Research interest
Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. We have shown that homocysteine induces expression of monocyte chemoattractant protein-1 and interleukin 8 in cultured human aortic endothelial cells. Using in vitro model systems, we have studied the vascular biochemistry of homocysteine and cysteine in circulation. Albumin-Cys34 thiolate anion attacks cystine to form albumin-S-S-cysteine. Homocysteine thiolate anion then attacks the cysteine sulfur of albumin-S-S-cysteine to form homocysteine-cysteine mixed disulfide and albumin-Cys34 thiolate anion. The albumin thiolate anion reacts with either the mixed disulfide or homocystine to form albumin-S-S-homocysteine, which accounts for up to 80% of circulating homocysteine. This process, which we term “molecular targeting”, has been observed with fibronectin, transthyretin, alpha-2-macroglobulin and the intracellular protein metallothionein (MT). Homocysteinylated-MT looses its ability to bind zinc and scavenge superoxide anion radical. Vitamin B12 (cobalamin; Cbl) is a B-complex micronutrient that drives homocysteine metabolism. We believe that the vascular endothelium plays a major role in Cbl homeostasis by regulating its transport. We are also studying intracellular processing of Cbl in cultured human aortic endothelial and smooth muscle cells. The cblC gene product MMACHC catalyzes the dealkylation of newly internalized alkylcobalamins.
In other words ...
We study the essential micronutrients vitamin B12 and folate (vitamin B9) and roles they play in metabolism. A deficiency of either B12 or B9 causes blood levels of homocysteine, a sulfur-containing amino acid, to rise. Elevated homocysteine is a risk factor for cardiovascular diseases that can lead to heart attack, stroke and blood clots in the arms and legs. A major focus of our work is to determine the mechanism of homocysteine toxicity and its role in the development of atherosclerosis. Elevated homocysteine is also a risk factor for cognitive impairment (dementia and Alzheimer's disease) and complications of pregnancy (neural tube defects). We believe that elevated homocysteine adversely affects the functions of endothelium, which are the inner layer of cells lining all blood vessels in the body. Vitamin B12 deficiency can be caused by both environmental and genetic factors. Our lab recently discovered the function of a new enzyme (MMACHC) involved in intracellular B12 processing and trafficking. Mutations in the gene for this enzyme cause elevated blood levels of homocysteine.
Highlighted Publications
1. Hannibal L Kim J Brasch NE Wang S Rosenblatt DS Banerjee R and Jacobsen DW. Processing of alkylcobalamins by mammalian cells: a role for the MMACHC (cblC) gene product. Mol Genet Metabol 9:260-6, 2009.
2. Kim J Hannibal L Gherasim C Jacobsen DW and Banerjee R. A human B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins. J Biol Chem 284:33418-24, 2009.
3. DiBello PM Dayal S Kaveti S Zhang D Kinter MT Lentz SR and Jacobsen DW. The nutrigenetics of hyperhomocysteinemia. Quantitative proteomics reveals differences in the methionine cycle enzymes of gene-induced versus diet-induced hyperhomo-cysteinemia. Mol Cell Proteomics 9:471-85, 2010.
4. Hannibal L Smith CA and Jacobsen DW. The X-ray crystal structure of glutathionylcobalamin revealed. Inorg Chem 49:9921-7, 2010.
5. Hannibal L DiBello PM Yu M Miller A Wang S Willard B Rosenblatt DS and Jacobsen DW. The MMACHC proteome: hallmarks of functional cobalamin deficiency in humans. Mol Genet Metabol 103:226-39, 2011.
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