The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia

被引：343

作者：

Guenther B.D. ^{[1
]}

Sheppard C.A. ^{[2
]}

Tran P. ^{[4
]}

Rozen R. ^{[4
]}

Matthews R.G. ^{[1
,3
]}

Ludwig M.L. ^{[1
,3
]}

机构：

[1] Bioohvsics Research Division, University of Michigan, Ann Arbor

[2] Proaram in Cellular and Molecular Biology, University of Michigan, Ann Arbor

[3] Department of Bioloqical Chemistry, University of Michigan, Ann Arbor

[4] Departments of Human Genetics, Pediatrics and Biology, McGill University, Montreal Children's Hospital

来源：

Nature Structural Biology | 1999年 / 6卷 / 4期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

D O I：

10.1038/7594

中图分类号：

学科分类号：

摘要：

Elevated plasma homocysteine levels are associated with increased risk for cardiovascular disease and neural tube defects in humans. Folate treatment decreases homocysteine levels and dramatically reduces the incidence of neural tube defects. The flavoprotein methylenetetrahydrofolate reductase (MTHFR) is a likely target for these actions of folate. The most common genetic cause of mildly elevated plasma homocysteine in humans is the MTHFR polymorphism A222V (base change C677→T). The X-ray analysis of E. coli MTHFR, reported here, provides a model for the catalytic domain that is shared by all MTHFRs. This domain is a β8α8 barrel that binds FAD in a novel fashion. Ala 177, corresponding to Ala 222 in human MTHFR, is near the bottom of the barrel and distant from the FAD. The mutation A177V does not affect K(m) or k(cat) but instead increases the propensity for bacterial MTHFR to lose its essential flavin cofactor. Folate derivatives protect wild- type and mutant E. coli enzymes against flavin loss, and protect human MTHFR and the A222V mutant against thermal inactivation, suggesting a mechanism by which folate treatment reduces homocysteine levels.

引用

页码：359 / 365

页数：6

共 38 条

[1] Frosst, P., A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase (1995) Nature Genet., 10, pp. 111-113
[2] Kluijtmans, L.A., Molecular genetic analysis in mild hyperhomocysteinemia: A common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease (1996) Am. J. Hum. Genet., 58, pp. 35-41
[3] Morita, H., Genetic polymorphism of 5, 10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease (1997) Circulation, 95, pp. 2032-2036
[4] Wilcken, D.E., Wang, X.L., Sim, A.S., McCredie, R.M., Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation (1996) Arteroider. Thromb. Vase. Biol., 16, pp. 878-882
[5] Ma, J., Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians (1996) Circulation, 94, pp. 2410-2416
[6] Jacques, P.F., Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations (1996) Circulation, 93, pp. 7-9
[7] Harmon, D.L., The common "thermolabile" variant of methylenetetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia (1996) Q. J. Med., 89, pp. 515-577
[8] Van Der Put, N., (1995) Mutated Methylenetetrahydrofolate Reductase as a Risk Factor for Spina Bifida. Lancet, 346, pp. 1070-1071
[9] Refsum, H., Ueland, P.M., Nygard, O., Vollset, S., Homocysteine and cardiovascular disease (1998) Annu. Rev. Med., 49, pp. 31-62
[10] Van Der Put, N.M.J., Eskes, T.K.A.B., Blom, H.J., Is the common 677C-VT mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? a meta-analysis (1997) Q. J. Med., 90, pp. 111-115

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