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Mutations in cystathionine β‐synthase or methylenetetrahydrofolate reductase gene increase N ‐homocysteinylated protein levels in humans
Author(s) -
Jakubowski Hieronim,
Boers Godfried H. J.,
Strauss Kevin A.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-112086
Subject(s) - methylenetetrahydrofolate reductase , cystathionine beta synthase , homocysteine , medicine , reductase , homocystinuria , endocrinology , fibrinogen , methionine synthase , chemistry , biology , biochemistry , gene , enzyme , methionine , cysteine , amino acid , allele
Severely elevated plasma homocysteine (Hcy) levels observed in genetic disorders of Hcy metabolism are associated with pathologies in multiple organs and lead to premature death due to vascular complications. In addition to elevating plasma Hcy, mutations in cystathionine β‐synthase (CBS) or methyl enetetrahydrofolate reductase (MTHFR) gene lead to markedly elevated levels of circulating Hcy‐thiolactone. The thiooester chemistry of Hcy‐thiolactone underlies its ability to form isopeptide bonds with protein lysine residues ( N ‐Hcy‐protein), which may impair or alter the protein's function. However, it was not known whether genetic deficiencies in Hcy metabolism affect N ‐Hcy‐protein levels in humans. Here we show that plasma N ‐Hcy‐protein levels are significantly elevated in CBS‐ and MTHFR‐deficient patients. We also show that CBS‐deficient patients have significantly elevated plasma levels of prothrombotic N ‐Hcy‐fibrinogen. These results pro vide a possible explanation for increased atherothrombosis observed in CBS‐deficient patients.— Jakubowski, H., Boers, G. H. J., Strauss, K. A. Mutations in cystathionine β‐synthase or methylenetetrahydrofolate reductase gene increase N ‐homocysteinylated protein levels in humans. FASEB J. 22, 4071–4076 (2008)

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