个人简介

2010 Organic and Biomolecular Chemistry Lecture Award 2007 Alfred P. Sloan Fellowship 2006 American Cancer Society Research Scholar 2004 National Science Foundation CAREER Award 2004 Hellman Fellow 2003 Ellison Medical Foundation, New Scholar Award in Global Infectious Disease 1999-2002 NIH Postdoctoral Fellowship 1998 Bristol-Myers Squibb Graduate Fellowship 1994 Zevi & Bertha Salsburg Award for Excellence in Chemistry

研究领域

Organic Chemistry

Project 1: Proteomic Tools for Natural Product Biosynthetic Pathways We focus on polyketide (PK) and non-ribosomal peptide (NRP) synthases in the development of small-molecule probes to guide metabolic engineering and discover natural product systems. We began by probing the carrier protein domain essential to all PK, NRP, and fatty acid biosyntheses. Using fluorescent and affinity reporters, we are able to visualize, isolate, and manipulate carrier protein domains from natural and engineered pathways. Using this methodology, we have created a general profiling system via multiplex analysis of fluorescent substrates that offers a unique classification scheme for carrier protein domains within NRPS and PKS synthases. We are currently developing molecules to target other domains within modular synthases and envision a set of domain specific markers for each stage in PK and NRP biosynthesis. We anticipate that all of these tools will serve as diagnostic reporters for metabolic engineering, visualization probes for natural product discovery, and as potential antibiotics against virulence factor-producing pathogens. Project 2: Chemical Direction of Coenzyme A Biosynthesis Our natural product research led us into the investigation of coenzyme A (CoA) biosynthesis and analog design. We have developed new synthetic techniques to synthesize analogs of CoA precursors, pantetheine and phosphopantetheine, in an effort to design novel CoA analogs to understand functional requirements of CoA-dependent enzymes. This has led us to study the enzymes involved in CoA biosynthesis and the chemo-enzymatic synthesis of coenzyme A analogs in vitro and in vivo. Here, we found that pantetheine analogs may be incubated with cell culture, where uptake and metabolic transformation into labeled CoA analogs via takes place. This pathway may be used to deliver reporter molecules or selective inhibitors of CoA-dependent enzymes to intracellular locations. This scheme also works well in vitro. Our efforts have forwarded what is arguably one of the most versatile tools for multifunctional protein labeling, including bio-orthogonal reactive probes that can be applied to a variety of in vivo applications. We have also adapted this biosynthetic access to rare analogs to prepare tailored probes for the mechanistic examination of CoA-driven biosynthesis. Here we can visualize protein-protein interactions via covalent protein attachment of transition-state designed inhibitors. This technique introduces a powerful new tool to probe the structural biology of biosynthetic enzymes. Project 3: Biofuels and products from Algae The Burkart lab has played a major role in the creation of the San Diego Center for Algae Biotechnology (SD-CAB). We are currently involved in the study of algal metabolic pathways with an emphasis upon engineering improved biofuel production. Using the proteomic tools developed for modular synthases, we perform activity, structural, and engineering studies in single-cellular algae.

近期论文

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Nguyen C, Haushalter RW, Lee DJ, Markwick PR, Bruegger J, Caldara-Festin G, Finzel K, Jackson DR, Ishikawa F, O'Dowd B, McCammon JA, Opella SJ, Tsai SC, Burkart MD, "Trapping the dynamic acyl carrier protein in fatty acid biosynthesis.", Nature, 2014, Vol. 505, Issue 7483, 427-31 [View Abstract] Schoepp NG, Stewart RL, Sun V, Quigley AJ, Mendola D, Mayfield SP, Burkart MD, "System and method for research-scale outdoor production of microalgae and cyanobacteria.", Bioresour Technol, 2014, Vol. 166, 273-81 [View Abstract] Vickery CR, Kosa NM, Casavant EP, Duan S, Noel JP, Burkart MD, "Structure, Biochemistry, and Inhibition of Essential 4'-Phosphopantetheinyl Transferases from Two Species of Mycobacteria.", ACS Chem Biol, 2014, [View Abstract] Ishikawa F, Haushalter RW, Lee DJ, Finzel K, Burkart MD, "Sulfonyl 3-alkynyl pantetheinamides as mechanism-based cross-linkers of acyl carrier protein dehydratase.", J Am Chem Soc, 2013, Vol. 135, Issue 24, 8846-9 [View Abstract] Rothmann M, Kang M, Villa R, Ntai I, La Clair JJ, Kelleher NL, Chapman E, Burkart MD, "Metabolic perturbation of an essential pathway: evaluation of a glycine precursor of coenzyme A.", J Am Chem Soc, 2013, Vol. 135, Issue 16, 5962-5 [View Abstract] Villa R, Kashyap MK, Kumar D, Kipps TJ, Castro JE, La Clair JJ, Burkart MD, "Stabilized Cyclopropane Analogs of the Splicing Inhibitor FD-895.", J Med Chem, 2013, [View Abstract] Blatti JL, Beld J, Behnke CA, Mendez M, Mayfield SP, Burkart MD, "Manipulating fatty acid biosynthesis in microalgae for biofuel through protein-protein interactions.", PLoS One, 2012, Vol. 7, Issue 9, e42949 [View Abstract] Ishikawa F, Haushalter RW, Burkart MD, "Dehydratase-specific probes for fatty acid and polyketide synthases.", J Am Chem Soc, 2012, Vol. 134, Issue 2, 769-72 [View Abstract] Kosa NM, Haushalter RW, Smith AR, Burkart MD, "Reversible labeling of native and fusion-protein motifs.", Nat Methods, 2012, Vol. 9, Issue 10, 981-4 [View Abstract] van der Westhuyzen R, Hammons JC, Meier JL, Dahesh S, Moolman WJ, Pelly SC, Nizet V, Burkart MD, Strauss E, "The antibiotic CJ-15,801 is an antimetabolite that hijacks and then inhibits CoA biosynthesis.", Chem Biol, 2012, Vol. 19, Issue 5, 559-71 [View Abstract] Haushalter RW, Filipp FV, Ko KS, Yu R, Opella SJ, Burkart MD, "Binding and "pKa" modulation of a polycyclic substrate analogue in a type II polyketide acyl carrier protein.", ACS Chem Biol, 2011, Vol. 6, Issue 5, 413-8 [View Abstract]