Michelle Chang: Designing Microbes to Make Fuels and Drugs

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Monday, 15 August 2011 08:30

Organisms that live in exotic environments have evolved unique traits in order to survive. Michelle Chang, an assistant professor of chemistry at UC Berkeley, hijacks the chemical reactions that confer those traits, combining them in novel ways. By inserting borrowed genes into easy-to-grow microbes such as E. coli, she creates organisms with new abilities. In one project, she is creating a system that takes lignin, a tough polymer abundant in agricultural waste, and breaks it into molecules that can be converted into biofuels. Chang is also developing a way to incorporate fluorine into organic molecules. Many modern drugs--Lipitor, for instance--require at least one fluorine atom per molecule to perform their functions. But fluorine is difficult to add to molecules using traditional chemistry.

While her projects have important practical applications, Chang hopes that her work will lead to basic tools for engineering organisms that can perform all kinds of reactions that are too difficult, expensive, or dangerous with traditional chemistry. Read Chang's insights on why biomass could improve biofuel production.

Research Interests

Biochemistry, Chemical Biology, and Synthetic Biology — Designing new biosynthetic pathways for in vivo cellular production of biofuels and pharmaceuticals

Our research laboratory utilizes the approaches of mechanistic biochemistry, molecular and cell biology, metabolic engineering, and synthetic biology to address problems in energy and human health. We design and create new biosynthetic pathways in microbial hosts for in vivo production of biofuels from abundant crop feedstocks and pharmaceuticals from natural products or natural product scaffolds. A unifying theme of all of our projects is a focus on gaining a detailed molecular understanding of how living cells control enzymatic processes within the context of the entire metabolic network. Specific projects under current investigation include (i) the in vivo production of biofuels from plant biomass, and (ii) the development of new biosynthetic methods for selective, catalytic C-F bond formation under mild conditions.

Biofuels

Sustainable energy is a significant challenge facing our planet and securing carbon-neutral sources of energy is essential to meeting growing energy demands while addressing environmental concerns. Energy and fuels produced from plant biomass offer an important renewable solution to this problem and also allow reduction in the overall release of greenhouse gases. We are constructing new biosynthetic pathways in bacterial hosts that can convert plant biomass into fuel molecules. Using synthetic biology methods, we can draw enzymes from a variety of different environmental organisms and combine them in a single genetically-engineered host. This mix-and-match approach allows us to create and tailor new biological tools for multi-step, multi-enzyme chemical synthesis.

Enzymatic Fluorinations

Natural products and their scaffolds continue to provide a rich source for the discovery and development of new therapeutics to treat human conditions ranging from cancer to neurodegeneration to microbial infections. In this regard, halogenated natural products (vancomycin and chloramphenicol) as well as synthetic drugs (Prozac, Lipitor, Cipro) encompass a growing class of important organohalogen-based pharmaceuticals. Organofluorine compounds are of particular interest as the introduction of C-F bonds can tune drug activity and specificity as well as in vivo metabolism of drugs. However, one of the major limitations in drug development is ability to selectively form C-F bonds as the available chemical methods for fluorination are difficult and typically carried out with harsh reagents without sufficient control over regio- or stereospecificity. We are developing new biocatalysts for selective and efficient C-F bond formation under mild conditions through the isolation, characterization, and mechanistic investigation of new enzymes involved in biological halogenations. These designer enzymes will have broad impact as synthetic tools for drug discovery and development.

Chang's Research Group

Publication:

M.C.Y. Chang, "Harnessing energy from plant biomass", Curr. Opin. Chem. Biol. 2007, 11, 677-684.
M.C.Y. Chang, R.A. Eachus, W. Trieu, D.-K. Ro, and J.D. Keasling, "Engineering Escherichia coli for production of functionalized terpenoids using plant P450s", Nature Chem. Biol. 2007, 3, 274-277.
M.C.Y. Chang and J.D. Keasling, "Production of isoprenoid pharmaceuticals by engineered microbes", Nature Chem. Biol. 2006, 2, 674-681.
J.D. Newman, J. Marshall, M.C.Y. Chang, F. Nowroozi, E.M. Paradise, D.P. Pitera, K.L. Newman, and J.D. Keasling, "High-level production of amorpha-4,11-diene in a two-phase partitioning bioreactor of metabolically-engineered Escherichia colii", Biotechnol. Bioeng. 2006, 95, 684-691.
D.-K. Ro, E.M. Paradise, M. Ouellet, K.J. Fisher, K.L. Newman, J.M. Ndungu, K.A. Ho, R.A. Eachus, T. Ham, J. Kirby, M.C.Y. Chang, S.T. Withers, Y. Shiba, R. Sarpong, and J.D. Keasling, "Production of the antimalarial drug precursor artemisinic acid in engineered yeast", Nature 2006, 440, 940-943.
M.C.Y. Chang, C.S. Yee, D.G. Nocera, and J. Stubbe, "Site-specific replacement of a conserved tyrosine in ribonucleotide reductase with an aniline amino acid: A mechanistic probe for redox-active tyrosines", J. Am. Chem. Soc. 2004, 126, 16702-16703.
M.C.Y. Chang, A. Pralle, E.Y. Isacoff, and C.J. Chang, "A selective, cell-permeable optical probe for hydrogen peroxide in living cells", J. Am. Chem. Soc. 2004, 126, 15392-15393.
M.C.Y. Chang, C.S. Yee, J. Stubbe, and D.G. Nocera, "Turning on ribonucleotide reductase by light-initiated radical generation", Proc. Natl. Acad. Sci. USA 2004, 101, 6882-6887.
C.J. Chang, M.C.Y. Chang, N.H. Damrauer, and D.G. Nocera, "Proton-coupled electron transfer: A unifying mechanism for biological charge transport, amino acid radical initiation and propagation, and bond making/breaking reactions of water and oxygen", Biochim. Biophys. Acta 2004, 1655, 13-28.
C.S. Yee, M.S. Seyedsayamdost, M.C.Y. Chang, D.G. Nocera, and J. Stubbe, "Generation of the R2 subunit of ribonucleotide reductase by intein chemistry: Insertion of 3-nitrotyrosine at residue 356 as a probe of the radical initiation process", Biochemistry 2003, 42, 14541-14552.
C.S. Yee, M.C.Y. Chang, J. Ge, D.G. Nocera, and J. Stubbe, "2,3-Difluorotyrosine at position 356 of ribonucleotide reductase R2: A probe of long-range proton-coupled electron transfer", J. Am. Chem. Soc. 2003, 125, 10506-10507.
J. Stubbe, D.G. Nocera, C.S. Yee, and M.C.Y. Chang, "Radical initiation in the class I ribonucleotide reductase: Long range proton-coupled electron transfer?", Chem. Rev. 2003, 103, 2167-21201.
M.C.Y. Chang, S.E. Miller, S.D. Carpenter, J. Stubbe, and D.G. Nocera, "Nanosecond generation of tyrosyl radicals via laser initiated decaging of oxalate-modified amino acids", J. Org. Chem. 2002, 67, 6820-6822.
C.J. Chang, J.D.K. Brown, M.C.Y. Chang, E.A. Baker, and D.G. Nocera. "Electron Transfer in Hydrogen-Bonded Donor-Acceptor Supramolecules", In Electron Transfer in Chemistry, V. Balzani Ed., Wiley-VCH, Weinheim, Germany, 2001, Vol. 3.2.4., p 409-461.
P.A. Sobecky, T.J. Mincer, M.C. Chang, A. Toukdarian and D.R. Helinski, "Isolation of broad-host-range replicons from marine sediment bacteria", Appl. Environ. Microbiol 1998, 64, 2822-2830.
P.A. Sobecky, T.J. Mincer, M.C. Chang, and D.R. Helinski. "Plasmids isolated from marine sediment microbial communities contain replication and incompatibility regions unrelated to those of known plasmid groups", Appl. Environ. Microbiol. 1997, 63, 888-895.