Associate Professor, Medicinal Chemistry
Department of Pharmaceutical Sciences
College of Pharmacy
Oregon State University
203 Pharmacy Building
Corvallis, OR 97331-3507
Phone: 541-737-5776
Phil.Proteau@oregonstate.edu
University of Utah, NIH Postdoctoral Fellow, 1994–1995
Postdoctoral Research Associate, 1993–1994
Oregon State University, Ph.D., 1993
California Institute of Technology, M.S., 1989
University of Washington, B.S., 1985
Two main research projects are being pursued in Philip Proteau's laboratory. One involves the study of the methylerythritol phosphate (non-mevalonate) pathway to isoprenoids, a target for new antimalarial and antibacterial agents, and the other seeks to explore the chemistry, enzymology and genetics of diterpene antibiotic biosynthesis. These projects incorporate a blend of organic synthesis, spectroscopy, enzymology and molecular biology.
The methyerythritol phosphate (MEP) pathway to isoprenoid metabolites has been shown to be present in numerous bacteria, higher plants, algae and in the malarial parasite Plasmodium falciparum. Unlike the classical mevalonate pathway in which the 5-carbon building block of terpenes, isopentenyl diphosphate (IPP), is derived from three acetate groups, IPP is synthesized from pyruvate and glyceraldehyde-3-phosphate in the MEP pathway. These two precursors condense to give the five-carbon sugar 1-deoxyxylulose-5-phosphate. Deoxyxylulose 5-phosphate is then converted to IPP in six additional steps. We have mainly studied the second enzyme in the pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase, from the cyanobacterium Synechocystis sp. PCC6803, examining aspects of stereochemistry of the reaction, as well as characterizing mutants and inhibitors of the enzyme. Long term goals are to design and synthesize inhibitors of the pathway as potential new antibacterials, antimalarials or herbicides.
In addition to the research on the early steps of isoprenoid biosynthesis, we also have an interest in the biosynthesis of bioactive diterpenoids. Nature has many ways to cyclize geranylgeranyl diphosphate (GGPP), the universal precursor to diterpenes, to form the core scaffolds of a variety of bioactive natural products. Our aim is to discover the diterpene synthases that cyclize GGPP and attempt to understand the structural features of these enzymes that allow the formation of specific diterpene products.
Additional projects in Philip Proteau’s laboratory include the biosynthesis of phytol and tocopherols in Euglena gracilis by a unique biosynthetic pathway; the assessment of cardioactive principles in Hawthorn extract, a collaborative project with Theresa Filtz (Oregon State University); and an investigation of scytonemin biosynthesis in cyanobacteria in collaboration with Bill Gerwick (U.C. San Diego) and Richard Castenholz (U. Oregon).
Long SR, Carey RA, Crofoot KM, Proteau PJ, Filtz TM. Effect of Hawthorn (Crataegus oxycantha) Crude Extract and Chromatographic Fractions on Multiple Activities in a Cultured Cardiomyocyte Assay. Phytomedicine. 2006;13:643-650.
Woo Y-H, Fernandes RPM, Proteau PJ. Evaluation of Fosmidomycin Analogs as Inhibitors of the Synechocystis sp. PCC6803 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase. Bioorganic & Medicinal Chemistry. 2006;14:2375-2385.
Fernandes RPM, Proteau PJ. Kinetic Characterization of Synechocystis sp. PCC6803 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase Mutants. Biochimica et Biophysica Acta. 2006;1764:223-229.
Fernandes RPM, Phaosiri C, Proteau PJ. Mutation in the Flexible Loop of 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase Broadens Substrate Utilization. Archives of Biochemistry and Biophysics. 2005;444:159-164.
Mac Sweeney A, Lange R, Fernandes RPM, Schulz H, Dale GE, Douangamath A, Proteau PJ, Oefner C. The Crystal Structure of E. coli 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase in a Ternary Complex with the Antimalarial Compound Fosmidomycin and NADPH Reveals a Tight-binding Closed Enzyme Conformation. Journal of Molecular Biololgy. 2005;345:115-127.
Proteau PJ. 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase: An Overview. Bioorganic Chemistry. 2004;32:483-493.
Phaosiri C, Proteau PJ. Substrate Analogs for the Investigation of Deoxyxylulose 5-Phosphate Reductoisomerase Inhibition: Synthesis and Evaluation. Bioorganic & Medicinal Chemistry Letters. 2004;14:5309-5312.
Kim D, Filtz MR, Proteau PJ. The Methylerythritol Phosphate Pathway Contributes to Carotenoid – but Not Phytol Biosynthesis in Euglena gracilis. Journal of Natural Products. 2004;67:1067-1069.
Yin XH, Proteau PJ. Characterization of Native and Histidine-tagged Deoxyxylulose 5-Phosphate Reductoisomerase from the Cyanobacterium Synechocystis sp. PCC6803. Biochimica et Biophysica Acta. 2003;1652:75-81.
