个人简介

Ph.D., Marquette University, 1975

研究领域

Biochemistry Bioorganic Chemistry Center for Structural Biology Chemical Biology VICB Mechanistic Enzymology

Structural And Mechanistic Enzymology Research efforts in Professor Armstrong's laboratory are embodied in three projects directed at elucidating the mechanisms of action of enzymes involved in the metabolism of foreign or xenobiotic molecules. These catalysts, known as detoxication enzymes, are essential components of any organism's ability to resist chemical insult. The first project is a study of glutathione transferases, a family of enzymes involved in the metabolism of electrophilic molecules such as expoxides, alkyl halides and a,b-unsaturated carbonyl compounds. From studies of the physical organic chemistry occurring in the active site, aspects of the kinetic, chemical, and stereochemical mechanisms of these enzymes have been elucidated. In addition, high-resolution three-dimensional structures of several glutathione transferases have been solved and are being used as a guide in the construction of chimeric or hybrid enzymes with altered catalytic properties. The functional properties of the mutant enzymes provide insight into the specific role of various amino acid residues in the region of the active site. The site-general and site-specific incorporation of unnatural amino acids into this enzyme is being investigated as a tool to refine our understanding of the mechanism of catalysis. Many detoxication enzymes are membrane-bound and pose unique problems for mechanistic analysis. In a second project two membrane-bound detoxication enzymes, enzymes epoxide hydrolase and UDP-glucuronosyltransferase are being investigated. Efficient expression systems are being developed for these enzymes to facilitate structural and mechanistic studies. The discovery that epoxide hydrolase proceeds via a covalent ester intermediate has aided in the identification of active site residues that participate in catalysis and has helped define the evolutionary relationship of this protein with other hydrolase enzymes. Microorganisms also have detoxication enzymes which allow them to use many organic compounds as energy sources or to resist the toxic effect of antibiotics. This later phenomenon contributes to the erosion of the efficacy of clinically useful antibiotics and represents a serious human health problem. The objectives of the third research project are to elucidate the catalytic mechanisms and structures of enzymes involved in the resistance of microorganisms to the antibiotic fosfomycin. These objectives include, (i) the construction of high-level expression systems for fosfomycin resistance proteins; (ii) elucidation of the catalytic mechanisms of the enzymes, by spectroscopic, steady state and pre-steady state kinetic techniques; and (iii) determination of the three-dimensional structures by X-ray crystallography. The information will provide a rational basis for the design of new drugs to counter antibiotic resistance.

近期论文

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Thompson MK, Keithly ME, Goodman MC, Hammer ND, Cook PD, Jagessar KL, Harp J, Skaar EP, Armstrong RN. Structure and Function of the Genomically Encoded Fosfomycin Resistance Enzyme, FosB, from Staphylococcus aureus. Biochemistry. 2014, 53 (4): 755-765. Benovic JL, Armstrong RN. Call for papers! A special thematic compilation/special issue crossover with ACS Chemical Biology, ACS Medicinal Chemistry Letters, and the Journal of Medicinal Chemistry focused on new frontiers in kinases. Biochemistry. 2014, 53 (11): 1723. Mashiyama ST, Malabanan MM, Akiva E, Bhosle R, Branch MC, Hillerich B, Jagessar K, Kim J, Patskovsky Y,Seidel RD, Stead M, Toro R, Vetting MW, Almo SC, Babbitt PC. Large-Scale Determination of Sequence, Structure, and Function Relationships in Cytosolic Glutathione Transferases across the Biosphere. PLoS Biology. 2014, 12 (4): e1001843. Dong GQ, Calhoun S, Fan H, Kalyanaraman C, Branch MC, Mashiyama ST, London N, Jacobson MP, Babbitt PC, Shoichet BK, Armstrong RN, Sali A. Prediction of substrates for glutathione transferases by covalent docking. Journal of chemical information and modeling. 2014, 54 (6): 1687-99. Thompson MK, Keithly ME, Harp J, Cook PD, Jagessar KL, Sulikowski GA, Armstrong RN, Sali A. Structural and chemical aspects of resistance to the antibiotic fosfomycin conferred by FosB from Bacillus cereus. Biochemistry. 2013, 52 (41): 7350-62. Del Rey M, O'Hagan K, Dellett M, Aibar S, Colyer HA, Alonso ME, Díez-Campelo M, Armstrong RN, Sharpe DJ, Gutiérrez NC, García JL, De Las Rivas J, Mills KI, Hernández-Rivas JM. Genome-wide profiling of methylation identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes. Leukemia. 2013, 27 (3): 610-8. Pettigrew KA, Armstrong RN, Colyer HA, Zhang SD, Rea IM, Jones RE, Baird DM, Mills KI. Differential TERT promoter methylation and response to 5-aza-2'-deoxycytidine in acute myeloid leukemia cell lines: TERT expression, telomerase activity, telomere length, and cell death. Genes, chromosomes & cancer. 2012, 51 (8): 768-80. Preininger AM, Kaya AI, Gilbert JA, Busenlehner LS, Armstrong RN, Hamm HE. Myristoylation Exerts Direct and Allosteric Effects on G alpha Conformation and Dynamics in Solution. Pharmazeutische Industrie. 2012, 74 (2): 1911-1924. Prage EB, Morgenstern R, Jakobsson PJ, Stec DF, Voehler MW, Armstrong RN. Observation of Two Modes of Inhibition of Human Microsomal Prostaglandin E Synthase 1 by the Cyclopentenone 15-Deoxy-Delta(12,14)-prostaglandin J(2). Biochemistry. 2012, 51 (11): 2348-2356. Gerlt JA, Allen KN, Almo SC, Armstrong RN, Babbitt PC, Cronan JE, Dunaway-Mariano D, Imker HJ, Jacobson MP, Minor W, Poulter CD, Raushel FM, Sali A, Shoichet BK, Sweedler JV. The Enzyme Function Initiative. Biochemistry. 2011, 50 (46): 9950-9962. Prage EB, Pawelzik SC, Busenlehner LS, Kim K, Morgenstern R, Jakobsson PJ, Armstrong RN. Structure Location of Inhibitor Binding Sites in the Human Inducible Prostaglandin E Synthase, MPGES1. Biochemistry. 2011, 50 (35): 7684-93.