Chemistry at Illinois University of Illinois at Urbana-Champaign

Robert M. Coates

Emeritus Professor of Chemistry

Professor Coates received his BS in Chemistry from Yale University in 1960 and his Ph.D. from the University of California-Berkeley in 1964. After postdoctoral research at Stanford University, he joined the faculty at Illinois. His major research interests lay in synthetic and mechanistic organic chemistry, natural products, and biosynthesis, focusing on the chemistry and biochemistry of isoprenoid compounds. His research group primarily engaged in synthesis and investigation of novel carbocyclic structures, isotope labeling for elucidation of stereochemistry, and inhibitors of key enzymes on the isoprenoid biosynthesis pathway.

Research

The research in our group is primarily concerned with the organic chemistry and biochemistry of isoprenoid compounds .

This natural product family is characterized by an amazing variety of chain and ring structures that originate from a few biosynthetic precursors; many of these compounds have important biological functions in plant and animal cells. The recent discovery of the non-mevalonate pathway for biosynthesis of critical isoprenoid constituents in bacteria and plants presents many new questions and significant research opportunities. A new asymmetric synthesis of 2-C-methylerythritol derivatives from benzylidene arabitol developed in our lab affords convenient access to labeled forms, novel analogues, and potential inhibitors.

One major goal is understanding the biosynthetic pathways and mechanisms of individual enzyme-catalyzed reactions which lead to the polyisoprenoid chains and cyclic structures. The transferases and cyclases responsible for terpene biosynthesis exhibit unusual catalytic activities and characteristic stereospecificities. Elucidation of stereochemical relationships and catalytic mechanisms relies on chemical synthesis of isotope-labeled substrates and intermediates, transition state inhibitors, and model compounds. In collaboration with biochemists at Washington State University, we have established that abietadiene synthase, the enzyme responsible for biosynthesis of abietane diterpene intermediates in conifer oleoresin production, has two active sites. The tricyclic structure and characteristic isopropyl group are formed at the second site by a stereospecific cyclization-rearrangement mechanism elucidated with the aid of isotope labeling, site-specific inhibitors, and intermediate analogs. Isotope labeling experiments with taxadiene synthase, which catalyzes the first committed step in the biosynthesis of the cancer chemotherapeutic agent taxol, have revealed the stereochemistry of the initial macrocyclization and the facial bias of the terminating elimination.

The biosynthesis of the sesquiterpene phytoalexin capsidiol by tobacco and green pepper plants involves cyclization of farnesyl diphosphate by epiaristolochene synthase followed by double hydroxylation of the hydrocarbon by epiaristolochene hydroxylase. We prepared a variety of novel eremophilanes by chemical transformations of capsidiol isolated from cellulase-elicited bell peppers. Kinetic studies by our collabor-ators at the University of Kentucky with these compounds as substrates and standards recently established that epiaristolochene is hydroxylated first at C-1 and then at C-3.

Other objectives of our research are the total or partial synthesis of biogenetically significant natural products, and development of methods for stereo-controlled construction of carbocyclic structures. In the course of studies on total synthesis of silphinane sesquiterpenes, we discovered a stereoselective Prins-type cyclization of , -unsaturated ketones. Another aspect is the design, synthesis, and evaluation of mechanism-based inhibitors of isoprenoid biosynthesis enzymes to illuminate transition states, to identify transient intermediates, and to serve as active site markers in protein crystallography. For example, synthetic aza analogs, i.e., protonated amines that resemble carbocation intermediates, have proven to be potent and selective inhibitors of terpene synthases and prenyl transferases. We utilize the experimental methods and concepts of structural, mechanistic, and synthetic organic chemistry to accomplish these objectives.

Publications

"Stereochemistry of the Macrocyclization and Elimination Steps in Taxadiene Biosynthesis through Deuterium Labeling," Q. W. Jin, D. C. Williams, M. Hezari, R. Croteau, and R. M. Coates, J. Org. Chem., 70, 4667-4675 (2005).

"Taxadiene Synthase-Catalyzed Cyclization of 6-Fluorogeranylgeranyl Diphosphate to 7-Fluoroverticillenes," Y. H. Jin, D. C. Williams, R. Croteau, and R. M. Coates, J. Am. Chem. Soc., 127, 7834-7842 (2005).

"Kinetic and Molecular Dissection of 5-Epi-Aristolochene-1,3-Dihydroxylase, a Cytochrome P450 Enzyme Catalyzing Successive Hydroxylations of Sesquiterpenes," S Takahashi, Y. Zhao, P. E. O' Maille, B. T. Greenhagen, J. P. Noel, R. M. Coates, J. Chappell, J. Biol. Chem, 280, 3686-3696 (2005).

"Molecular Recognition of the Substrate Diphosphate Group Governs Product Diversity in Trichodiene Synthase Mutants," L. S. Vedula, M. J. Rynkiewicz, H. J. Pyun, R. M. Coates, D. E. Cane, and D. W. Christianson, Biochemistry, 44, 6153-6163, (2005).

Awards

  • Eli Lilly Grantee
  • Alfred P. Sloan Fellowship
  • Guggenheim Fellowship
  • Fellow, AAAS
  • Fellow, Japan Society for the Promotion of Science

Highlights

Patents

Photo of Robert M. Coates