Faculty and Staff Directory
Thomas M. Makris
|Title:||Associate Professor / Biochemistry and Molecular Biology
Bioinorganic / Bioorganic / Biophysical / Catalysis / Crystallography / Inorganic / Spectroscopy
|Department:||Chemistry and Biochemistry
Department of Chemistry and Biochemistry
Office: GSRC 329
Lab: GSRC 326, 803-777-2720
Lab 2: GSRC 327
Thomas Makris Group Website
Department of Chemistry and Biochemistry
B.A., 1996, University of Pennsylvania
Ph.D., 2003, University of Illinois Urbana - Champaign
Honors and Awards
Breakthrough Rising Star, 2018; National Science Foundation Career Award, 2016-2021.
Natural product biosynthesis; non-ribosomal peptides; bioinorganic and biophysical chemistry; oxygen activation; sustainable chemistry; biofuels
My laboratory is interested in the chemical biology of enzymes involved in pharmaceutical biosynthesis and bioenergy production. We are interested in developing tools to understand the detailed molecular mechanisms of these potent catalysts, and ultimately leverage them for the synthesis of natural products of pharmacological or industrial importance. As a result, we utilize a large spectrum of techniques in our studies, ranging from genome mining, molecular biology, metabolic engineering, enzymology, transient kinetics, and biophysical spectroscopy.
There is growing interest in developing biochemical strategies to produce compounds with similar properties to petroleum-derived fuels. We are exploring enzymatic routes to produce hydrocarbons from biologically-derived fatty acid precursors, with the ultimate goal of preparing a sustainable route for generating these compounds. To this end, we are currently studying a number of enzymes which perform the oxidative cleavage of fatty acids and metabolites. The chemical mechanisms of these enzymes, largely unknown, present some fascinating deviations from typical oxygen insertion chemistries. We are exploring both the substrate selectivity and mechanistic biochemistry of these C-C cleaving catalysts. Our goals are to optimize the selectivity of these enzymes, and to leverage their catalysis for the efficient production of commercially viable drop-in fuels and specialty chemicals.
Selective C-H Bond Functionalization of Natural Products
Peptide-derived natural products, including many antibiotics and chemotherapy drugs, are synthesized by complex multi-modular enzymes termed non-ribosomal peptide synthetases (NRPS). The general peptide structure of a maturing natural product is tailored by accessory enzymes. The antimicrobial and apoptotic activity of natural products are controlled by these modifications, and engenders a unique opportunity to produce new therapeutics or to inhibit the production of microbial virulence factors generated by these pathways in a controlled fashion.
My lab is specifically interested in understanding the molecular mechanisms underlying antibiotic tailoring towards the generation of new antimicrobial compounds. We currently study tailoring enzymes that are involved in altering the solubility, peptide structure, glycosylation pattern, and stability of a wide variety of pharmaceuticals. In order to ultimately harness the catalytic versatility of tailoring enzymes, we require a detailed understanding of the molecular recognition events that control the exquisite specificity of a tailoring enzyme to the NRPS and of the detailed catalytic mechanism that occurs at the enzyme active-site. As each enzyme class is comprised of a unique complex structure and catalytic mechanism, our goal is to develop general paradigms which may enable us to make new compounds in a systematic and combinatorial fashion.
Amaya, J. A., Rutland, C. D., Leschinsky, N., Makris, T. M. (2018) A Distal Loop Controls Product Release and Chemo and Regioselectivity in Cytochrome P450 Decarboxylases, Biochemistry 57 (3) 344-353. DOI: 10.1021/acs.biochem.7b01065.
Wise, C. E., and Makris, T. M. (2017) Recruitment and Regulation of the Non-ribosomal Peptide Synthetase Modifying Cytochrome P450 Involved in Nikkomycin Biosynthesis, ACS Chem Biol. DOI: 10.1021/acschembio.7b00081.
Hsieh, C. H., Huang, X., Amaya, J. A., Rutland, C. D., Keys, C. L., Groves, J. T., Austin, R. N., and Makris, T. M. (2017) The Enigmatic P450 Decarboxylase OleT is Capable of, but Evolved to Frustrate, Oxygen Rebound Chemistry, Biochemistry 56 (26), 3347–3357. DOI: 10.1021/acs.biochem.7b00338.
Grant, J. L, Mitchell, M. E., Makris, T. M. (2016) Catalytic Strategy for Carbon-Carbon Bond Scission by the Cytochrome P450 OleT, Proc. Nat. Acad. Sci. USA 113, 10049-54. DOI: 10.1073/pnas.1606294113.
Grant, J. L.; Hsieh, C. H.; Makris, T. M. (2015) Decarboxylation of fatty acids to terminal alkenes by cytochrome P450 compound I. J. Am. Chem. Soc. 137, 4940-4943. DOI: 10.1021/jacs.5b01965.