Faculty

Research Foci: Chemical biology of mammalian sulfur metabolism, structural enzymology of human B12 trafficking proteins and enzymes involved in H2S biogenesis and catabolism.

Sulfur metabolism furnishes cells with four important reagents: S-adenosylmethionine, which serves as the dominant cellular methyl donor, glutathione, the cell’s most abundant antioxidant, taurine an osmoregulator present at high concentrations and hydrogen sulfide, a gaseous signaling molecule. We are investigating the reaction mechanisms of the human cytosolic enzymes that generate H2S and the mitochondrial enzymes involved in the pathway for H2S oxidation.

The enzymes in the sulfur metabolic pathway are richly dependent on multiple B vitamins for their catalytic functions including vitamin B12. 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 being involved. In recent years, the identities of most of these genes have been discovered and our laboratory is elucidating novel enzymatic functions of the individual proteins and the thermodynamics and kinetics of protein-protein interactions in the pathway. Our studies are demonstrating that many of these proteins are chaperones that bind and deliver B12, which is both rare and reactive, while others function both as enzymes, tailoring the active form of the cofactor, and as escorts, delivering B12 to target enzymes. We are studying the reaction mechanisms of the radical B12 enzymes methylmalonyl-CoA mutase and isobutyryl-CoA mutase and are interested in how biology exploits the reactivity of radicals on the one hand while containing it on the other to turn over substrates to products with high fidelity. We use a variety of biophysical (EPR spectroscopy, stopped-flow kinetics) approaches to elucidate the mechanisms and regulation of these clinically important enzymes.

Our laboratory is interested also in deciphering the traffic lights that govern flux of sulfur via competing metabolic pathways at the organismal, cellular, molecular and computational levels to elucidate key regulatory switch points and to illuminate the mechanisms of regulation of individual enzymes. In addition, we are interested in elucidating the mechanism by which cells in the nervous and immune systems, which show a high level of metabolic interdependence on each other, meet their sulfur metabolic needs and identify the sulfur metabolites they use for communication and remodeling of the extracellular redox milieu.

Awards

Representative Publications

1. Iskandar, B. I., Rizk, E., Meier, B., Hogan, K., Finnell, R., Bottiglieri, T., Jarrard, D. F., Gherasim, C., Banerjee, R., Skene, J. H. P., Nelson, A., Simon, K., Cook, T. D., Hariharan, N., Folate regulation of CNS regeneration through DNA methylation, J. Clin. Invest, (2010) 120:1603–1616. PMID: 17554763
   Commentary in: Neuronal Injury: Folate to the rescue? J. Clin. Invest. (2010) 120: doi:10.1172/JCI40764

2. Kabil, O. and Banerjee, R. The Redox Biochemistry of H2S, J. Biol. Chem., (2010), 285:21903-21907.PMID: 20448039

3. Yan, Z., Garg, S., Kipnis, J. and Banerjee, R (2009) Modulation of Extracellular Redox Remodeling by Regulatory T Cells, Nature Chem. Biol. 2009 5, 721 – 723 PMID: 19718041
   News and Views by Rubartelli, A. and Sitia, R. Nature Chem. Biol. (2009) Chemo-metabolic regulation of immune responses by Tregs, 5: 709 – 710.

4. Padovani, D. and Banerjee, R. (2009) A G protein editor gates coenzyme B12 loading and is corrupted in methylmalonic aciduria, Proc. Natl. Acad. Sci. 106(51):21567-72. 
   Editor’s Choice highlight in Science, 2009, 326: 1590-91.

5. Banerjee, R., Gherasim, C. and Padovani, D. (2009) The tinker, tailor and mailman in B12 trafficking, Curr. Op. Chem. Biol., Aug 7. [Epub ahead of print].PMID: 19665918

6. Singh, S., Padovani, D., Leslie, R.A., Chiku, T. and Banerjee, R., The relative contributions of cystathionine β-synthase and γ-cystathionase to H2S biogenesis via alternative transsulfuration reactions, J. Biol. Chem., 2009, 284(33):22457-66.

7. Padovani, D., Labunska, T., Palfey, B.A., Ballou, D. P. and Banerjee, R. (2008) Adenosyltransferase Tailors and Delivers Coenzyme B12. Nature Chem. Biol., 4(3):194-6 Read news and views article at: Bandarian V. Delivery of tailor-made cobalamin to methylmalonyl-CoA mutase. Nat Chem Biol. 2008 Mar;4(3):158-9.PMID: 18264093
   Read news and view article at Bandarian V. Delivery of tailor-made cobalamin to methylmalonyl-CoA mutase. Nature Chem Biol. 2008 Mar;4(3):158-9.

Textbooks

1. The Chemistry and Biochemistry of B12. Ed. R. Banerjee. John Wiley and Sons, N.Y. 1999.

2. Redox Biochemisry. Ed. R. Banerjee.John Wiley and Sons, N.Y. 2007.
   See Review: Wood MJ. Refocusing redox biochemistry. Nat Chem Biol. 2008 May;4(5):267.