Research
The main research projects being pursued in Philip Proteau's laboratory involve various aspects of the chemistry and biosynthesis of natural products. All of these projects are collaborative in nature. One project is aimed at the discovery of novel bioactive compounds from Indonesian soil bacteria, a second focuses on the isolation and characterization of the cardioactive principles of hawthorn extract, and a third is focused on the chemistry, enzymology and genetics of diterpene antibiotic biosynthesis. These projects incorporate a blend of natural products chemistry, organic synthesis, spectroscopy, and enzymology.
A key effort is a joint project with Drs. Zabriskie and Mahmud in collaboration with Dr. Dwi Andreas Santosa from the Indonesian Center for Biodiversity and Biotechnology. Dr. Santosa has isolated numerous novel actinomycetes (soil bacteria) from the unique Black Water Ecosystem in Kalimantan, Indonesia and we at OSU culture these bacteria and screen their extracts for biological activity, mainly focusing on antibiotic action. Active extracts are then subjected to fractionation and ultimately isolation and structural elucidation of the active components.
The second project is in collaboration with a pharmacology colleague, Dr. Theresa Filtz. Hawthorn extracts (Crataegus spp.) have been used for centuries to treat mild heart conditions in Europe. Although hawthorn has been studied for many years, it is still unclear what components of the extract lead to the cardiotonic effects of hawthorn. Flavonoids and procyanidins have been used to standardize extracts, but the cardioactive actions of these components is uncertain. Dr. Filtz has developed a murine cardiomyocyte assay which is being used in a bioassay-guided fractionation of the extract to determine the cardioactive agents.
In an extension of our earlier work on the early steps of isoprenoid biosynthesis, we 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. This project is being pursued with Dr. Xihou Yin, who provides expertise in the molecular biology aspects of antibiotic biosynthesis.
An additional project is a collaborative effort with Dr. Kerry McPhail to synthesize bioactive compounds from marine cyanobacteria in order to sufficient quantities for further biological testing.
Selected Publications
Fotso, S, Zabriskie, TM, Proteau, PJ, Flatt, PM, Santosa, DA, Sulastri, Mahmud, T. Limazepines A–F, Pyrrolo[1,4]Benzodiazepine Antibiotics from an Indonesian Micrococcus sp. Journal of Natural Products. 2009. (accepted for publication)
Salehi, S, Long, SR, Proteau, PJ, Filtz, TM. Hawthorn (Crataegus monogyna Jacq.) extract exhibits atropine-sensitive activity in a cultured cardiomyocyte assay. Natural Medicines (Tokyo). 2009;6:1-8.
Fotso, S, Mahmud, T, Zabriskie, TM, Santosa, DA, Sulastri, Proteau, PJ. Rearranged and Unrearranged Angucyclinones from Indonesian Streptomyces spp. Journal of Antibiotics. 2008;61:449-456.
Fotso, S, Mahmud, T, Zabriskie, TM, Santosa, DA, Sulastri, Proteau, PJ. Angucyclinones from an Indonesian Streptomyces sp. Journal of Natural Products. 2008; 71:61-65.
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.
