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Michael Burkart
Natural product synthesis/biosynthesis, Biological chemistry and enzymology, Metabolic engineering. |
| Contact Information |
| Office: PACH 6100D |
| Phone: (858) 534-5673 |
| Fax: (858) 534-6693 |
| Email: mburkart@ucsd.edu |
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| Education and Appointments |
| 2000 |
N.I.H., Harvard Medical School
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| 1999 |
Ph.D., Scripps Research Institute
Organic Chemistry
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| 1994 |
B.A., Rice University
Chemistry
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| Awards and Academic Honors |
| 2007 |
Alfred P. Sloan Fellowship |
| 2006 |
American Cancer Society Research Scholar |
| 2004 |
Hellman Fellow |
| 2004 |
National Science Foundation CAREER Award |
| 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 |
| Research Interests |
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: Compact Disc - Based Molecular Diagnostics
The third project in the lab is the development of inexpensive screens for the quantitative and qualitative analysis of biomolecular species. We have introduced a new technology to detect biomolecular interactions using a standard compact disc (CD) and CD player. This work has gained broad scientific and popular interest. We are currently exploring additional biomolecular species (DNA, RNA, carbohydrates, and peptides) for identification with this system. We have demonstrated how a digital architecture can inherently benefit biomolecular assays because of direct interaction with digital algorithms. Currently, we are programming self-executing assays using artificially intelligent algorithms that allow unskilled users to perform complex assays and deliver results to trained professionals via conventional digital networks. We are also improving the chemistry of polycarbonate surface modification to be applicable to production scales. We believe that this technology could revolutionize the way molecules are visualized and understood by non-scientists.
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| Primary Research Area: |
Interdisciplinary Specialties: |
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Organic Chemistry
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Bioorganic
Synthesis
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| Selected Publications |
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Alexander MD, Fontaine SD, La Clair JJ, DiPasquale AG, Rheingold AL, Burkart MD. Synthesis of the mycolactone core by ring-closing metathesis. Chem. Commun. 2006, 44, 4602-4604.
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Worthington AS, Rivera H, Torpey JW, Alexander MD, Burkart MD. Mechanism-based protein crosslinking probes to investigate carrier protein mediated synthesis. ACS Chem. Biol. 2006, 1, 687-691.
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Meier JL, Mercer AC, Rivera H, Burkart MD. Synthesis and evaluation of bioorthogonal pantetheine analogues for in vivo protein modification. J. Am. Chem. Soc. 2006, 128, 12174-84.
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Clarke KM, Mercer AC, La Clair JJ, Burkart MD. In Vivo Reporter Labeling of Proteins via Metabolic Delivery of Coenzyme A Analogues. J. Am. Chem. Soc., 2005, 127, 11234-5.
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La Clair JJ, Foley TL, Schegg TR, Regan CM, Burkart MD. Manipulation of Carrier Proteins in Antibiotic Biosynthesis, Chem. Biol. 2004, 11, 195-201. Featured in Chem Biol, 2004, 11, 290-1.
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