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We study aspects of one-carbon metabolism. Namely, the micronutrients folate and vitamin B12, which serve as substrate and cofactor, respectively, in the methionine cycle. Homocysteine, which is a branch-point metabolite in the methionine cycle, is an independent risk factor for cardiovascular disease (coronary artery, cerebrovascular and peripheral vascular disease), cognitive impairment (dementia and Alzheimer’s disease) and complications of pregnancy (neural tube defects). Both folate and vitamin B12 are determinants of blood homocysteine levels. Deficiencies of either of the two micronutrients, will lead to hyperhomocysteinemia. Our recent work on vitamin B12 has focused on the intracellular processing of the vitamin. We discovered that an enzyme called “MMACHC” catalyzes the removal of the upper-axial ligand of alkylcobalamins (e.g., methyl-B12 and adenosyl-B12). Mutations in cblC gene, which codes for the MMACHC protein, results in severe hyperhomocysteinemia and methylmalonic acidemia. Our recent work on homocysteine has focused on mechanisms of pathophysiology. Patients with inborn errors of homocysteine metabolism have exceedingly high levels of blood homocysteine (up to 500 µM; normal 8-12 µM) and invariably suffer cardiovascular complications if left untreated. We developed the “molecular targeting hypothesis” to explain the pathophysiology of elevated homocysteine. Homocysteine and homocystine can attack an exposed disulfide bond or cysteine residue, respectively, on proteins to form cysteine-homocysteine mixed disulfides, which may lead to the functional inactivation of the protein. Molecular targeting explains how albumin-bound homocysteine (80-90% of circulating homocysteine) is formed.
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Food and nutrition bulletinno. 1_suppl (2024): S58-S66
Luciana Hannibal, Keerthana Bolisetty,Armend Axhemi,Patricia M DiBello,Edward V Quadros,Sergey Fedosov,Donald W Jacobsen
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#Papers: 194
#Citation: 10787
H-Index: 56
G-Index: 100
Sociability: 7
Diversity: 0
Activity: 0
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