Qi-Zhuang Ye, Ph.D.
Associate Professor
Department of Biochemistry and Molecular Biology
Indiana University School of Medicine
John D. Van Nuys Medical Science Building
635 Barnhill Drive, Room 1007G
Indianapolis, Indiana 46202-5126
Phone: (317) 278-0304
Facsimile: (317) 274-4686
E-mail: yeq@iupui.edu
Dr. Ye's Web Site
B.S. in Pharmaceutical Sciences, 1982, Nanjing College of Pharmacy, Nanjing, Jiangsu, China
Ph.D. in Medicinal Chemistry, 1988, University of Kansas, Lawrence, Kansas
Post Doc. in Biochemistry, 1988-1990, Harvard Medical School, Boston, Massachusetts
Area of Study
Proteases and Protein Phosphatases: Enzyme Catalysis and Inhibition, Protein Structure and Function, and Drug Discovery. More details...
Recent Publications
Chai SC, Wang WL, Ding DR, Ye QZ* (2011) Growth inhibition of Escherichia coli and methicillin-resistant Staphylococcus aureus by targeting cellular methionine aminopeptidase, Eur J Med Chem, in press.
Yuan H, Chai SC, Lam CK, Xu HH, Ye QZ* (2011) Two methionine aminopeptidases from Acinetobacter baumannii are functional enzymes, Bioorg Med Chem Lett, in press.
Lu JP, Yuan XH, Yuan H, Wang WL, Wan B, Franzblau SG, Ye QZ* (2011) Inhibition of Mycobacterium tuberculosis methionine aminopeptidases by bengamide derivatives, ChemMedChem, in press.
Lu JP, Ye QZ* (2010) Expression and characterization of Mycobacterium tuberculosis methionine aminopeptidase type 1a, Bioorg Med Chem Lett, 20, 2776-9.
Chai SC, Ye QZ* (2010) A cell-based assay that targets methionine aminopeptidase in a physiologically relevant environment, Bioorg Med Chem Lett, 20, 2129-32.
Lu JP, Chai SC, Ye QZ* (2010) Catalysis and inhibition of Mycobacterium tuberculosis methionine aminopeptidase, J Med Chem, 53, 1329-37.
Chai SC, Ye QZ* (2009) Analysis of the stoichiometric metal activation of methionine aminopeptidase, BMC Biochemistry, 10, 32.
Chai SC, Lu JP, Ye QZ* (2009) Determination of binding affinity of metal cofactor to the active site of methionine aminopeptidase based on quantitation of functional enzyme, Anal Biochem, 395, 263-4.
Chai SC, Ye QZ* (2009) Metal-mediated inhibition is a viable approach for inhibiting cellular methionine aminopeptidase, Bioorg Med Chem Lett, 19, 6862-4.
Zhao Y,Bacher A, Illarionov B, Fischer M, Georg G, Ye QZ, Fanwick PE, Franzblau SG, Wan B, Cushman M* (2009) Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis, J Org Chem, 74, 5297-303.
Talukdar A, Breen M, Bacher A, Illarionov B, Fischer M, Georg G, Ye QZ, Cushman M* (2009) Discovery and development of a small molecule library with lumazine synthase inhibitory activity, J Org Chem, 74, 5123-34.
Wang WL, Chai SC, Ye QZ* (2009) Synthesis and structure-function analysis of Fe(II)-form-selective antibacterial inhibitors of Escherichia coli methionine aminopeptidase, Bioorg Med Chem Lett, 19, 1080-3.
Chai SC, Wang WL, Ye QZ* (2008) Fe(II) is the native cofactor for Escherichia coli methionine aminopeptidase, J Biol Chem, 283, 26879-85.
Wang WL, Chai SC, Huang M, He HZ, Hurley TD, Ye QZ* (2008) Discovery of inhibitors of Escherichia coli methionine aminopeptidase with the Fe(II)-form selectivity and antibacterial activity, J Med Chem, 51, 6110-20.
Vedantham P, Guerra JM, Schoenen F, Huang M, Gor PJ, Georg GI, Wang JL, Neuenswander B, Lushington GH, Mitscher LA, Ye QZ, Hanson PR* (2008) Ionic immobilization, diversification, and release: application to the generation of a library of methionine aminopeptidase inhibitors, J Comb Chem, 10, 185-94.
Vedantham P, Zhang M, Gor PJ, Huang M, Georg GI, Lushington GH, Mitscher LA, Ye QZ, Hanson PR* (2008) Studies towards the synthesis of methionine aminopeptidase inhibitors: diversification utilizing a ROMP-derived coupling reagent, J Comb Chem, 10, 195-203.
Ma ZQ, Xie SX, Huang QQ, Nan FJ, Hurley TD, Ye QZ* (2007) Structural analysis of inhibition of E. coli methionine aminopeptidase: implication of loop adaptability in selective inhibition of bacterial enzymes, BMC Struct Biol, 7, 84.
Huang M, Xie SX, Ma ZQ, Huang QQ, Nan FJ, Ye QZ* (2007) Inhibition of monometalated methionine aminopeptidase: inhibitor discovery and crystallographic analysis, J Med Chem, 50, 5735-5742.
Zhang Y, Illarionov B, Bacher A, Fischer M, Georg GI, Ye QZ, Velde DV, Fanwick PE, Song Y, Cushman M* (2007) A Novel Lumazine Synthase Inhibitor Derived from Oxidation of 1,3,6,8-Tetrahydroxy-2,7-naphthyridine to a Tetraazaperylenehexaone Derivative, J Org Chem, 72, 2769-76.
Galam L, Hadden MK, Ma Z, Ye QZ, Yun BG, Blagg BS, Matts RL* (2007) High-throughput assay for the identification of Hsp90 inhibitors based on Hsp90-dependent refolding of firefly luciferase, Bioorg Med Chem, 15, 1939-46.
Xie SX, Schalkhausser F, Ye QZ, Seifert R, Buschauer A* (2007) Effects of Impromidine- and Arpromidine-Derived Guanidines on Recombinant Human and Guinea Pig Histamine H(1) and H(2 )Receptors. Arch Pharm (Weinheim), 340, 9-16.
Ahn YM, Vogeti L, Liu CJ, Santhapuram HKR, White JM, Vasandani V, Mitscher LA, Lushington GH, Hanson PR, Powell DR, Himes RH, Roby KF, Ye QZ, Georg GI* (2007) Design, synthesis, and antiproliferative and CDK2-cyclin A inhibitory activity of novel flavopiridol analogues, Bioorg Med Chem, 15, 702-13.
Ye QZ,* Xie SX, Ma ZQ, Huang M, Hanzlik RP (2006) Structural basis of catalysis by monometalated methionine aminopeptidase, Proc Natl Acad Sci USA, 103, 9470-5.
Xie SX, Huang WJ, Ma ZQ, Huang M, Hanzlik RP, Ye QZ* (2006) Structural analysis of metalloform-selective inhibition of methionine aminopeptidase, Acta Crystallogr D Biol Crystallogr, 62, 425-32.
Huang M, Xie SX, Ma ZQ, Hanzlik RP, Ye QZ* (2006) Metal mediated inhibition of methionine aminopeptidase by quinolinyl sulfonamides, Biochem Biophys Res Commun, 339, 506-13.
Huang QQ, Huang M, Nan FJ,* Ye QZ* (2005) Metalloform-selective inhibition: Synthesis and structure-activity analysis of Mn(II)-form-selective inhibitors of Escherichia coli methionine aminopeptidase, Bioorg Med Chem Lett, 15, 5386-91.
Li JY, Chen LL, Cui YM, Luo QL, Gu M, Nan FJ,* Ye QZ* (2004) Characterization of full length and truncated type I human methionine aminopeptidases expressed from Escherichia coli, Biochemistry, 43, 7892-8.
Li JY, Cui YM, Chen LL, Gu M, Li J, Nan FJ,* Ye QZ* (2004) Mutations at the S1 sites of methionine aminopeptidases from Escherichia coli and Homo sapiens reveal the residues critical for substrate specificity, J Biol Chem, 279, 21128-34.
Ye QZ,* Xie SX, Huang M, Huang WJ, Lu JP, Ma ZQ (2004) Metalloform-selective inhibitors of E. coli methionine aminopeptidase and X-ray structure of a Mn(II)-form enzyme complexed with an inhibitor, J Am Chem Soc, 126, 13940-1.
Luo QL, Li JY, Liu ZY, Chen LL, Li J, Qian Z, Shen Q, Li Y, Lushington GH, Ye QZ,* Nan FJ* (2003) Discovery and structural modification of inhibitors of methionine aminopeptidases from Escherichia coli and Saccharomyces cerevisiae, J Med Chem, 46, 2631-40.
Li JY, Chen LL, Cui YM, Luo QL, Li J, Nan FJ,* Ye QZ* (2003) Specificity for inhibitors of metal-substituted methionine aminopeptidase, Biochem Biophys Res Commun, 307, 172-9.
Ye QZ,* Xie SX, Ma ZQ, Huang M, Hanzlik RP (2006) Structural basis of catalysis by monometalated methionine aminopeptidase, Proc Natl Acad Sci USA, 103, 9470-5.
Xie SX, Huang WJ, Ma ZQ, Huang M, Hanzlik RP, Ye QZ* (2006) Structural analysis of metalloform-selective inhibition of methionine aminopeptidase, Acta Crystallogr D Biol Crystallogr, 62, 425-32.
Huang M, Xie SX, Ma ZQ, Hanzlik RP, Ye QZ* (2006) Metal mediated inhibition of methionine aminopeptidase by quinolinyl sulfonamides, Biochem Biophys Res Commun, 339, 506-13.
Huang QQ, Huang M, Nan FJ,* Ye QZ* (2005) Metalloform-selective inhibition: Synthesis and structure-activity analysis of Mn(II)-form-selective inhibitors of Escherichia coli methionine aminopeptidase, Bioorg Med Chem Lett, 15, 5386-91.
Li JY, Chen LL, Cui YM, Luo QL, Gu M, Nan FJ,* Ye QZ* (2004) Characterization of full length and truncated type I human methionine aminopeptidases expressed from Escherichia coli, Biochemistry, 43, 7892-8.
Li JY, Cui YM, Chen LL, Gu M, Li J, Nan FJ,* Ye QZ* (2004) Mutations at the S1 sites of methionine aminopeptidases from Escherichia coli and Homo sapiens reveal the residues critical for substrate specificity, J Biol Chem, 279, 21128-34.
Ye QZ,* Xie SX, Huang M, Huang WJ, Lu JP, Ma ZQ (2004) Metalloform-selective inhibitors of E. coli methionine aminopeptidase and X-ray structure of a Mn(II)-form enzyme complexed with an inhibitor, J Am Chem Soc, 126, 13940-1.
Luo QL, Li JY, Liu ZY, Chen LL, Li J, Qian Z, Shen Q, Li Y, Lushington GH, Ye QZ,* Nan FJ* (2003) Discovery and structural modification of inhibitors of methionine aminopeptidases from Escherichia coli and Saccharomyces cerevisiae, J Med Chem, 46, 2631-40.
Li JY, Chen LL, Cui YM, Luo QL, Li J, Nan FJ,* Ye QZ* (2003) Specificity for inhibitors of metal-substituted methionine aminopeptidase, Biochem Biophys Res Commun, 307, 172-9.
* corresponding author
Research Interests
My research currently focuses on studying structure and function of methionine aminopeptidases (MetAPs). In the near future, the focus will be on these and other metallohydrolases that are important in human diseases. By discovering novel enzyme inhibitors and elucidating their mechanisms of inhibition, we are working toward the long-term goal of developing these inhibitors as effective antibacterial, antifungal and anticancer therapeutics. In addition to using standard approaches of biochemistry, medicinal chemistry and structural biology, I am especially interested in applying chemical biology and high throughput screening technologies to biomedical research.
MetAP is a metal-dependent enzyme that removes N-terminal methionine residue from nascent proteins in all types of cells. Prokaryotic cells express only one MetAP that is essential for survival. Therefore, MetAP is a target for developing novel broad-spectrum antibacterial agents. Eukaryotic cells have two subtypes of MetAP, and eukaryotic MetAPs are the targets of anticancer compounds like fumagillin analogs and bengamides. By high throughput screening, we identified several classes of novel MetAP inhibitors that are not only very potent but also highly selective for a specific MetAP enzyme with different metal at the active site. We call these inhibitors "metalloform-selective inhibitors". Based on the initial inhibitors from screening, derivatives were synthesized to understand the structure-activity relationship of these inhibitors. X-ray structures of enzyme-inhibitor complexes were solved to reveal the binding mode of these inhibitors. Understanding the metalloform selective inhibition and using these inhibitors as research tools to characterize the activity of cellular MetAPs are some of the crucial steps to obtain effective MetAP inhibitors for therapeutic applications.
