 |
Donald W. Jacobsen, Ph.D., F.A.H.A.Staff, Joint Appointment with Department of Cardiovascular Medicine
Department of Cell Biology |
Cardiovascular disease, homocysteine metabolism, endothelial cell function, cobalamin and folate biochemistry
Our laboratory does clinical and basic research on homocysteine, a modifiable, independent risk factor for cardiovascular disease. Homocysteine, a product of methionine metabolism, is cytotoxic to cells if allowed to accumulate. Hence, it is remethylated back to methionine, or is converted to cysteine by metabolism through the transsulfuration pathway. Impairment of homocysteine metabolism, caused either by genetic or acquired factors, can lead to higher intracellular concentrations and export to the blood. The incidence of hyperhomocysteinemia in patients with coronary artery disease at the Cleveland Clinic is 30-50%. These patients usually have mild hyperhomocysteinemia (>12-25 µM). Approximately 65% of the 180 heart transplant recipients we have studied have mild to intermediate hyperhomocysteinemia (>12-50 µM). Post-transplant hyperhomocysteinemia occurs within three months and by one year most of these patients have developed vasculopathies in their coronary arteries. We have also studied 200 dialysis patients with end-stage renal disease. Greater than 85% have hyperhomo-cysteinemia, which is often severe (50-150 µM total plasma homocysteine). Associated with end-stage renal disease is a high incidence of cardiovascular disease. Because the incidence of hyperhomocysteinemia in patients with cardiovascular disease is high, we hypothesize that elevated homocysteine plays a causal role in disease progression. Homocysteine can undergo thiol-disulfide exchange reactions with specific protein cysteine and cysteine disulfide residues with the formation of S-homocysteinylated protein with impaired or altered function.
We also study vitamin B12 deficiency, which causes hyperhomocysteinemia, and the vascular biochemistry of B12 (cobalamin). Until recently, little was known about B12 transport and processing by cells throughout the body. B12 forms a complex with the serum protein transcobalamin and the complex is endocytosed into cells after binding to the transcobalamin receptor. Intracellular processing of newly internalized B12 is mediated by the MMACHC (cblC) gene product. This protein removes the cyanide group from cyanocobalamin as well as the alkyl groups from methyl- and adenosylcobalamin. The dealkylation reactions require glutathione as the reducing substrate.
Key References:
Carmel, R., and D.W. Jacobsen (eds). Homocysteine in Health and Disease, Cambridge University Press, Cambridge, UK, 2001, 510 p.
Sengupta, S., Chen, H., Togawa, T., DiBello, P.M., Majors, A.K., Büdy, B., Ketterer, M.E. and D.W. Jacobsen. Albumin thiolate anion is an intermediate in the formation of albumin-bound homocysteine. J Biol Chem 276:30111-7, 2001.
Sengupta, S., Wehbe, C., Majors, A.K., Ketterer, M.E., DiBello, P.M. and D.W. Jacobsen. Relative Roles of albumin and ceruloplasmin in the formation of homocystine, homocysteine-cysteine mixed disulfide and cystine in circulation. J Biol Chem 276:46896-904, 2001.
Poddar, R., Sivasubramanian, N., DiBello, P.M., Robinson, K. and D.W. Jacobsen. Homocysteine induces expression and secretion of MCP-1 and IL-8 in human aortic endothelial cells: Implications for vascular disease. Circulation 103:2717-23, 2001.
Majors, A.K., Sengupta, S., Willard, B., Kinter, M.T., Pyeritz, R.E. and D.W. Jacobsen. Homocysteine binds to human plasma fibronectin and inhibits its interaction with fibrin. Arterioscler Thromb Vas Biol 22:1354-9, 2002.
Lim, A., Sengupta, S., McComb, M.E., Théberge, R., Wilson, W.G., Costello, C.E. and D.W. Jacobsen. In vitro and in vivo interactions of homocysteine with human plasma transthyretin. J Biol Chem 278:49707-13, 2003.
Wang, L., Jhee, K.-H., Hua, X., DiBello, P.M., Jacobsen, D.W. and W.D. Kruger Modulation of cystathionine b-synthase level regulates total serum homocysteine in mice. Circ Res 94:1318-24, 2004.
Büdy, B., O’Neill, R.M., DiBello, P.M., Sengupta, S. and D.W. Jacobsen. Homocysteine transport by human aortic endothelial cells: Identification and properties of import systems. Arch Biochem Biophys 446:119-130, 2006.
Barbato, J.C., Catanescu, O., Murray, K., DiBello, P.M. and D.W. Jacobsen. Targeting of metallothionein by L-homocysteine: A novel mechanism for disruption of zinc and redox homeostasis. Arterioscler Thromb Vas Biol 27:49-54, 2007.
Glushchenko, A.V. and D.W. Jacobsen. Molecular targeting of protein by L-homocysteine: Mechanistic implications for vascular disease. Antioxid Redox Signal 9:1883-98, 2007.
Hannibal, L., Bunge, S.D., van Eldik, R., Jacobsen, D.W., Kratky, C., Gruber, K. and N.E. Brasch X-ray structural characterization of imidazolylcobalamin and histidinylcobalamin: Cobalamin models for aquacobalamin bound to the B12 transporter protein transcobalamin.Inorg Chem 46:3613-3618, 2007.
Hannibal, L., Smith, C.A., Jacobsen, D.W. and N.E. Brasch. Nitrosylcob(III)alamin: Synthesis and X-ray structural characterization. Angew Chem Int Ed 46:5140-3, 2007.
Jacobsen, D.W. and A.V. Glushchenko. The transcobalamin receptor, redux. Blood 113:2-3, 2009 (editorial).
Chen, X., Sebastian, B.M., McMullen, M.M., Axhemi, A., Jacobsen, D.W. and L.E. Nagy. Taurine supplementation prevents ethanol-induced decrease in serum adiponectin and reduces hepatic steatosis in rats. Hepatology 49:1554-62, 2009.
Cohen, J.I., Roychowdhury, S., DiBello, P.M., Jacobsen, D.W. and L.E. Nagy. Exogenous thioredoxin prevents ethanol-induced oxidative damage and apoptosis in mouse liver. Hepatology 49:1709-17, 2009.
Hannibal, L., Smith, C.A., Smith, J.A., Axhemi, A., Miller, A., Wang, S., Brasch, N.E. and D.W. Jacobsen. High resolution crystal structure of the methylcobalamin analogues ethylcobalamin and butylcobalamin by X-ray synchrotron diffraction. Inorg Chem 48:6615-22, 2009.
Hannibal, L., Kim, J., Brasch, N.E., Wang, S., Rosenblatt, D.S., Banerjee, R. and D.W. Jacobsen. Processing of alkylcobalamins by mammalian cells: A role for the cblC gene product. Mol Genet Metabol 97:260-6, 2009.
Kim, J., Hannibal, L., Gherasim, C., Jacobsen, D.W. and R. Banerjee. A human B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins. J Biol Chem 284:33418-24, 2009.
Tsitsiou, E., Sibley, C.P., D’Souza, S., Catanescu, O., Jacobsen, D.W. and J.D. Glazier. Homocysteine transport by systems L, A and y+L across the microvillous plasma membrane of human placenta. J Physiol 587:4001-13, 2009.
DiBello, P.M., Dayal, S., Kaveti, S., Zhang, D., Kinter, M.T., Lentz, S.R. and D.W. Jacobsen. The nutrigenetics of hyperhomocysteinemia. Quantitative proteomics reveals differences in the methionine cycle enzymes of gene-induced versus diet-induced hyperhomocysteinemia. Mol Cell Proteomics 9:471-85, 2010.
Hannibal*, L., Smith*, C.A. and D.W. Jacobsen. The X-ray crystal structure of glutathionylcobalamin revealed. Inorg Chem, in press, 2010. (*Both authors contributed equally to this work)