Natural Product Diversification
Research in the Singh laboratory lies at the interface of chemistry and biology. We use tools and methods from biochemistry and structural biology to characterize new enzymes from natural product biosynthetic pathways; molecular biology techniques to engineer enzymes to generate better biocatalysts; and synthetic chemistry methods for the generation of precursors necessary for natural product diversification. The fundamental goal of research in Singh laboratory is to understand and exploit natural product enzymes for developing biologically active molecules against cancer and infectious diseases. Our lab is especially interested in exploiting the ability of late stage enzymes from natural product biosynthetic pathways for the structural diversification of complex natural products. Despite the fact that structural diversification of biologically active molecules by attaching different chemical moieties has great potential to generate new drug leads, chemical methods often suffer from selectivity and tedious purification steps. Our goal is to exploit the potential of natural product enzymes and generate chemoenzymatic-tools for facile attachment of chemical moieties in a stereo- and regio- selective fashion to complex molecules towards the generation of biologically active compounds.
Structure and specificity of a permissive bacterial C-prenyltransferase. Elshahawi SI, Cao H, Shaaban KA, Ponomareva LV, Subramanian T, Farman ML, Spielmann HP, Phillips GN Jr, Thorson JS, Singh S. Nat Chem Biol. 2017 Feb 6. doi: 10.1038/nchembio.2285. [Epub ahead of print]
Functional AdoMet Isosteres Resistant to Classical AdoMet Degradation Pathways. Huber TD, Wang F, Singh S, Johnson BR, Zhang J, Sunkara M, Van Lanen SG, Morris AJ, Phillips GN Jr, Thorson JS. ACS Chem Biol. 2016, 11(9), 2484-2491.
Structural characterization of CalS8, a TDP-a-D-glucose dehydrogenase involved in calicheamicin aminodideoxypentose biosynthesis.. Singh S, Michalska K, Bigelow L, Endres M, Kharel MK, Babnigg G, Yennamalli RM, Bingman CA, Joachimiak A,Thorson JS, Phillips Jr GN. J. Biol. Chem. 2015, 290, 26249-58.
Facile strategies for the synthesis and utilization of S-adenosyl-L-methionine analogs. Singh S, Zhang J, Huber TD, Sunkara M, Hurley K, Goff RD, Wang G, Zhang W, Liu C, Rohr J, Van Lanen SG, Morris AJ, Thorson JS. Angew.Chem. Intl. Ed. 2014, 53, 3965-9.
A general NMR-based strategy for the in situ characterization of sugar-nucleotide-dependent biosynthetic pathways. Singh S, Peltier-Pain P, Tonelli M,Thorson JS. Org Lett. 2014, 16, 3220-3.
Structural and functional characterization of CalS11, a TDP-rhamnose 3'-O-methyltransferase involved in calicheamicin biosynthesis. Singh S, Chang A, Helmich KE, Bingman CA, Wrobel RL, Beebe ET, Makino S, Aceti DJ, Dyer K, Hura GL, Sunkara M, Morris AJ, Phillips GN Jr, Thorson JS..ACS Chem Biol. 2013 8,1632-9.
Research keywords: chemoenzymatic, chemical biology, enzymes, X-ray, NMR