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The essential micronutrients vitamin B12 and folate play critical in metabolism. A deficiency of either B12 or folate 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.
Although I retired from the Department and closed my lab in early 2013, I remain active in the study of essential micronutrients and the roles they play in the prevention of cardiovascular disease.
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.
L. Hannibal*, C.A. Smith*, D.W. Jacobsen. The X-Ray crystal structure of glutathionylcobalamin revealed. Inorg Chem 49:9921-9927, 2010. (*Both authors contributed equally to this work).
P.M. DiBello, S. Dayal, S. Kaveti, D. Zhang, M.T. Kinyer, S.R. Lentz and D.W. Jacobsen. 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(3):471-85, 2010.
L. Hannibal, P.M. DiBello, M. Yu, A. Miller, S. Wang, B. Willard, D.S. Rosenblatt and D.W. Jacobsen . The MMACHC proteome: hallmarks of functional cobalamin deficiency in humans. Mol Genet Metabol 103:226-239, 2011.
L. Hannibal, P.M. DiBello, and D.W. Jacobsen . Proteomics of vitamin B12 processing. Clin Chem Lab Med 51:477-488, 2013.
M.B. Guzzo, H.T. Nguyen, T.H. Pham, M. Wyszczelska-Rokiel, H. Jakubowski, K.A. Wolff, S. Ogwang, J.L. Timpona, S. Gogula, M.R. Jacobs, M. Ruetz, B. Kräutler, D.W. Jacobsen, G.-F. Zhang, and L. Nguyen. Methylfolate trap promotes bacterial thymineless death by sulfa drugs. PLOS Pathog,12(10):e1005949, 2016.
L. Hannibal, V. Lysne, A.L. Bjorke-Monsen , S. Behringer, S.C. Grunert, U. Spiekerkotter , D.W. Jacobsen and H.J. Blom. Biomarkers and algorithms for the diagnosis of vitamin B12 deficiency. Front Mol Bios 3, Article 27, pp1-16, 2016.
L. Hannibal, and D.W. Jacobsen. Intracellular processing and utilization of cobalamins. In: Vitamin B12: Advances and Insights, R. Obeid (ed), CRC Press/Taylor and Francis Group, pp 46-93, 2017.
L. Hannibal, K. Bolisetty, A. Axhemi, P.M. DiBello, E.V. Quadros, S. Fedosov and D.W. Jacobsen. Transcellular transport of cobalamin in aortic endothelial cells. FASEB J, 32(10):5506-19, 2018.
A. Jindal, S. Rajagopal, L. Winter, J.W. Miller,D. W. Jacobsen, J. Brigman, A.M. Allan, S. Pauland R. Poddar. Hyperhomocysteinemia leads to exacerbation of ischemic brain damage: role of GluN2A NMDA receptors. Neurobiol Dis 127:287-302, 2019.
D.W. Jacobsen and L. Hannibal. Redox signaling in inherited diseases of metabolism. Special Issue: Redox Regulation in Physiology and Disease, Curr Opin Physiol 9:48-55,2019.
S. Behringer , V. Wingert, V. Oria , A. Schumann, S. Grünert, A. Cieslar-Pobuda, S. Kölker, A.-K. Lederer, D. W. Jacobsen, J. Staerk, O. Schilling, U. Spiekerkoetter and L. Hannibal. Targeted metabolic profiling of methionine cycle metabolites and redox thiol pools in mammalian plasma, cells and urine. Metabolites 9(10): 235, 2019.
J. Hinkel, J. Schmitt, M. Wurm, S. Rosenbaum-Fabian, K. Otfried Schwab, D.W. Jacobsen, U. Spiekerkoetter, S.N. Fedosov, L. Hannibal and S.C. Grunert. Elevated plasma vitamin B12 in patients with hepatic glycogen storage diseases. J Clin Med 9(8): 2326, 2020.
V. Wingert, S. Mukherjee, A.J. Esser, S. Behringer, S. Tanimowo, M. Klenzendorf, I.A. Derevenkov, S.V. Makarov, D.W. Jacobsen, U. Spiekerkoetter and L. Hannibal. Thiolato-cobalamins repair the activity of pathogenic variants of the human cobalamins processing enzyme CblC. Biochimie, 2020, in press.
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