Scalia made the comparison between "Planned Parenthood v. Casey" (1992) and "Dred Scott" in an effort to see "Roe v. Wade" overturned:


title: Dred Scott v. Sandford

text: "Dred Scott" ... rested upon the concept of "substantive due process" that the Court praises and employs today. Indeed, "Dred Scott" was very possibly the first application of substantive due process in the Supreme Court, the original precedent for... "Roe v. Wade".


title: Dred Scott v. Sandford

text: Scalia noted that the "Dred Scott" decision had been written and championed by Taney and left the justice's reputation irrevocably tarnished. Taney, who was attempting to end the disruptive question of the future of slavery, wrote a decision that "inflamed the national debate over slavery and deepened the divide that led ultimately to the American Civil War".


title: Dred Scott v. Sandford

text: Chief Justice John Roberts compared "Obergefell v. Hodges" (2015) to "Dred Scott", as another example of trying to settle a contentious issue through a ruling that went beyond the scope of the Constitution.


Grand Theft Auto: The Trilogy – The Definitive Edition is a 2021 compilation of three action-adventure games in the "Grand Theft Auto" series: "Grand Theft Auto III" (2001), "" (2002), and "" (2004). It was developed by Grove Street Games and published by Rockstar Games. All three games are remastered, with visual enhancements and gameplay upgrades. The games feature different protagonists and locations within the same continuity. "Grand Theft Auto III" follows silent protagonist Claude in Liberty City; "Vice City", set in 1986, features ex-mobster Tommy Vercetti in the titular Vice City; and "San Andreas", set in 1992, follows gangster Carl "CJ" Johnson within the fictional state of San Andreas.


title: Grand Theft Auto: The Trilogy – The Definitive Edition

text: The two-year development focused on maintaining the look and feel of the original games; the physics code was copied from the originals, and artificial intelligence was used to automatically upscale textures. The development team studied the distinctive qualities of the original games. They added several colouring, weathering, and lighting effects, as well as new assets from "Grand Theft Auto V" (2013). The team consulted with the original developers at Rockstar North when upgrading the character designs. Prior to release, existing versions of the three games were removed from sale from digital retailers, which led to criticism from audiences and journalists; in response, Rockstar restored the original versions on the Rockstar Store.


text: "The Definitive Edition" was released for Nintendo Switch, PlayStation 4, PlayStation 5, Windows, Xbox One, and Xbox Series X/S on 11 November 2021, and is scheduled for release on Android and iOS devices in 2022/2023. The Windows launch was marred by problems with the Rockstar Games Launcher, rendering it unplayable for three days. The game received poor reviews; critics generally praised the enhanced visuals, upgraded lighting, improved controls, and added gameplay mechanics, but criticised its technical problems, art direction, and character models. It was one of the lowest-scoring games of 2021, and was the subject of review bombing on Metacritic. Rockstar apologised for the technical problems and announced its intentions to improve the game through updates.


text: "Grand Theft Auto: The Trilogy – The Definitive Edition" contains three games in the "Grand Theft Auto" series: "Grand Theft Auto III" (2001), "" (2002), and "" (2004). They are action-adventure games played from a third-person perspective wherein players complete missions—linear scenarios with set objectives—to progress through the story. Outside of missions, players can freely roam the open world and have the ability to complete optional side missions. Some areas of the games become unlocked as the player progresses through the storyline.


text: "Grand Theft Auto III" is set in Liberty City, loosely based on New York City; it follows a silent protagonist, Claude, who is betrayed and left for dead by his girlfriend during a robbery and embarks on a quest for revenge that leads him to become entangled in a world of crime, drugs, gang warfare, and corruption. "Vice City", set in 1986 in the titular Vice City (based on Miami), follows mobster Tommy Vercetti who, after being released from prison and becoming caught up in an ambushed drug deal, begins slowly building an empire by seizing power from other criminal organisations in the city. "San Andreas" is set in 1992 within the fictional state of San Andreas, consisting of three main cities: Los Santos (based on Los Angeles), San Fierro (based on San Francisco), and Las Venturas (based on Las Vegas); the game follows former gangster Carl "CJ" Johnson, who returns home following his mother's murder and is drawn back into his former gang and a life of crime while clashing with corrupt authorities and powerful criminals.


text: All three titles are remastered for "The Definitive Edition", including a rebuilt lighting system, upgraded vehicle and character models, new navigation and heads-up display designs, and improved shadows, reflections, and draw distances. The controls were updated to match those of "Grand Theft Auto V" (2013), and the checkpoint system was improved to allow for an automatic restart. On Nintendo Switch, the game includes gyro aiming and touchscreen support. Some music tracks and cheats from the original versions of the games were removed.


text: "Grand Theft Auto: The Trilogy – The Definitive Edition" was developed by Grove Street Games and published by Rockstar Games. Under its former name War Drum Studios, Grove Street Games previously developed mobile versions of the trilogy, as well as the PlayStation 3 and Xbox 360 versions of "San Andreas". "The Definitive Edition" was in development for two years, and used Unreal Engine 4 for rendering; the original games used RenderWare. The development team found porting the game to the engine made it look "clean", requiring them to make it appear dirtier to maintain the original look. Rockstar had resisted the trend of video game remakes as the team found they required care and attention, but they ultimately felt the remaster was "a way to maintain the titles for the next decade-plus" without dealing with the outdated technology. They found "Grand Theft Auto III" the most difficult of the trilogy to update due to the outdated assets; in comparison, "San Andreas" was much easier, as the original art department had learned to take advantage of the hardware at the time.


text: The team wanted "The Definitive Edition" to maintain the feeling of the original games; as part of this, they copied the original physics code. They originally attempted to rebuild some of the main buildings from scratch, such as the player characters' houses, but noticed a discrepancy in quality compared to other buildings. Some assets were improved from the original games, while others were ultimately rebuilt entirely. The team used an artificial intelligence program to upscale textures before making manual adjustments; producer Rich Rosado estimated over 100,000 textures were changed. The added navigation feature was implemented using pathfinding as well as analysing the routes taken by the non-player characters (NPCs), though it required some manual adjustments; the team found these implementations to be "easy wins" due to the existing technology. They wanted "The Definitive Edition" to run smoothly across all platforms while taking advantage of the higher-end hardware.


text: The team studied all three games to determine their distinct qualities, such as "Vice City"s "bright neons" and "San Andreas"s orange sky. They added dynamic colours that shift throughout the day, and corrected the placement and movement of the Sun, Moon, stars, and clouds. They changed some weather effects, such as the falling of rain and accumulation of puddles and their reflections. While the original games used "baked lighting"—"lighting [that] would just come from nowhere because we just need to light the scene"—"The Definitive Edition" uses the lighting from the sky, which forced the team to add artificial lights to avoid darkness in some locations, such as lampposts in alleys. All trees and foliage in the games, as well as some interior design elements, were replaced with higher-quality assets from "Grand Theft Auto V"; the team wanted them to naturally blend into the environment.


text: Rosado claimed "the art challenge alone felt insurmountable early on" due to the scale of remastering three games simultaneously, particularly the immensity of "San Andreas". The team avoided making the games look too realistic as they felt the characters—whose motion capture data was coded to the original caricaturised wire-frame models—would look out of place. They wanted the characters to maintain their original appearance, noting the game "must look like you remember it". They faced difficulty when working on characters, as they felt adding detail "where there was no detail before" might conflict with the player's "mental image" of the character designs; the team consulted developers at Rockstar North, including some of the games' original artists. Much of the material from the original games—such as the source audio, textures, reference material, and character models—were unable to be found due to a lack of archives, as the original development team "never thought [they would] have to revisit these projects".


text: The existence of "The Definitive Edition" was first reported in August 2021 by "Kotaku", claiming its development was led by Rockstar Dundee. Media speculation continued in September after the Game Rating and Administration Committee in South Korea gave the trilogy a game rating, and in early October after an update to the Rockstar Games Launcher included data referencing the game, such as logos, art, and achievements. Rockstar announced the trilogy on 8 October 2021, coinciding with the 20th anniversary month of "Grand Theft Auto III"s original release. It revealed the trilogy would feature "across-the-board upgrades ... while still maintaining the classic look and feel of the originals".


text: Existing versions of the three games were removed from sale from digital retailers on consoles and Windows on 13 October 2021. Audiences and journalists criticised the move, citing concerns with video game preservation, a lack of choice between versions, and the potential removal of music due to expired licences, which had occurred with previous re-releases. Wesley Yin-Poole of "Eurogamer" called the decision a "blow to video game preservation" and said it was poor for player choice. Upon the game's release, Rockstar confirmed the game's music matched the trilogy's most recent re-releases in 2014, with over 30 songs missing from "Vice City" and "San Andreas" collectively. Some cheats were removed from the game as they "didn't play well" in Unreal Engine. On 19 November, Rockstar announced that the original versions of the games would be released as a bundle on the Rockstar Store; they were delivered for free to owners of "The Definitive Edition" on 3 December, and remained available with all purchases of the game until 30 June 2022. Customers who bought "The Definitive Edition" through the Rockstar Games Launcher were eligible to receive one free Rockstar game between 20 December 2021 and 5 January 2022.


text: Preorders for "The Definitive Edition" began on 22 October 2021, alongside the release of the first full trailer and screenshots demonstrating the graphical enhancements. The game was released for Nintendo Switch, PlayStation 4, PlayStation 5, Windows, Xbox One, and Xbox Series X/S on 11 November 2021. Physical versions for PlayStation 4, Xbox One, and Xbox Series X were released on 17 December 2021, and for Switch on 11 February 2022; all physical versions were initially scheduled for 7 December 2021. The Windows version supports Nvidia DLSS, while the PlayStation 5 and Xbox Series X versions display at 4K resolution with up to 60 frames per second. Android and iOS versions of the game were scheduled to be released in the first half of 2022; in May 2022, Rockstar's parent company Take-Two Interactive updated the mobile version's release window to its 2023 fiscal year, ending 31 March 2023.


text: The game was expected to launch on 11 November at 10 a.m. Eastern Standard Time (), but an error on the PlayStation Store caused pre-orders to unlock at midnight locally, granting players in Australia and New Zealand access more than 24 hours before planned on PlayStation 4 and PlayStation 5. The digital listing was temporarily removed from the PlayStation Store in the interim. Upon the game's release, the Rockstar Games Launcher went offline for a period of roughly 28 hours for "maintenance", rendering the game unplayable and unpurchaseable on Windows; the game remained unavailable after the launcher was restored, while Rockstar "remove[d] files unintentionally included" in the game. Based on information discovered by data miners, journalists suggested those files included the removed radio station songs, hidden notes from the developers, and "San Andreas"s controversial Hot Coffee minigame. Following three days of unavailability, the Windows version was restored on 14 November. On 19 November 2021, Rockstar announced it would work to fix and improve the game through updates, the first of which was released the following day. On 30 November, an option was added to "San Andreas" to view ground fog following criticism of its absence. An update in February 2022 resolved more than 100 bugs.


text: "The Definitive Edition" received "mixed or average reviews" for PlayStation 5 and Xbox Series X/S, based on forty-six and eleven reviews, respectively, and "generally unfavorable reviews" for Nintendo Switch and Windows based on fourteen and eight critics, according to review aggregator Metacritic. It was one of the lowest-scoring games on Metacritic in 2021. Jordan Middler of "Video Games Chronicle" described the collection as "far from 'definitive, and Chris Shive of "Hardcore Gamer" wrote "these games are all masterpieces and as such deserve a better collection than this". "GameSpot"s Justin Clark was confused as to why Rockstar Games, known for its high-quality and detailed games like "Red Dead Redemption 2" (2018), would publish a remaster "that turns its most iconic games into app store shovelware". "Jeuxvideo.com"s Jerome Joffard felt the games maintained their original charm and feeling of freedom.


text: "Destructoid"s Dan Roemer wrote the updated visuals "look pretty solid", particularly praising the neon signs of "Vice City". "Screen Rant"s Christopher J. Teuton said the games "look better here than they ever have before", excluding mods, though noted the increased draw distance in "San Andreas" made the map feel simpler and smaller. Several critics echoed the latter sentiment; "Video Games Chronicle"s Middler said it "feels like something you were never supposed to see", and "IGN"s Tristan Ogilvie wrote it "completely shatters the convincing illusion of scale". Zack Zwiezen of "Kotaku" described the improved graphics as "at times stunning and distracting", praising the improvements and additions of trees and foliage, but noting some broken or improperly-upscaled textures. "VideoGamer.com"s Josh Wise found the improved draw distances and lighting removed the dirtier mood of the originals, with "Grand Theft Auto III" and "San Andreas" missing the "grey-green murk" and the "beer-tinted haze", respectively. Clark of "GameSpot" echoed this sentiment and stressed the importance of art direction, noting the mood and personality of the games, cities, and characters had been largely lost.


text: "Jeuxvideo.com"s Joffard felt the improved lighting system highlights the themes of each game: the darker atmosphere of "Grand Theft Auto III", bright colours of "Vice City", and dusty roads of "San Andreas". Sam Machkovech of "Ars Technica" called the lighting the "best part" of the game, and Middler of "Video Games Chronicle" felt it "captures the vibe perfectly", especially in "Vice City", though noted the sunlight was occasionally too bright. "NME"s Jordan Olomon wrote the improved lighting effects "make it feel like what you imagined these games looked like when you were a kid". "IGN"s Ogilvie thought the lighting was inconsistent, enjoying the neon lights of "Vice City" and the general reflections in cars and puddles, but criticising the intense shadows and distracting rain effects; "The Guardian"s Keza MacDonald called the rain effects "so ugly that they obscure your view", and "GameSpot"s Clark said they render the games "virtually unplayable". Several critics found the lighting changes would often make scenes too dark.


text: Critics praised the addition of mission checkpoints, the weapon wheel and map navigation, and the improved shooting controls, which many felt made the game easier and more enjoyable. Conversely, while "IGN"s Ogilvie enjoyed the addition of the map navigation, he noted some inconsistencies when attempting to place a custom waypoint while in a mission; he felt the mission checkpoints remained too unforgiving and found the auto-targeting to be inconsistent across the three games, with "San Andreas" performing better than the others. "Destructoid"s Roemer considered the combat disappointingly similar to the original games, calling it "incredibly rough and unforgiving at times". "Screen Rant"s Teuton criticised the removal of the cinematic and top-down camera angles from "Grand Theft Auto III". Some critics voiced their disapproval at the removal of some radio station songs. Shive of "Hardcore Gamer" questioned the removal of the Confederate flag from a character's outfit, and Joffard of "Jeuxvideo.com" criticised the removal of the two-player mode from "San Andreas".


text: The updated character designs received mixed responses. Machkovech of "Ars Technica" wrote they "generally shine" in comparison to the originals, though noted some "look pretty bad". "IGN"s Ogilvie similarly thought the designs were only occasionally distracting during cutscenes. Shive of "Hardcore Gamer" liked Claude's new character model, but felt Tommy looked "too young" and some NPC models "look like horrible mutant abominations". Olomon of "NME" described the models as "outright ridiculous". Joffard of "Jeuxvideo.com" felt the cartoonish designs of the new character models negatively juxtaposed the realistic graphical changes, and made several characters lose some of their personality and charisma; Middler of "Video Games Chronicle" concurred, noting "it doesn't seem like every character was given the care and attention they deserve". "Polygon"s Cameron Kunzelman and "Destructoid"s Roemer criticised Tommy's updated model, describing him as a "G.I. Joe doll" and "a bloated Ken doll", respectively. "GameSpot"s Clark called the character models "absolutely hideous".


text: Several reviewers recalled encountering technical errors and crashes. "The Guardian"s MacDonald wrote the "remasters feel less stable" than the original games; Teuton of "Screen Rant" found "Vice City" to be the most unstable of the three games. "Ars Technica"s Machkovech felt the game did not take advantage of the advanced hardware like the Xbox Series X, and criticised the "botched" high dynamic range; "Push Square"s Sammy Barker noted significant frame rate drops on the PlayStation 5 version. The Nintendo Switch version of the game was particularly criticised for its technical flaws; "Nintendo Life"s PJ O'Reilly censured the awkward shooting controls, frequent frame rate dips, and some character designs, though enjoyed the graphical upgrade for the world and lighting, particularly in "Vice City". Middler of "Video Games Chronicle" denounced the Switch version's low-quality textures and lower display resolution compared to other platforms. Machkovech of "Ars Technica" criticised the game's pricing and frame rate issues, and noted he experienced at least one hardware crash in all three games.


text: The game was the subject of review bombing on Metacritic, resulting in a user review score of 0.4/10 at its nadir, among the lowest on the site. Reporters noted some user reviews cited a dislike of the game's art style and the lack of advance copies sent to press, with several demanding refunds. Journalists noted a general backlash from players due to the unusual look of some updated character models, textual errors on in-game surfaces, issues related to draw distance increase, and model and physics glitches. Following criticism, mods were created to improve the game's rain and restore removed content.


text: In response to the game's negative reception, Grove Street Games chief executive officer (CEO) Thomas Williamson said he was "enjoying this unparalleled level of scrutiny on our studio". On 19 November 2021, Rockstar apologised for the technical problems, admitting the games "did not launch in a state that meets our own standards of quality, or the standards our fans have come to expect". Rockstar reported members of the development team had been harassed online, and urged its community to "maintain a respectful and civil discourse". In January 2022, Strauss Zelnick, CEO of Take-Two Interactive, said the game had a "glitch" at launch was resolved and the game performed "just great for the company"; some journalists felt Zelnick's comments were an attempt to downplay the release's major issues. The following month, Zelnick reiterated the game "definitely had some quality issues" and the company "did fall short", but noted the issues were being addressed. According to industry sources, the game's backlash resulted in Rockstar shelving remasters of "Grand Theft Auto IV" (2008) and "Red Dead Redemption" (2010), instead increasing focus on development for the next entry in the "Grand Theft Auto" series.


text: In the United Kingdom, "The Definitive Edition" was the eighth-best-selling game in November 2021, and the 20th-best-selling in December; the chart combines physical and digital sales for consoles, though the game was only available digitally in November. Following its physical release, the game charted sixth in the United Kingdom's weekly boxed charts; 67 per cent of copies sold were for PlayStation 4, with the remainder on Xbox. In its second week, the physical version fell to 23rd after sales dropped 70 per cent, and it exited the top 40 the following week. On the PlayStation Store in November 2021, the game was the third-best-selling PlayStation 5 game in Europe and North America; it was the sixth-best-selling for PlayStation 4 in North America, and the eighth in Europe. In December, it was the 20th-best-selling PlayStation 5 game in Europe, and it placed 17th in the region for the year overall. In the United States, the physical version was the 57th-best-selling game of January 2022, and the 16th-best-selling of February.


text: Journalists estimated the game could have sold up to ten million copies by December 2021. In February 2022, Zelnick said sales exceeded expectations and the company felt "very good about how the title has performed commercially", though analyst Michael Pachter of Wedbush Securities said "everyone knew [it] underperformed".


title: Enzyme

text: Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. The study of enzymes is called "enzymology" and the field of pseudoenzyme analysis recognizes that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their amino acid sequences and unusual 'pseudocatalytic' properties.


title: Enzyme

text: Enzymes are known to catalyze more than 5,000 biochemical reaction types. Other biocatalysts are catalytic RNA molecules, called ribozymes. Enzymes' specificity comes from their unique three-dimensional structures.


title: Enzyme

text: Like all catalysts, enzymes increase the reaction rate by lowering its activation energy. Some enzymes can make their conversion of substrate to product occur many millions of times faster. An extreme example is orotidine 5'-phosphate decarboxylase, which allows a reaction that would otherwise take millions of years to occur in milliseconds. Chemically, enzymes are like any catalyst and are not consumed in chemical reactions, nor do they alter the equilibrium of a reaction. Enzymes differ from most other catalysts by being much more specific. Enzyme activity can be affected by other molecules: inhibitors are molecules that decrease enzyme activity, and activators are molecules that increase activity. Many therapeutic drugs and poisons are enzyme inhibitors. An enzyme's activity decreases markedly outside its optimal temperature and pH, and many enzymes are (permanently) denatured when exposed to excessive heat, losing their structure and catalytic properties.


title: Enzyme

text: Some enzymes are used commercially, for example, in the synthesis of antibiotics. Some household products use enzymes to speed up chemical reactions: enzymes in biological washing powders break down protein, starch or fat stains on clothes, and enzymes in meat tenderizer break down proteins into smaller molecules, making the meat easier to chew.


title: Enzyme

text: By the late 17th and early 18th centuries, the digestion of meat by stomach secretions and the conversion of starch to sugars by plant extracts and saliva were known but the mechanisms by which these occurred had not been identified.


title: Enzyme

text: French chemist Anselme Payen was the first to discover an enzyme, diastase, in 1833. A few decades later, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that this fermentation was caused by a vital force contained within the yeast cells called "ferments", which were thought to function only within living organisms. He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells."


title: Enzyme

text: In 1877, German physiologist Wilhelm Kühne (1837–1900) first used the term "enzyme", which comes from Greek ἔνζυμον, "leavened" or "in yeast", to describe this process. The word "enzyme" was used later to refer to nonliving substances such as pepsin, and the word "ferment" was used to refer to chemical activity produced by living organisms.


title: Enzyme

text: Eduard Buchner submitted his first paper on the study of yeast extracts in 1897. In a series of experiments at the University of Berlin, he found that sugar was fermented by yeast extracts even when there were no living yeast cells in the mixture. He named the enzyme that brought about the fermentation of sucrose "zymase". In 1907, he received the Nobel Prize in Chemistry for "his discovery of cell-free fermentation". Following Buchner's example, enzymes are usually named according to the reaction they carry out: the suffix "-ase" is combined with the name of the substrate (e.g., lactase is the enzyme that cleaves lactose) or to the type of reaction (e.g., DNA polymerase forms DNA polymers).


title: Enzyme

text: The biochemical identity of enzymes was still unknown in the early 1900s. Many scientists observed that enzymatic activity was associated with proteins, but others (such as Nobel laureate Richard Willstätter) argued that proteins were merely carriers for the true enzymes and that proteins "per se" were incapable of catalysis. In 1926, James B. Sumner showed that the enzyme urease was a pure protein and crystallized it; he did likewise for the enzyme catalase in 1937. The conclusion that pure proteins can be enzymes was definitively demonstrated by John Howard Northrop and Wendell Meredith Stanley, who worked on the digestive enzymes pepsin (1930), trypsin and chymotrypsin. These three scientists were awarded the 1946 Nobel Prize in Chemistry.


title: Enzyme

text: The discovery that enzymes could be crystallized eventually allowed their structures to be solved by x-ray crystallography. This was first done for lysozyme, an enzyme found in tears, saliva and egg whites that digests the coating of some bacteria; the structure was solved by a group led by David Chilton Phillips and published in 1965. This high-resolution structure of lysozyme marked the beginning of the field of structural biology and the effort to understand how enzymes work at an atomic level of detail.


title: Enzyme

text: Enzymes can be classified by two main criteria: either amino acid sequence similarity (and thus evolutionary relationship) or enzymatic activity.


title: Enzyme

text: Enzyme activity. An enzyme's name is often derived from its substrate or the chemical reaction it catalyzes, with the word ending in "-ase". Examples are lactase, alcohol dehydrogenase and DNA polymerase. Different enzymes that catalyze the same chemical reaction are called isozymes.


title: Enzyme

text: The International Union of Biochemistry and Molecular Biology have developed a nomenclature for enzymes, the EC numbers (for "Enzyme Commission"). Each enzyme is described by "EC" followed by a sequence of four numbers which represent the hierarchy of enzymatic activity (from very general to very specific). That is, the first number broadly classifies the enzyme based on its mechanism while the other digits add more and more specificity.


title: Enzyme

text: These sections are subdivided by other features such as the substrate, products, and chemical mechanism. An enzyme is fully specified by four numerical designations. For example, hexokinase (EC 2.7.1.1) is a transferase (EC 2) that adds a phosphate group (EC 2.7) to a hexose sugar, a molecule containing an alcohol group (EC 2.7.1).


title: Enzyme

text: Sequence similarity. EC categories do not reflect sequence similarity. For instance, two ligases of the same EC number that catalyze exactly the same reaction can have completely different sequences. Independent of their function, enzymes, like any other proteins, have been classified by their sequence similarity into numerous families. These families have been documented in dozens of different protein and protein family databases such as Pfam.


title: Enzyme

text: Enzymes are generally globular proteins, acting alone or in larger complexes. The sequence of the amino acids specifies the structure which in turn determines the catalytic activity of the enzyme. Although structure determines function, a novel enzymatic activity cannot yet be predicted from structure alone. Enzyme structures unfold (denature) when heated or exposed to chemical denaturants and this disruption to the structure typically causes a loss of activity. Enzyme denaturation is normally linked to temperatures above a species' normal level; as a result, enzymes from bacteria living in volcanic environments such as hot springs are prized by industrial users for their ability to function at high temperatures, allowing enzyme-catalysed reactions to be operated at a very high rate.


title: Enzyme

text: Enzymes are usually much larger than their substrates. Sizes range from just 62 amino acid residues, for the monomer of 4-oxalocrotonate tautomerase, to over 2,500 residues in the animal fatty acid synthase. Only a small portion of their structure (around 2–4 amino acids) is directly involved in catalysis: the catalytic site. This catalytic site is located next to one or more binding sites where residues orient the substrates. The catalytic site and binding site together compose the enzyme's active site. The remaining majority of the enzyme structure serves to maintain the precise orientation and dynamics of the active site.


title: Enzyme

text: In some enzymes, no amino acids are directly involved in catalysis; instead, the enzyme contains sites to bind and orient catalytic cofactors. Enzyme structures may also contain allosteric sites where the binding of a small molecule causes a conformational change that increases or decreases activity.


title: Enzyme

text: A small number of RNA-based biological catalysts called ribozymes exist, which again can act alone or in complex with proteins. The most common of these is the ribosome which is a complex of protein and catalytic RNA components.


title: Enzyme

text: Enzymes must bind their substrates before they can catalyse any chemical reaction. Enzymes are usually very specific as to what substrates they bind and then the chemical reaction catalysed. Specificity is achieved by binding pockets with complementary shape, charge and hydrophilic/hydrophobic characteristics to the substrates. Enzymes can therefore distinguish between very similar substrate molecules to be chemoselective, regioselective and stereospecific.


title: Enzyme

text: Some of the enzymes showing the highest specificity and accuracy are involved in the copying and expression of the genome. Some of these enzymes have "proof-reading" mechanisms. Here, an enzyme such as DNA polymerase catalyzes a reaction in a first step and then checks that the product is correct in a second step. This two-step process results in average error rates of less than 1 error in 100 million reactions in high-fidelity mammalian polymerases. Similar proofreading mechanisms are also found in RNA polymerase, aminoacyl tRNA synthetases and ribosomes.


title: Enzyme

text: Conversely, some enzymes display enzyme promiscuity, having broad specificity and acting on a range of different physiologically relevant substrates. Many enzymes possess small side activities which arose fortuitously (i.e. neutrally), which may be the starting point for the evolutionary selection of a new function.


title: Enzyme

text: To explain the observed specificity of enzymes, in 1894 Emil Fischer proposed that both the enzyme and the substrate possess specific complementary geometric shapes that fit exactly into one another. This is often referred to as "the lock and key" model. This early model explains enzyme specificity, but fails to explain the stabilization of the transition state that enzymes achieve.


title: Enzyme

text: In 1958, Daniel Koshland suggested a modification to the lock and key model: since enzymes are rather flexible structures, the active site is continuously reshaped by interactions with the substrate as the substrate interacts with the enzyme. As a result, the substrate does not simply bind to a rigid active site; the amino acid side-chains that make up the active site are molded into the precise positions that enable the enzyme to perform its catalytic function. In some cases, such as glycosidases, the substrate molecule also changes shape slightly as it enters the active site. The active site continues to change until the substrate is completely bound, at which point the final shape and charge distribution is determined.


title: Enzyme

text: Induced fit may enhance the fidelity of molecular recognition in the presence of competition and noise via the conformational proofreading mechanism.


title: Enzyme

text: Enzymes can accelerate reactions in several ways, all of which lower the activation energy (ΔG, Gibbs free energy)


title: Enzyme

text: Enzymes may use several of these mechanisms simultaneously. For example, proteases such as trypsin perform covalent catalysis using a catalytic triad, stabilise charge build-up on the transition states using an oxyanion hole, complete hydrolysis using an oriented water substrate.


title: Enzyme

text: Enzymes are not rigid, static structures; instead they have complex internal dynamic motions – that is, movements of parts of the enzyme's structure such as individual amino acid residues, groups of residues forming a protein loop or unit of secondary structure, or even an entire protein domain. These motions give rise to a conformational ensemble of slightly different structures that interconvert with one another at equilibrium. Different states within this ensemble may be associated with different aspects of an enzyme's function. For example, different conformations of the enzyme dihydrofolate reductase are associated with the substrate binding, catalysis, cofactor release, and product release steps of the catalytic cycle, consistent with catalytic resonance theory.


title: Enzyme

text: Substrate presentation is a process where the enzyme is sequestered away from its substrate. Enzymes can be sequestered to the plasma membrane away from a substrate in the nucleus or cytosol. Or within the membrane, an enzyme can be sequestered into lipid rafts away from its substrate in the disordered region. When the enzyme is released it mixes with its substrate. Alternatively, the enzyme can be sequestered near its substrate to activate the enzyme. For example, the enzyme can be soluble and upon activation bind to a lipid in the plasma membrane and then act upon molecules in the plasma membrane.


title: Enzyme

text: Allosteric sites are pockets on the enzyme, distinct from the active site, that bind to molecules in the cellular environment. These molecules then cause a change in the conformation or dynamics of the enzyme that is transduced to the active site and thus affects the reaction rate of the enzyme. In this way, allosteric interactions can either inhibit or activate enzymes. Allosteric interactions with metabolites upstream or downstream in an enzyme's metabolic pathway cause feedback regulation, altering the activity of the enzyme according to the flux through the rest of the pathway.


title: Enzyme

text: Some enzymes do not need additional components to show full activity. Others require non-protein molecules called cofactors to be bound for activity. Cofactors can be either inorganic (e.g., metal ions and iron–sulfur clusters) or organic compounds (e.g., flavin and heme). These cofactors serve many purposes; for instance, metal ions can help in stabilizing nucleophilic species within the active site. Organic cofactors can be either coenzymes, which are released from the enzyme's active site during the reaction, or prosthetic groups, which are tightly bound to an enzyme. Organic prosthetic groups can be covalently bound (e.g., biotin in enzymes such as pyruvate carboxylase).


title: Enzyme

text: An example of an enzyme that contains a cofactor is carbonic anhydrase, which uses a zinc cofactor bound as part of its active site. These tightly bound ions or molecules are usually found in the active site and are involved in catalysis. For example, flavin and heme cofactors are often involved in redox reactions.


title: Enzyme

text: Enzymes that require a cofactor but do not have one bound are called "apoenzymes" or "apoproteins". An enzyme together with the cofactor(s) required for activity is called a "holoenzyme" (or haloenzyme). The term "holoenzyme" can also be applied to enzymes that contain multiple protein subunits, such as the DNA polymerases; here the holoenzyme is the complete complex containing all the subunits needed for activity.


title: Enzyme

text: Coenzymes are small organic molecules that can be loosely or tightly bound to an enzyme. Coenzymes transport chemical groups from one enzyme to another. Examples include NADH, NADPH and adenosine triphosphate (ATP). Some coenzymes, such as flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), thiamine pyrophosphate (TPP), and tetrahydrofolate (THF), are derived from vitamins. These coenzymes cannot be synthesized by the body "de novo" and closely related compounds (vitamins) must be acquired from the diet. The chemical groups carried include:


title: Enzyme

text: Since coenzymes are chemically changed as a consequence of enzyme action, it is useful to consider coenzymes to be a special class of substrates, or second substrates, which are common to many different enzymes. For example, about 1000 enzymes are known to use the coenzyme NADH.


title: Enzyme

text: Coenzymes are usually continuously regenerated and their concentrations maintained at a steady level inside the cell. For example, NADPH is regenerated through the pentose phosphate pathway and "S"-adenosylmethionine by methionine adenosyltransferase. This continuous regeneration means that small amounts of coenzymes can be used very intensively. For example, the human body turns over its own weight in ATP each day.


title: Enzyme

text: As with all catalysts, enzymes do not alter the position of the chemical equilibrium of the reaction. In the presence of an enzyme, the reaction runs in the same direction as it would without the enzyme, just more quickly. For example, carbonic anhydrase catalyzes its reaction in either direction depending on the concentration of its reactants:


title: Enzyme

text: The rate of a reaction is dependent on the activation energy needed to form the transition state which then decays into products. Enzymes increase reaction rates by lowering the energy of the transition state. First, binding forms a low energy enzyme-substrate complex (ES). Second, the enzyme stabilises the transition state such that it requires less energy to achieve compared to the uncatalyzed reaction (ES). Finally the enzyme-product complex (EP) dissociates to release the products.


title: Enzyme

text: Enzymes can couple two or more reactions, so that a thermodynamically favorable reaction can be used to "drive" a thermodynamically unfavourable one so that the combined energy of the products is lower than the substrates. For example, the hydrolysis of ATP is often used to drive other chemical reactions.


title: Enzyme

text: Enzyme kinetics is the investigation of how enzymes bind substrates and turn them into products. The rate data used in kinetic analyses are commonly obtained from enzyme assays. In 1913 Leonor Michaelis and Maud Leonora Menten proposed a quantitative theory of enzyme kinetics, which is referred to as Michaelis–Menten kinetics. The major contribution of Michaelis and Menten was to think of enzyme reactions in two stages. In the first, the substrate binds reversibly to the enzyme, forming the enzyme-substrate complex. This is sometimes called the Michaelis–Menten complex in their honor. The enzyme then catalyzes the chemical step in the reaction and releases the product. This work was further developed by G. E. Briggs and J. B. S. Haldane, who derived kinetic equations that are still widely used today.


title: Enzyme

text: Enzyme rates depend on solution conditions and substrate concentration. To find the maximum speed of an enzymatic reaction, the substrate concentration is increased until a constant rate of product formation is seen. This is shown in the saturation curve on the right. Saturation happens because, as substrate concentration increases, more and more of the free enzyme is converted into the substrate-bound ES complex. At the maximum reaction rate ("V") of the enzyme, all the enzyme active sites are bound to substrate, and the amount of ES complex is the same as the total amount of enzyme.


title: Enzyme

text: "V" is only one of several important kinetic parameters. The amount of substrate needed to achieve a given rate of reaction is also important. This is given by the Michaelis–Menten constant ("K"), which is the substrate concentration required for an enzyme to reach one-half its maximum reaction rate; generally, each enzyme has a characteristic "K" for a given substrate. Another useful constant is "k", also called the "turnover number", which is the number of substrate molecules handled by one active site per second.


title: Enzyme

text: The efficiency of an enzyme can be expressed in terms of "k"/"K". This is also called the specificity constant and incorporates the rate constants for all steps in the reaction up to and including the first irreversible step. Because the specificity constant reflects both affinity and catalytic ability, it is useful for comparing different enzymes against each other, or the same enzyme with different substrates. The theoretical maximum for the specificity constant is called the diffusion limit and is about 10 to 10 (M s). At this point every collision of the enzyme with its substrate will result in catalysis, and the rate of product formation is not limited by the reaction rate but by the diffusion rate. Enzymes with this property are called "catalytically perfect" or "kinetically perfect". Example of such enzymes are triose-phosphate isomerase, carbonic anhydrase, acetylcholinesterase, catalase, fumarase, β-lactamase, and superoxide dismutase. The turnover of such enzymes can reach several million reactions per second. But most enzymes are far from perfect: the average values of formula_1 and formula_2 are about formula_3 and formula_4, respectively.


title: Enzyme

text: Michaelis–Menten kinetics relies on the law of mass action, which is derived from the assumptions of free diffusion and thermodynamically driven random collision. Many biochemical or cellular processes deviate significantly from these conditions, because of macromolecular crowding and constrained molecular movement. More recent, complex extensions of the model attempt to correct for these effects.


title: Enzyme

text: A competitive inhibitor and substrate cannot bind to the enzyme at the same time. Often competitive inhibitors strongly resemble the real substrate of the enzyme. For example, the drug methotrexate is a competitive inhibitor of the enzyme dihydrofolate reductase, which catalyzes the reduction of dihydrofolate to tetrahydrofolate. The similarity between the structures of dihydrofolate and this drug are shown in the accompanying figure. This type of inhibition can be overcome with high substrate concentration. In some cases, the inhibitor can bind to a site other than the binding-site of the usual substrate and exert an allosteric effect to change the shape of the usual binding-site.


title: Enzyme

text: A non-competitive inhibitor binds to a site other than where the substrate binds. The substrate still binds with its usual affinity and hence K remains the same. However the inhibitor reduces the catalytic efficiency of the enzyme so that V is reduced. In contrast to competitive inhibition, non-competitive inhibition cannot be overcome with high substrate concentration.


title: Enzyme

text: An uncompetitive inhibitor cannot bind to the free enzyme, only to the enzyme-substrate complex; hence, these types of inhibitors are most effective at high substrate concentration. In the presence of the inhibitor, the enzyme-substrate complex is inactive. This type of inhibition is rare.


title: Enzyme

text: A mixed inhibitor binds to an allosteric site and the binding of the substrate and the inhibitor affect each other. The enzyme's function is reduced but not eliminated when bound to the inhibitor. This type of inhibitor does not follow the Michaelis–Menten equation.


title: Enzyme

text: An irreversible inhibitor permanently inactivates the enzyme, usually by forming a covalent bond to the protein. Penicillin and aspirin are common drugs that act in this manner.


title: Enzyme

text: In many organisms, inhibitors may act as part of a feedback mechanism. If an enzyme produces too much of one substance in the organism, that substance may act as an inhibitor for the enzyme at the beginning of the pathway that produces it, causing production of the substance to slow down or stop when there is sufficient amount. This is a form of negative feedback. Major metabolic pathways such as the citric acid cycle make use of this mechanism.


title: Enzyme

text: Since inhibitors modulate the function of enzymes they are often used as drugs. Many such drugs are reversible competitive inhibitors that resemble the enzyme's native substrate, similar to methotrexate above; other well-known examples include statins used to treat high cholesterol, and protease inhibitors used to treat retroviral infections such as HIV. A common example of an irreversible inhibitor that is used as a drug is aspirin, which inhibits the COX-1 and COX-2 enzymes that produce the inflammation messenger prostaglandin. Other enzyme inhibitors are poisons. For example, the poison cyanide is an irreversible enzyme inhibitor that combines with the copper and iron in the active site of the enzyme cytochrome c oxidase and blocks cellular respiration.


title: Enzyme

text: As enzymes are made up of proteins, their actions are sensitive to change in many physio chemical factors such as pH, temperature, substrate concentration, etc.


title: Enzyme

text: Enzymes serve a wide variety of functions inside living organisms. They are indispensable for signal transduction and cell regulation, often via kinases and phosphatases. They also generate movement, with myosin hydrolyzing ATP to generate muscle contraction, and also transport cargo around the cell as part of the cytoskeleton. Other ATPases in the cell membrane are ion pumps involved in active transport. Enzymes are also involved in more exotic functions, such as luciferase generating light in fireflies. Viruses can also contain enzymes for infecting cells, such as the HIV integrase and reverse transcriptase, or for viral release from cells, like the influenza virus neuraminidase.


title: Enzyme

text: An important function of enzymes is in the digestive systems of animals. Enzymes such as amylases and proteases break down large molecules (starch or proteins, respectively) into smaller ones, so they can be absorbed by the intestines. Starch molecules, for example, are too large to be absorbed from the intestine, but enzymes hydrolyze the starch chains into smaller molecules such as maltose and eventually glucose, which can then be absorbed. Different enzymes digest different food substances. In ruminants, which have herbivorous diets, microorganisms in the gut produce another enzyme, cellulase, to break down the cellulose cell walls of plant fiber.


title: Enzyme

text: Several enzymes can work together in a specific order, creating metabolic pathways. In a metabolic pathway, one enzyme takes the product of another enzyme as a substrate. After the catalytic reaction, the product is then passed on to another enzyme. Sometimes more than one enzyme can catalyze the same reaction in parallel; this can allow more complex regulation: with, for example, a low constant activity provided by one enzyme but an inducible high activity from a second enzyme.


title: Enzyme

text: Enzymes determine what steps occur in these pathways. Without enzymes, metabolism would neither progress through the same steps and could not be regulated to serve the needs of the cell. Most central metabolic pathways are regulated at a few key steps, typically through enzymes whose activity involves the hydrolysis of ATP. Because this reaction releases so much energy, other reactions that are thermodynamically unfavorable can be coupled to ATP hydrolysis, driving the overall series of linked metabolic reactions.


title: Enzyme

text: Enzymes can be either activated or inhibited by other molecules. For example, the end product(s) of a metabolic pathway are often inhibitors for one of the first enzymes of the pathway (usually the first irreversible step, called committed step), thus regulating the amount of end product made by the pathways. Such a regulatory mechanism is called a negative feedback mechanism, because the amount of the end product produced is regulated by its own concentration. Negative feedback mechanism can effectively adjust the rate of synthesis of intermediate metabolites according to the demands of the cells. This helps with effective allocations of materials and energy economy, and it prevents the excess manufacture of end products. Like other homeostatic devices, the control of enzymatic action helps to maintain a stable internal environment in living organisms.


title: Enzyme

text: Examples of post-translational modification include phosphorylation, myristoylation and glycosylation. For example, in the response to insulin, the phosphorylation of multiple enzymes, including glycogen synthase, helps control the synthesis or degradation of glycogen and allows the cell to respond to changes in blood sugar. Another example of post-translational modification is the cleavage of the polypeptide chain. Chymotrypsin, a digestive protease, is produced in inactive form as chymotrypsinogen in the pancreas and transported in this form to the stomach where it is activated. This stops the enzyme from digesting the pancreas or other tissues before it enters the gut. This type of inactive precursor to an enzyme is known as a zymogen or proenzyme.


title: Enzyme

text: Enzyme production (transcription and translation of enzyme genes) can be enhanced or diminished by a cell in response to changes in the cell's environment. This form of gene regulation is called enzyme induction. For example, bacteria may become resistant to antibiotics such as penicillin because enzymes called beta-lactamases are induced that hydrolyse the crucial beta-lactam ring within the penicillin molecule. Another example comes from enzymes in the liver called cytochrome P450 oxidases, which are important in drug metabolism. Induction or inhibition of these enzymes can cause drug interactions. Enzyme levels can also be regulated by changing the rate of enzyme degradation. The opposite of enzyme induction is enzyme repression.


title: Enzyme

text: Enzymes can be compartmentalized, with different metabolic pathways occurring in different cellular compartments. For example, fatty acids are synthesized by one set of enzymes in the cytosol, endoplasmic reticulum and Golgi and used by a different set of enzymes as a source of energy in the mitochondrion, through β-oxidation. In addition, trafficking of the enzyme to different compartments may change the degree of protonation (e.g., the neutral cytoplasm and the acidic lysosome) or oxidative state (e.g., oxidizing periplasm or reducing cytoplasm) which in turn affects enzyme activity. In contrast to partitioning into membrane bound organelles, enzyme subcellular localisation may also be altered through polymerisation of enzymes into macromolecular cytoplasmic filaments.


title: Enzyme

text: In multicellular eukaryotes, cells in different organs and tissues have different patterns of gene expression and therefore have different sets of enzymes (known as isozymes) available for metabolic reactions. This provides a mechanism for regulating the overall metabolism of the organism. For example, hexokinase, the first enzyme in the glycolysis pathway, has a specialized form called glucokinase expressed in the liver and pancreas that has a lower affinity for glucose yet is more sensitive to glucose concentration. This enzyme is involved in sensing blood sugar and regulating insulin production.


title: Enzyme

text: Since the tight control of enzyme activity is essential for homeostasis, any malfunction (mutation, overproduction, underproduction or deletion) of a single critical enzyme can lead to a genetic disease. The malfunction of just one type of enzyme out of the thousands of types present in the human body can be fatal. An example of a fatal genetic disease due to enzyme insufficiency is Tay–Sachs disease, in which patients lack the enzyme hexosaminidase.


title: Enzyme

text: One example of enzyme deficiency is the most common type of phenylketonuria. Many different single amino acid mutations in the enzyme phenylalanine hydroxylase, which catalyzes the first step in the degradation of phenylalanine, result in build-up of phenylalanine and related products. Some mutations are in the active site, directly disrupting binding and catalysis, but many are far from the active site and reduce activity by destabilising the protein structure, or affecting correct oligomerisation. This can lead to intellectual disability if the disease is untreated. Another example is pseudocholinesterase deficiency, in which the body's ability to break down choline ester drugs is impaired.


title: Enzyme

text: Oral administration of enzymes can be used to treat some functional enzyme deficiencies, such as pancreatic insufficiency and lactose intolerance.


title: Enzyme

text: Another way enzyme malfunctions can cause disease comes from germline mutations in genes coding for DNA repair enzymes. Defects in these enzymes cause cancer because cells are less able to repair mutations in their genomes. This causes a slow accumulation of mutations and results in the development of cancers. An example of such a hereditary cancer syndrome is xeroderma pigmentosum, which causes the development of skin cancers in response to even minimal exposure to ultraviolet light.


title: Enzyme

text: Similar to any other protein, enzymes change over time through mutations and sequence divergence. Given their central role in metabolism, enzyme evolution plays a critical role in adaptation. A key question is therefore whether and how enzymes can change their enzymatic activities alongside. It is generally accepted that many new enzyme activities have evolved through gene duplication and mutation of the duplicate copies although evolution can also happen without duplication. One example of an enzyme that has changed its activity is the ancestor of methionyl amino peptidase (MAP) and creatine amidinohydrolase (creatinase) which are clearly homologous but catalyze very different reactions (MAP removes the amino-terminal methionine in new proteins while creatinase hydrolyses creatine to sarcosine and urea). In addition, MAP is metal-ion dependent while creatinase is not, hence this property was also lost over time. Small changes of enzymatic activity are extremely common among enzymes. In particular, substrate binding specificity (see above) can easily and quickly change with single amino acid changes in their substrate binding pockets. This is frequently seen in the main enzyme classes such as kinases.


title: Enzyme

text: Artificial (in vitro) evolution is now commonly used to modify enzyme activity or specificity for industrial applications (see below).


title: Enzyme

text: Enzymes are used in the chemical industry and other industrial applications when extremely specific catalysts are required. Enzymes in general are limited in the number of reactions they have evolved to catalyze and also by their lack of stability in organic solvents and at high temperatures. As a consequence, protein engineering is an active area of research and involves attempts to create new enzymes with novel properties, either through rational design or "in vitro" evolution. These efforts have begun to be successful, and a few enzymes have now been designed "from scratch" to catalyze reactions that do not occur in nature.


title: Louisa May Alcott

text: Louisa May Alcott (; November 29, 1832March 6, 1888) was an American novelist, short story writer, and poet best known as the author of the novel "Little Women" (1868) and its sequels "Little Men" (1871) and "Jo's Boys" (1886). Raised in New England by her transcendentalist parents, Abigail May and Amos Bronson Alcott, she grew up among many well-known intellectuals of the day, such as Ralph Waldo Emerson, Nathaniel Hawthorne, Henry David Thoreau, and Henry Wadsworth Longfellow.


title: Louisa May Alcott

text: Alcott's family suffered from financial difficulties, and while she worked to help support the family from an early age, she also sought an outlet in writing. She began to receive critical success for her writing in the 1860s. Early in her career, she sometimes used pen names such as A. M. Barnard, under which she wrote lurid short stories and sensation novels for adults that focused on passion and revenge.


title: Louisa May Alcott

text: Published in 1868, "Little Women" is set in the Alcott family home, Orchard House, in Concord, Massachusetts, and is loosely based on Alcott's childhood experiences with her three sisters, Abigail May Alcott Nieriker, Elizabeth Sewall Alcott, and Anna Alcott Pratt. The novel was well-received at the time and is still popular today among both children and adults. It has been adapted many times to stage, film, and television.


title: Louisa May Alcott

text: Alcott was an abolitionist and a feminist and remained unmarried throughout her life. All her life she was active in such reform movements as temperance and women's suffrage. She died from a stroke, two days after her father, in Boston on March 6, 1888.


title: Louisa May Alcott

text: Louisa May Alcott was born on November 29, 1832, in Germantown, which is now part of Philadelphia, Pennsylvania, on her father's 33rd birthday. She was the daughter of transcendentalist and educator Amos Bronson Alcott and social worker Abby May and the second of four daughters: Anna Bronson Alcott was the eldest; Elizabeth Sewall Alcott and Abigail May Alcott were the two youngest. As a child, she was a tomboy who preferred boys’ games. The family moved to Boston in 1834, where Alcott's father established an experimental school and joined the Transcendental Club with Ralph Waldo Emerson and Henry David Thoreau. Bronson Alcott's opinions on education and tough views on child-rearing as well as his moments of mental instability shaped young Alcott's mind with a desire to achieve perfection, a goal of the transcendentalists. His attitudes towards Alcott's wild and independent behavior, and his inability to provide for his family, created conflict between Bronson Alcott and his wife and daughters. Abigail resented her husband's inability to recognize her sacrifices and related his thoughtlessness to the larger issue of the inequality of sexes. She passed this recognition and desire to redress wrongs done to women on to Louisa.