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Mutations in cystathionine β-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans

Hieronim Jakubowski^*,,1, Godfried H. J. Boers and Kevin A. Strauss

^* Department of Microbiology and Molecular Genetics, New Jersey Medical School, International Center for Public Health, Newark, New Jersey, USA;

Institute of Bioorganic Chemistry, Polish Academy of Sciences, Pozna, Poland;

Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; and

Clinic for Special Children, Strasburg, Pennsylvania, USA

¹Correspondence: Department of Microbiology & Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, 225 Warren St., Newark, NJ 07101-1709, USA. E-mail: jakubows{at}umdnj.edu

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 methylenetetrahydrofolate 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 provide 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.

Key Words: genetic hyperhomocysteinemia • homocysteine thiolactone • fibrinogen • atherothrombosis

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