Department of Cellular and Molecular Medicine
Donald W. Jacobsen, Ph.D.
Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
Phone: (503) 436-9622
This laboratory studies aspects of one-carbon metabolism, namely the micronutrients folate and vitamin B12, which serve as substrate and cofactor, respectively, in the methionine cycle and homocysteine, which is a branch-point metabolite in the methionine cycle and an independent risk factor for cardiovascular disease (coronary artery, cerebrovascular and peripheral vascular disease), cognitive impairment (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 2 micronutrients, will lead to hyperhomocysteinemia and, in severe cases, homocystinuria. 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.
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.
J. Kim, L. Hannibal, C. Gherasim, D.W. Jacobsen and R. Banerjee. A human B12 trafficking protein uses glutathione transferase activity for processing akylcobalamins. J Biol Chem 284(48):33418-2, 2009.
Hannibal* L, Smith* CA, Jacobsen DW. 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.
Hannibal L, DiBello PM, Yu M, Miller A, Wang S, Willard B, Rosenblatt DS Jacobsen DW. The MMACHC proteome: hallmarks of functional cobalamin deficiency in humans. Mol Genet Metabol 103:226-239, 2011.
Hannibal L, DiBello PM, Jacobsen DW. Proteomics of vitamin B12 processing. Clin Chem Lab Med 51:477-488, 2013.
Gherasim C, Hannibal L, Rajagopalan D, Jacobsen DW, Banerjee R. The C-terminal domain of cblD interacts with cblC and influences intracellular cobalamin trafficking. Biochimie 95:1023-1032, 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 Pathogens,12(10):e1005949, 2016.
Hannibal L, Lysne V, Bjorke-Monsen AL, Behringer S, Grunert SC, Spiekerkotter U, Jacobsen DW, Blom HJ. Biomarkers and algorithms for the diagnosis of vitamin B12 deficiency. Frontiers in Molecular Biosciences 3, Article 3, pp1-16, 2016.
Hannibal L, Jacobsen DW. 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.