个人简介

B.A., 1996, University of Pennsylvania Ph.D., 2003, University of Illinois Urbana-Champaign Postdoctoral Fellow, University of Minnesota

研究领域

Biochemistry

Natural product biosynthesis; non-ribosomal peptides; bioinorganic and biophysical chemistry; oxygen activation; 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. Antibiotic Biosynthesis 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 the molecular mechanisms underlying antibiotic tailoring and exploiting these to make 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 tailoring 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. Our examination of non-ribosomal peptide and polyketide biosynthesis pathways affords an excellent opportunity to reveal novel enzymes with unique structures, cofactor requirements, and chemistries. We utilize structural, biochemical, and spectroscopic methods to characterize the catalytic mechanisms of these enzymes and use these as a framework to understood fundamental biochemical processes, such as C-H bond functionalization. Microbial Hydrocarbon Biosynthesis There is growing interest in developing biochemical methods to produce compounds with similar properties to petroleum-derived fuels. We are exploring enzymatic routes to produce suitable chain length hydrocarbons from biologically-derived fatty acid precursors, with the ultimate goal of preparing a genetically modified organism capable of efficiently generating these compounds in vivo. To this end, we are currently studying a number of enzymes which perform the oxidative cleavage of fatty acids and aldehydes. The chemical mechanisms of these enzymes, largely unknown, present some fascinating deviations from typical oxidative chemistries. For example, one enzyme under study, a cytochrome P450, efficiently catalyzes the oxidative decarboxylation of fatty acids. We are exploring both the substrate selectivity and mechanistic biochemistry (oxygen activation reaction) of this unique reaction. Our goals are to optimize the chain length selectivity of these enzymes, and utilize them in a pathway to efficiently produce commercially viable drop-in fuels.

近期论文

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Makris, T. M., Knoot, C. J., Wilmot, C. M. and Lipscomb, J. D., Structure of a dinuclear iron cluster-containing beta-hydroxylase active in antibiotic biosynthesis. Biochemistry 2013, 52 (38), 6662-71. Aukema, K. G., Makris, T. M., Stoian, S. A., Richman, J. E., Munck, E., Lipscomb, J. D. and Wackett, L. P. ACS Catalysis 2013, 3 (10), 2228-38. Thompson, J. W.; Salahudeen, A. A.; Chollangi, S.; Ruiz, J. C.; Brautigam, C. A.; Makris, T. M.; Lipscomb, J. D.; Tomchick, D. R.; Bruick, R. K. Structural and molecular characterization of iron-sensing hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5). J Biol Chem. 2012, 287, (10), 7357-65. Vu, V. V.; Makris, T. M.; Lipscomb, J. D.; Que, L., Jr., Active-site structure of a beta-hydroxylase in antibiotic biosynthesis. J Am Chem Soc 2011, 133 (18), 6938-41. Makris, T. M.; Chakrabarti, M.; Munck, E.; Lipscomb, J. D., A family of diiron monooxygenases catalyzing amino acid beta-hydroxylation in antibiotic biosynthesis. PNAS 2010, 107 (35), 15391-6. Denisov, I. G.; Mak, P. J.; Makris, T. M.; Sligar, S. G.; Kincaid, J. R., Resonance Raman characterization of the peroxo and hydroperoxo intermediates in cytochrome P450. J Phys Chem A 2008, 112 (50), 13172-9. Makris, T. M.; von Koenig, K.; Schlichting, I.; Sligar, S. G., Alteration of P450 distal pocket solvent leads to impaired proton delivery and changes in heme geometry. Biochemistry 2007, 46 (49), 14129-40. Mak, P. J.; Denisov, I. G.; Victoria, D.; Makris, T. M.; Deng, T.; Sligar, S. G.; Kincaid, J. R., Resonance Raman detection of the hydroperoxo intermediate in the cytochrome P450 enzymatic cycle. J Am Chem Soc 2007, 129 (20), 6382-3. Newcomb, M.; Zhang, R.; Chandrasena, R. E.; Halgrimson, J. A.; Horner, J. H.; Makris, T. M.; Sligar, S. G., Cytochrome P450 compound I. J Am Chem Soc 2006, 128 (14), 4580-1. Makris, T. M.; von Koenig, K.; Schlichting, I.; Sligar, S. G., The status of high-valent metal oxo complexes in the P450 cytochromes. J Inorg Biochem 2006, 100 (4), 507-18. Ke, N.; Baudry, J.; Makris, T. M.; Schuler, M. A.; Sligar, S. G., A retinoic acid binding cytochrome P450: CYP120A1 from Synechocystis sp. PCC 6803. Arch Biochem Biophys 2005, 436 (1), 110-20