Faculty

Research Foci: Chemical biology of mammalian sulfur metabolism, intercellular redox communication, mechanism of vitamin B12 trafficking and structural enzymology of human B12, PLP and heme enzymes and characterization of patient mutants in them.

Sulfur metabolism furnishes cells with two important reagents: S-adenosylmethionine or AdoMet, which serves as the dominant cellular methyl donor for methylation reactions, and glutathione, the cell's most abundant antioxidant. Homocysteine is an important intermediate in this pathway and, at elevated levels, is correlated with cardiovascular diseases, neural tube defects, neurodegenerative diseases and certain cancers. Our laboratory studies the coordinate regulation of methylation and redox homeostasis at the organismal, cellular, molecular and computational levels to elucidate key switchpoints and the traffic lights that regulate this metabolic nexus. We also study the gene-nutrient interactions that influence flux of sulfur metabolites by virtue of the B-vitamin dependence of several pathway enzymes. In addition, we are studying the co-dependence of cell types for their energy and redox metabolic needs. Specifically, we are interested in the mechanism of autoimmunity by which regulatory T cells can suppress the proliferation and clonal expansion of effector T cells following activation by antigen presenting cells such as dendritic cells. We are elucidating the mechanism by which dendritic cells remodel the extracellular environment and make it more reducing to support proliferation of T cells and how regulatory T cells interfere with this process. We are also examining how effector T cells can modulate the phenotype of astrocytes and endow them with a neuroprotective phenotype and the role of regulatory T cells in this process.

The two vitamin B12 enzymes used by humans reside in the sulfur metabolic neighborhood and are methionine synthase and methylmalonyl-CoA mutase. Despite the paucity of B12 -dependent enzymes in humans, the pathway for B12 assimilation and trafficking is rather complex with at least half a dozen proteins, identified by genetic complementation studies in patients, being involved. In recent years, the identities of most of these genes have been discovered and our laboratory is elucidating functions of the individual proteins and the thermodynamics and kinetics of protein-protein interactions in the pathway. We have postulated that most of these proteins are chaperones that bind and deliver B12, which is both rare and reactive, and those which are enzymes and involved in B12 assimilation also function as escorts, delivering B12 to the target enzymes. We are studying the reaction mechanisms of B12 enzymes, methionine synthase and its activation partner, methionine synthase reductase as well as the radical B12 enzyme methylmalonyl-CoA mutase. We are interested in how biology exploits the reactivity of radicals on the one hand while containing it on the other to turnover substrates to products with high fidelity. We use a variety of biophysical (EPR spectroscopy, stopped-flow kinetics) approaches together with biochemical analysis of patient mutations to elucidate the mechanisms of these clinically important enzymes and understand the biochemical basis of metabolic defects caused by their impairments.

Awards

Pfizer Award, American Chemical Society
Established Investigator, American Heart Association
Basil O'Connor Award, March of Dimes Birth Defects Foundation
Shorb Lecturer, University of Maryland

Representative Publications

1. Yan, Z., Garg, S., Kipnis, J., and Banerjee, R., "Modulation of Extracellular Redox Remodeling by Regulatory T Cells", Nature Chem. Biol., 2009, (in press).

2. Banerjee, R., Gherasim, C., and Padovani, D., "The tinker, tailor and mailman in B12 trafficking", Curr. Op. Chem. Biol., 2009, (in press).

3. Chiku, T., Padovani, D., Zhu, W., Singh, S., Vitvitsky, V. and Banerjee, R., "H2S biogenesis by cystathionine g-lyase leads to the novel sulfur metabolites, lanthionine and homolanthionine, and is responsive to the grade of hyperhomocysteinemia", J. Biol. Chem., 2009, 284, 11601.

4. Kim, J., Gherasim, C. and Banerjee, R., "Decyanation of Vitamin B12 by a trafficking chaperone," PNAS, 2008, 105, 14551.

5. Banerjee, R., Vitvitsky, V. and Garg, S.K., " The undertow of Sulfur metabolism on glutaminergic neurotransmission," Trends in Biochem. Sci., 2008, 33, 413-419.

6. Garg, S., Banerjee, R., Kipnis, S., "Neuroprotective Immunity: T cell-derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype", J. Immunol., 2008, 180(6), 3866.

7. Padovani, D., Labunska, T., Palfey, B.A., Ballou, D.P. and Banerjee, R., "Adenosyltransferase Tailors and Delivers Coenzymes B 12" Nature Chem. Biol., 2008, 4(3), 194.