PDB entry The HMG-CoA reductase pathway, which is blocked by<unk> s via inhibiting the rate limiting enzyme HMG-CoA reductase.<unk> s act by competitively inhibiting HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Because<unk> s are similar in structure to HMG-CoA on a molecular level, they will fit into the enzyme's active site and compete with the native substrate (HMG-CoA). This competition reduces the rate by which HMG-CoA reductase is able to produce mevalonate, the next molecule in the cascade that eventually produces cholesterol. A variety of natural<unk> s are produced by Penicillium and Aspergillus fungi as secondary metabolites. These natural<unk> s probably function to inhibit HMG-CoA reductase enzymes in bacteria and fungi that compete with the producer. Inhibiting cholesterol synthesis By inhibiting HMG-CoA reductase,<unk> s block the pathway for synthesizing cholesterol in the liver. This is significant because most circulating cholesterol comes from internal manufacture rather than the diet. When the liver can no longer produce cholesterol, levels of cholesterol in the blood will fall. Cholesterol synthesis appears to occur mostly at night, so<unk> s with short half-lives are usually taken at night to maximize their effect. Studies have shown greater LDL and total cholesterol reductions in the short-acting simvastatin taken at night rather than the morning, but have shown no difference in the long-acting atorvastatin. Increasing LDL uptake In rabbits, liver cells sense the reduced levels of liver cholesterol and seek to compensate by synthesizing LDL receptors to draw cholesterol out of the circulation. This is accomplished via proteases that cleave membrane-bound sterol regulatory element binding proteins, which then migrate to the nucleus and bind to the sterol response elements. The sterol response elements then facilitate increased transcription of various other proteins, most notably, LDL receptor. The LDL receptor is transported to the liver cell membrane and binds to passing LDL and VLDL particles, mediating their uptake into the liver, where the cholesterol is reprocessed into bile salts and other byproducts. This results in a net effect of less LDL circulating in blood. Decreasing of specific protein prenylation<unk> s, by inhibiting the HMG CoA reductase pathway, inhibit downstream synthesis of isoprenoids, such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Inhibition of protein prenylation for proteins such as RhoA (and subsequent inhibition of Rho-associated protein kinase) may be involved, at least partially, in the improvement of endothelial function, modulation of immune function, and other pleiotropic cardiovascular benefits of<unk> s, as well as in the fact that a number of other drugs that lower LDL have not shown the same cardiovascular risk benefits in studies as<unk> s, and may also account for some of the benefits seen in cancer reduction with<unk> s. In addition, the inhibitory effect on protein prenylation may also be involved in a number of unwanted side effects associated with<unk> s, including muscle pain (myopathy) and elevated blood sugar (diabetes). Other effects As noted above,<unk> s exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis through so-called "pleiotropic effects of<unk> s." The pleiotropic effects of<unk> s remain controversial. The ASTEROID trial showed direct ultrasound evidence of atheroma regression during<unk>  therapy. Researchers hypothesize that<unk> s prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research): # Improve endothelial function # Modulate inflammatory responses # Maintain plaque stability # Prevent blood clot formation In 2008, the JUPITER trial showed<unk> s provided benefit in those who had no history of high cholesterol or heart disease, but only in those with elevated high-sensitivity C-reactive protein (hsCRP) levels, an indicator for inflammation. The study has been criticized due to perceived flaws in the study design, although Paul M. Ridker, lead investigator of the JUPITER trial, has responded to these criticisms at length. As the target of<unk> s, the HMG-CoA reductase, is highly similar between eukaryota and archaea,<unk> s also act as antibiotics against archaea by inhibiting archaeal mevalonate biosynthesis. This has been shown in vivo and in vitro. Since patients with a constipation phenotype present with higher abundance of methanogenic archaea in the gut, the use of<unk> s for management of irritable bowel syndrome has been proposed and may actually be one of the hidden benefits of<unk>  use.
Statin
Anisatin
Arbekacin
Pitavastatin
Cortistatin 
Petroleum jelly
Anthopleurin
Clitoraid