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Satish K. Nair

Head and Gregorio Weber Chair, Department of Biochemistry
Director, Center for Biophysics & Quantitative Biology

Research Interests

Research Topics

Drug Discovery, Enzymology, Host-Pathogen Interactions, Membrane Biology, Microbial Physiology, Protein Structure

Disease Research Interests

Infectious Diseases, Metabolic Disorders/Diabetes

Research Description

Natural products biosynthesis, bacterial signalling, X-ray crystallography

Research in the Nair lab focuses on understanding the biosynthesis and use of bacterial natural products. We use biochemical and microbiological techniques, in combination with biophysical methods (in particular X-ray crystallography) to study how bacteria produce these small molecules and how they use these compounds to regulate intra-species behavior or to kill competing species. The development of such natural products can be used to combat the growth of pathogens including bacteria, fungi, and protozoa.

Ribosomally synthesized peptide antibiotics: A main research focus in our laboratory is on biosynthetic enzymes that modify ribosomally encoded peptides to yield macrocyclic natural products. We are specifically focused on understanding the mechanism for the synthesis of two classes of such compounds: lantibiotics and cyanobactins. For both classes of natural products, the genetic nature of the precursor and the modular architecture of the modification/processing enzymes may be exploited to yield novel molecules with improved therapeutic applications. Our work on lantibiotics, in collaboration with the laboratories of Wilfred van der Donk land Doug Mitchell (Chemistry: UIUC), has been aimed at characterization of several enzymes involved in biosynthesis. Our work on cyanobactin, in collaboration with Eric Schmidt (Medicinal Chemistry: Utah) focuses on structure-function characterization of enzymatic pathways for the production of these heterocyclized macrocyclic marine natural products.

Phosphonate biosynthesis and engineering: We are members of the Mining Microbial Genomes theme within the Institute of Genomic Biology (van Der Donk: Chemistry, Metcalf: Microbiology and Zhao: Chemical Engineering). In collaboration with the members of this theme, we are focused on characterization of enzymes involved in the biosynthesis of phosphonate antibiotics, with the aim of using the structural data to reprogram these enzymes to produce novel compounds.

Bacterial inter- and intracellular communication: Bacteria can utilize small molecules as signals and we are focusing on elucidating the mechanisms underlying this process. In quorum sensing, bacteria coordinate population growth by utilizing small molecule inducers (typically acylhomoserine lactones). When the population density exceeds some threshold, these autoinducers bind to their cognate receptor and activate the transcription of various genes. A second class of inter-cellular communication is predicated upon the action of a diffusible signal factors that are chemically distinct from quorum sensing autoinducers. In theory, as each of these pathways are regulated by small molecules, they represent ideal targets for therapeutic intervention against bacterial growth.

Education

B.S. 1989 Brown University
Ph.D. 1994 University of Pennsylvania
Postdoc. 1995-99 Rockefeller University

Highlighted Publications

Representative Publications

Zheng, Y., and Nair, S.K. (2022) "YcaO-mediated ATP-dependent peptidase activity in ribosomal peptide biosynthesis." Nature Chem. Biol. doi:10.1038/s41589-022-01141-0.

Pei, Z-F., Zhu, L., Sarksian, R., van der Donk, W.A., and Nair, S.K. (2022) “Class V lanthipeptide cyclase directs the biosynthesis of a stapled peptide natural product.” J. Am. Chem. Soc. 144, 17549-57.

Ongpipattanakul, C., Desormeaux, E.K., DiCaprio, A., van der Donk, W.A.*, Mitchell, D.A.*, and Nair, S.K.* (2022) “Mechanism of action of ribosomal synthesized and post-translationally modified peptide.” Chemical Reviews 122, 14722-14814. (*Corresponding author)

Cogan, D.P., Bhushan, A., Reyes, R., Zhu, L., Piel, J., and Nair, S.K. (2022) “Structure and mechanism for iterative amide N-methylation in the biosynthesis of channel-forming peptide cytotoxins.” Proc. Nat’l. Acad. Sci. doi:10.1073/pnas.2116578119.

Zheng, Y., Cong, Y., Schmidt, E.W., and Nair, S.K. (2022) “Catalysts for the enzymatic lipidation of peptides.” Acc. Chem. Res. doi:10.1021/acs.accounts.2c00108.

Simon, M.A., Ongpipattanakul, C., Nair, S.K., and van der Donk, W.A. (2021) “Biosynthesis of fosfomycin in pseudomonads reveals an unexpected enzymatic activity in the metallohydrolase superfamily.” Proc. Nat’l. Acad. Sci.,118, e2019863118.

Liu, A., Si, Y., Dong, S.H., Mahanta, N., Penkala, H.N., Nair, S.K. and Mitchell, D.A. (2021) “Functional elucidation of TfuA in peptide backbone thioamidation.” Nature Chem. Bio., 17, 585-92.

Cogan, D.P., Ly, J., and Nair, S.K. (2020) “Structural Basis for Enzymatic Off-Loading of Hybrid Polyketides by Dieckmann Condensation.” ACS Chem. Bio., 15, 2783-91.

Kapoor, I., Olivares, P., and Nair, S.K. (2020) “Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones.” eLife, doi:10.7554/eLife.57824.

Recent Publications

Lei, R., Hernandez Garcia, A., Tan, T. J. C., Teo, Q. W., Wang, Y., Zhang, X., Luo, S., Nair, S. K., Peng, J., & Wu, N. C. H. (2023). Mutational fitness landscape of human influenza H3N2 neuraminidase. Cell Reports, 42(1), [111951]. https://doi.org/10.1016/j.celrep.2022.111951

Ongpipattanakul, C., Liu, S., Luo, Y., Nair, S. K., & Van der donk, W. A. (2023). The mechanism of thia-Michael addition catalyzed by LanC enzymes. Proceedings of the National Academy of Sciences, 120(3), [e2217523120]. https://doi.org/10.1073/pnas.2217523120

Cogan, D. P., Bhushan, A., Reyes, R., Zhu, L., Piel, J., & Nair, S. K. (2022). Structure and mechanism for iterative amide N-methylation in the biosynthesis of channel-forming peptide cytotoxins. Proceedings of the National Academy of Sciences of the United States of America, 119(13), [e2116578119]. https://doi.org/10.1073/pnas.2116578119

Gu, W., Zheng, Y., Pogorelov, T., Nair, S. K., & Schmidt, E. W. (Accepted/In press). Control of Nucleophile Chemoselectivity in Cyanobactin YcaO Heterocyclases PatD and TruD. ACS chemical biology. https://doi.org/10.1021/acschembio.2c00147

Lei, R., Tan, T. J. C., Hernandez Garcia, A., Wang, Y., Diefenbacher, M., Teo, C., Gopan, G., Tavakoli Dargani, Z., Teo, Q. W., Graham, C. S., Brooke, C. B., Nair, S. K., & Wu, N. C. H. (2022). Prevalence and mechanisms of evolutionary contingency in human influenza H3N2 neuraminidase. Nature communications, 13(1), [6443]. https://doi.org/10.1038/s41467-022-34060-8

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