Donald W. Jacobsen, Ph.D.

Donald W. Jacobsen, Ph.D., F.A.H.A.

Emeritus Staff

Research interest

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.


Collaborators

  • Richard C. Austin, Ph.D., Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  • Ruma Banerjee, Ph.D., Department of Biological Chemistry, University of Michigan, Ann Arbor, MI
  • Nicola E. Brasch, Ph.D., Department of Chemistry, Kent State University, Kent, OH
  • Jocelyn D. Glazier, Ph.D., Maternal and Fetal Health Research Group, Research School of Clinical and Laboratory Sciences, University of Manchester, Manchester, U.K.
  • Warren D. Kruger, Ph.D., Fox Chase Cancer Center, Philadelphia, PA
  • Steven R. Lentz, M.D., Ph.D. Department of Internal Medicine, University of Iowa School of Medicine, Iowa City, IA
  • Laura E. Nagy, Ph.D., Department of Pathobiology, Lerner Research Institute, Cleveland Clinic
  • Edward V. Quadros, Ph.D., Department of Biochemistry, SUNY Downstate Medical Center, Brooklyn, N.Y.
  • David S. Rosenblatt, M.D., Department of Human Genetics, McGill University, Montreal, Quebec, Canada
  • Alexander A. Zhloba, M.D., Department of Biochemistry, Pavlov Medical University, St Petersburg, Russia

Highlighted Publications

1. Kim J, Hannibal l, Gherasim C, Jacobsen DW and R Banerjee. A human B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins. J Biol Chem 2009; 284:33418-24.

2. Hannibal L, Kim J, Brasch NE, Wang S, Rosenblatt DS, Banerjee R and DW Jacobsen. Processing of alkylcobalamins by mammalian cells: a role for the MMACHC (cblC) gene product. Mol Genet Metabol 2009; 97:260-6.

3. Hannibal* L, Smith* CA and DW Jacobsen. The X-ray crystal structure of glutathionylcobalamin revealed. Inorg Chem 2010; 49:9921-7. *Both authors contributed equally.

4. Hannibal L, Glushchenko AV and DW Jacobsen. Chapter 12, Folates and Cardiovascular Disease: Basic Mechanisms. In: Folates in Health and Disease, 2nd ed. (L. Bailey, ed.), CRC Press - Taylor and Francis, LLC. 2010; pp. 291-323.

5. Hannibal L, DiBello PM, Yu M, Miller A, Wang S, Willard B, Rosenblatt DS and DW Jacobsen. The MMACHC proteome: hallmarks of functional cobalamin deficiency in humans. Mol Genet Metabol 2011; 103:226-39.

6. Hannibal L, DiBello PM, and DW Jacobsen. Proteomics of Vitamin B12 Processing. Clin Chem Lab Med 2012; in press.

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