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|1xdl, resolution 3.00Å ()|
|Gene:||ALDOB, ALDB (Homo sapiens)|
Structure of human aldolase B associated with hereditary fructose intolerance (A149P), at 277K
Hereditary fructose intolerance (HFI) is a potentially lethal inborn error in metabolism caused by mutations in the aldolase B gene, which is critical for gluconeogenesis and fructose metabolism. The most common mutation, which accounts for 53% of HFI alleles identified worldwide, results in substitution of Pro for Ala at position 149. Structural and functional investigations of human aldolase B with the A149P substitution (AP-aldolase) have shown that the mutation leads to losses in thermal stability, quaternary structure, and activity. X-ray crystallography is used to reveal the structural basis of these perturbations. Crystals of AP-aldolase are grown at two temperatures (4 degrees C and 18 degrees C), and the structure solved to 3.0 angstroms resolution, using the wild-type structure as the phasing model. The structures reveal that the single residue substitution, A149P, causes molecular disorder around the site of mutation (residues 148-159), which is propagated to three adjacent beta-strand and loop regions (residues 110-129, 189-199, 235-242). Disorder in the 110-129-loop region, which comprises one subunit-subunit interface, provides an explanation for the disrupted quaternary structure and thermal instability. Greater structural perturbation, particularly at a Glu189-Arg148 salt bridge in the active-site architecture, is observed in the structure determined at 18 degrees C, which could explain the temperature-dependent loss in activity. The disorder revealed in these structures is far greater than that predicted by homology modeling and underscores the difficulties in predicting perturbations of protein structure and function by homology modeling alone. The AP-aldolase structure reveals the molecular basis of a hereditary disease and represents one of only a few structures known for mutant proteins at the root of the thousands of other inherited disorders.
Structure of the thermolabile mutant aldolase B, A149P: molecular basis of hereditary fructose intolerance., Malay AD, Allen KN, Tolan DR, J Mol Biol. 2005 Mar 18;347(1):135-44. Epub 2005 Jan 20. PMID:15733923
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[ALDOB_HUMAN] Defects in ALDOB are the cause of hereditary fructose intolerance (HFI) [MIM:229600]. HFI is an autosomal recessive disease that results in an inability to metabolize fructose and related sugars. Complete exclusion of fructose results in dramatic recovery; however, if not treated properly, HFI subjects suffer episodes of hypoglycemia, general ill condition, and risk of death the remainder of life.
About this Structure
- Malay AD, Allen KN, Tolan DR. Structure of the thermolabile mutant aldolase B, A149P: molecular basis of hereditary fructose intolerance. J Mol Biol. 2005 Mar 18;347(1):135-44. Epub 2005 Jan 20. PMID:15733923 doi:10.1016/j.jmb.2005.01.008
- ↑ Santamaria R, Esposito G, Vitagliano L, Race V, Paglionico I, Zancan L, Zagari A, Salvatore F. Functional and molecular modelling studies of two hereditary fructose intolerance-causing mutations at arginine 303 in human liver aldolase. Biochem J. 2000 Sep 15;350 Pt 3:823-8. PMID:10970798
- ↑ Cross NC, Tolan DR, Cox TM. Catalytic deficiency of human aldolase B in hereditary fructose intolerance caused by a common missense mutation. Cell. 1988 Jun 17;53(6):881-5. PMID:3383242
- ↑ Cross NC, de Franchis R, Sebastio G, Dazzo C, Tolan DR, Gregori C, Odievre M, Vidailhet M, Romano V, Mascali G, et al.. Molecular analysis of aldolase B genes in hereditary fructose intolerance. Lancet. 1990 Feb 10;335(8685):306-9. PMID:1967768
- ↑ Brooks CC, Tolan DR. A partially active mutant aldolase B from a patient with hereditary fructose intolerance. FASEB J. 1994 Jan;8(1):107-13. PMID:8299883
- ↑ Ali M, Sebastio G, Cox TM. Identification of a novel mutation (Leu 256-->Pro) in the human aldolase B gene associated with hereditary fructose intolerance. Hum Mol Genet. 1994 Jan;3(1):203-4. PMID:8162030
- ↑ Cross NC, Stojanov LM, Cox TM. A new aldolase B variant, N334K, is a common cause of hereditary fructose intolerance in Yugoslavia. Nucleic Acids Res. 1990 Apr 11;18(7):1925. PMID:2336380
- ↑ Lau J, Tolan DR. Screening for hereditary fructose intolerance mutations by reverse dot-blot. Mol Cell Probes. 1999 Feb;13(1):35-40. PMID:10024431 doi:S0890-8508(98)90208-0
- ↑ Sanchez-Gutierrez JC, Benlloch T, Leal MA, Samper B, Garcia-Ripoll I, Feliu JE. Molecular analysis of the aldolase B gene in patients with hereditary fructose intolerance from Spain. J Med Genet. 2002 Sep;39(9):e56. PMID:12205126
- ↑ Esposito G, Santamaria R, Vitagliano L, Ieno L, Viola A, Fiori L, Parenti G, Zancan L, Zagari A, Salvatore F. Six novel alleles identified in Italian hereditary fructose intolerance patients enlarge the mutation spectrum of the aldolase B gene. Hum Mutat. 2004 Dec;24(6):534. PMID:15532022 doi:10.1002/humu.9290
- ↑ Santer R, Rischewski J, von Weihe M, Niederhaus M, Schneppenheim S, Baerlocher K, Kohlschutter A, Muntau A, Posselt HG, Steinmann B, Schneppenheim R. The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe. Hum Mutat. 2005 Jun;25(6):594. PMID:15880727 doi:10.1002/humu.9343