Faculty Research Groups
Peter J. Tonge,
Professor
B.Sc., 1982, University of Birmingham, England
Ph.D., 1986, University of Birmingham, England
SERC-NATO Postdoctoral Research Fellowship, National Research Council Canada, 1986-1988
Alfred P. Sloan Research Fellowship, 2001
Phone: (631) 632-7907
Lab: (631) 632-5797
Fax: (631) 632-7934
Email:
Tonge Group Website
Recent News: Funding for Tuberculosis Program
Positions
Director of Infectious Disease Research, Insitute for Chemical Biology and Drug Discovery
Director of the Translational Experimental Therapeutics Laboratory, Stony Brook University School of Medicine
Member of the Graduate Programs in Biophysics, Biochemistry and Structural Biology, Molecular and Cellular Biology, Molecular Genetics and Microbiology, Molecular and Cellular Pharmacology
Chemical Biology, Enzymology and Spectroscopy
Research in the Tonge Group is focused on understanding how proteins control and modulate the properties of small molecule ligands. We are interested in understanding the fundamental aspects of enzyme catalysis and in determining how enzymes cause and stabilize charge rearrangement. Some of the enzymes we study are drug targets in pathogens such as Mycobacterium tuberculosis, Francisella tularensis, Burkholderia pseudomallei and methicillin-resistant Staphylococcus aureus (MRSA). We use mechanistic information to design and synthesize high affinity enzyme inhibitors that have long residence times on their targets based on the knowledge that drug-target residence time is a critcal factor for in vivo antibacterial activity (Lu and Tonge (2010) Curr. Opin. Chem. Biol. 14, 467-474). The long residence time inhibitors are also being used to image bacterial populations in humans using positron emission tomography (Liu et al. (2010) J. Med. Chem. 53, 2882-91). In addition to enzymes, we are also interested in understanding how fluorescent proteins, such as green fluorescent protein (GFP), control the formation and fluorescence of the embedded chromophore. Studies on GFP are now being extended to other light activated proteins such as AppA, a BLUF domain antirepressor from the photosynthetic bacterium Rhodobacter sphaeroides.
Fatty Acid Biosynthesis
Bacterial fatty acid biosynthesis is a validated target for drug discovery and our primary focus is on the enoyl reductase enzyme from this pathway (FabI). We hypothesize that high affinity inhibition of the FabI enzyme class is coupled to ordering of a loop of amino acids close to the active site slow onset inhibitors bind to the enzyme. Using structure-based approaches we developed a series of diphenyl ether inhibitors of InhA, the FabI enzyme from MTB. The most potent first generation compound has a Ki value of 1 nM for InhA and MIC90 values of 1-2 μg/mL against sensitive and INH resistant strains of MTB (Sullivan et al. (2006) ACS. Chem. Biol. 1, 43-53). Selected diphenyl ethers are also slow-onset nM inhibitors of the FabI enzyme from Francisella tularensis (ftuFabI), inhibit bacterial growth with MIC values of ~0.1 μg/ml and have antibacterial activity in an animal model of tularemia (Lu et al. (2009) ACS Chem. Biol. 4, 221-231). Importantly, the in vivo antibacterial activity of the compounds correlates with their residence time on the target rather than with their thermodynamic affinity for ftuFabI.
Future Directions
We are now expanding the chemical diversity of our compound libraries to improve the ADME properties of the inhibitors. This project requires close collaboration between compound design and synthesis, and studies involving pharmacokinetics, pharmacodynamics and compound evaluation in animal models of TB infection. In addition, we are focusing our efforts to probe interactions within the cell that are critical for enzyme and inhibitor activity. This will involve mass spectrometry and the dissection of protein-protein interactions using chemical tools. We are also expanding our inhibitor discovery efforts to other enzymes and we plan to screen focused chemical libraries using transferred NOE NMR spectroscopy to obtain inter-ligand NOEs.
β-Ketoacyl-ACP Synthases
We are extending our antibacterial discovery efforts to other targets in the FAS-II pathway including the β-ketoacyl-ACP synthases that catalyze the Claisen condensation of malonyl-ACP with the growing fatty acid. We have demonstrated that the natural product thiolactomycin (TLM) is a slow-onset inhibitor of KasA, the β-ketoacyl-AcpM synthase in the M. tuberculosis FAS-II pathway (Machutta et al. (2010) J. Biol. Chem. 285, 6161-9). TLM binds more tightly to the acyl-enzyme intermediate formed during the Claisen condensation catalyzed by KasA. We have determined X-ray structures of KasA-TLM inhibitor complexes and have elucidated the structural basis for the very long chain substrate specificity of the enzyme. This information is being used to rationally design novel TLM analogues with improved antibacterial activity. We are also using interligand NOE NMR to drive the fragment-based assembly of novel inhibitors.
Menaquinone Biosynthesis
Menaquinone (MK) is the sole quinone in the mycobacterial electron transport chain. Enzymes involved in MK biosynthesis are promising drug targets since the pathway is absent in humans and also because compounds that affect respiration may be active against latent MTB populations. We have initiated a coordinated series of activities to investigate the importance of this pathway including cloning, expressing and characterizing the putative TB men enzymes, as well as studying MK biosynthesis using mass spectrometry to follow the incorporation of isotopically labeled precursors into MK.
Light Activated Proteins
Interests in utilizing spectroscopic methods to elucidate the precisedetails of enzyme catalyzed reactions have expanded in several directions. The ability of enzymes to promote catalysis through noncovalent interactions has important parallels with the control of photophysical properties exerted by the green fluorescent protein on the embedded chromophore. Since optical and structural events in GFP occur on a very fast time scale following light absorption, our steady state vibrational methods have been supplemented with ultrafast time resolved infrared spectroscopy (TRIR). A highlight of this work was the use of TRIR to obtain direct proof that the excited state proton transfer (ESPT) reaction in GFP results in the protonation of a glutamate close to the chromophore (Stoner-Ma et al. (2005) J. Am. Chem. Soc., 127, 2864-5).
Time resolved studies on GFP are now being expanded to other light activated molecules including the BLUF (Blue Light Receptor Using FAD) protein AppA, an antirepressor from Rhodobacter sphaeroides. Light absorption by the AppA flavin chromophore causes subtle changes in chromophore-protein interactions that result in dissociation of AppA from the transcriptional repressor PpsR and the subsequent down regulation of photosystem biosynthesis. Using TRIR we are studying how formation of the FAD excitation causes structural changes to the protein matrix that are thought to include rotation of a glutamine side chain that is hydrogen bonded to the chromophore (Stelling et al. (2007) J. Am. Chem. Soc., 129, 15556-64).
Publications
2011
1. Liu, N., Cummings, A.J., England, K., Slayden, R.A.. and Tonge, P.J. (2011) J. Antimicrob. Chemother. in press. Mechanism and Inhibition of the FabI Enoyl-ACP Reductase from Burkholderia pseudomallei. Medline
2. Zhang, Z., Zhou, R., Sauder, J.M., Tonge, P.J., Burley, S.K. and Swaminathan, S. (2011) J. Mol. Biol. accepted. Structural and Functional Studies of Fatty Acyl-Adenylate Ligases from E. coli and L. pneumophila. Medline
2010
3. Kumar, K., Awasthi, D., Lee, S.Y., Zanardi, I., Ruzsicska, B., Knudson, S., Tonge, P.J., Slayden, R.A. and Ojima, I. (2010) J. Med. Chem. [Epub]. Novel trisubstituted benzimidazoles, targeting FtsZ, as a new class of antitubercular agents. Medline
4. Lu, H. and Tonge, P.J. (2010) Curr. Opin. Chem. Biol. 14, 467-474. Drug-target residence time: critical information for lead optimization. Medline
5. Li, X., Liu, N., Zhang, H., Knudson, S.E., Slayden, R.A. and Tonge, P.J. (2010) Bioorg. Med. Chem. Lett. 20, 6306-9. Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: novel antibacterial agents against Mycobacterium tuberculosis. Medline
6. Liu, L., Xu, Y., Shea, C., Fowler, J.S., Hooker, J.M. and Tonge, P.J. (2010) J. Med. Chem. 53, 2882-91. Radiosynthesis and Bioimaging of the Tuberculosis Chemotherapeutics Isoniazid, Rifampicin and Pyrazinamide in Baboons. Medline
7. Luckner, S.R., Liu, N., am Ende, C.W., Tonge, P.J. and Kisker C. (2010) J. Biol. Chem. Epub. A slow tight-binding inhibitor of InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis. Medline
8. Lu, H. and Tonge, P.J. (2010) Biochemistry 49, 1281-9. Mechanism and Inhibition of the FabV Enoyl-ACP Reductase from Burkholderia Mallei. Medline
9. Machutta, C.A., Reddy, B.G., Luckner, S.R., Kapilashrami, K., Ruzsicska, B., Simmerling, C., Kisker, C. and Tonge, P.J. (2010) J. Biol. Chem. 285, 6161-9. Slow onset inhibition of bacterial β-ketoacyl-ACP synthases by thiolactomycin. Medline
10. Kondo, M, Heisler, .IA., Stoner-Ma, D., Tonge, P.J. and Meech, S.R. (2010) J. Am Chem. Soc. 132, 1452-3. Ultrafast dynamics of protein proton transfer on short hydrogen bond potential energy surfaces: S65T/H148D GFP. Medline
2009
11. England, K., am Ende, C.W., Lu, H., Sullivan, T.J., Marlenee, N., Bowen, R.A., Knudson, S.E., Knudson, D.L., Tonge, P.J. and Slayden, R.A. (2009) J. Antimicrob. Chemother. 64, 1052-61. Substituted diphenyl ethers as a broad-spectrum platform for the development of chemotherapeutics for the treatment of tularaemia. Medline
12. Kinnings, S.L., Liu, N., Buchmeier, N., Tonge, P.J., Xie, L. and Bourne, P.E. (2009) PLoS Comput. Biol. 5, e1000423. Drug discovery using chemical systems biology: repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis. Medline
13. Luckner, S.R., Machutta, C.A., Tonge, P.J. and Kisker, C. (2009) Structure, 17, 1004-1013. Crystal Structures of Mycobacterium tuberculosisKasA Show Mode of Action within Cell Wall Biosynthesis and its Inhibition by Thiolactomycin. Medline
14. Lu, H. H., England, K., am Ende, C.W. Truglio, J.J., Luckner, S., Marlenee, N., Knudson, S.E., Knudson, D.L., Bowen, R.A., Kisker, C, Slayden, R.A. and Tonge, P.J. (2009) ACS Chem. Biol. 4, 221-231. Slow-Onset Inhibition of the FabI Enoyl Reductase from Francisella Tularensis: Residence Time and In Vivo Activity. Medline
2008
15. Lu, X., Zhang, H., Tonge, P.J. and Tan, D.S. (2008) Bioorg. Med. Chem. Lett. 18, 5963-5966. Mechanism-based inhibitors of MenE, an acyl-CoA synthetase involved in bacterial menaquinone biosynthesis. Medline
16. Kruh, N. A., Borgaro, J., Ruzsicska, B. P., Xu, H. and Tonge, P. J. (2008) J. Biol. Chem. 283, 31719-31725. A novel interaction linking the FAS-II and PDIM biosynthetic pathways.Medline
17. Respicio, L., Nair, P.A., Huang Q., Anil, B., Tracz, S., Truglio, J.J., Kisker, C., Raleigh, D.P., Ojima, I., Knudson, D.L., Tonge, P.J. and Slayden, R.A. (2008) Tuberculosis, 88, 420-429. High Content Multiple Feature Transcriptional Profile of Inhibition of Septum Formation inMycobacterium tuberculosisfor Use in Novel Drug Discovery. Medline
18. Karioti, A. Skaltsa, H., Zhang, X., Tonge, P.J., Perozzo, R., Kaiser, M., Franzblau, S.G., Tasdemir, D. (2008) Phytomedicine,15, 1125-1129. Inhibition of Enoyl-ACP Reductase (FabI) Across Pathogenic Microorganisms by Linear Sesquiterpene Lactones from Anthemis auriculata. Medline
19. Am Ende, C.W., Knudson, S.E., Liu, N., Childs, J., Sullivan, T.J., Boyne, M., Xu, H., Knudson, D.L., Johnson, F., Peloquin, C.A., Slayden, R.A., Tonge, P.J. (2008) Bioorg. Med. Chem. Lett.18, 3029-3033.Synthesis and in vitro anti-mycobacterial activity of B-ring modified diaryl ether InhA inhibitors. Medline
20. Malo, G.D., Wang, M., Wu, D., Stelling, A.L., Tonge, P.J. and Wachter R.M. (2008) J. Mol. Biol. 378, 869-84. Crystal Structure and Raman Studies of dsFP483, a Cyan Fluorescent Protein from Discosoma striata. Medline
21. Xu, H., Sullican, T.J., Sekiguchi, J., Kirikae, T., Ojima, I., Stratton, C.F., Mao, W., Rock, F.L., Alley, M.R., Johnson, F., Walker, S.G. and Tonge, P.J. (2008) Biochemistry, 47, 4228-36. Mechanism and Inhibition of saFabI, the Enoyl Reductase from Staphylococcus aureus.Medline
22. Stoner-Ma, D., Jaye, A.A., Ronayne, K. L., Nappa, J., Tonge, P.J. and Meech, S.R. (2008) Chem. Phys.350, 193-2000. Ultrafast Electronic and Vibrational Dynamics of Stabilized A State Mutants of the Green Fluorescent Protein (GFP): Snipping the Proton Wire. Medline
23. Stoner-Ma, D., Jaye, A.A., Ronayne, K. L., Nappa, J., Meech, S.R. and Tonge, P.J. (2008) J. Am. Chem. Soc.130,1227-35. An Alternate Proton Acceptor for Excited State Proton Transfer in Green Fluorescent Protein: Rewiring GFP.Medline
24. Lu, H. and Tonge, P.J. (2008) Acc. Chem. Res.41, 11-20. Inhibitors of FabI, an Enzyme Drug Target in the Bacterial Fatty Acid Biosynthesis Pathway. Medline
2007
25. Stelling, A., Ronayne, K. L., Nappa, J., Tonge, P.J. and Meech, S.R. (2007) J. Am. Chem. Soc. 129, 15556-64. Ultrafast Structural Dynamics in BLUF Domains: Transient Infrared Spectroscopy of AppA and its Mutants.
26. Tasdemir, D.; Topaloglu, B.; Perozzo, R.; Brun, R.; O'Neill, R.; Carballeira, N. M.; Zhang, X.; Tonge, P. J.; Linden, A.; Ruedi, P. (2007) Bioorg. Med. Chem. 15, 6834-45. Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli. Medline
27. Boyne, M. E.; Sullivan, T. J.; Amende, C. W.; Lu, H.; Gruppo, V.; Heaslip, D.; Amin, A. G.; Chatterjee, D.; Lenaerts, A.; Tonge, P. J.; Slayden, R. A. (2007) Antimicrob. Agents Chemother. 51, 3562-7. Targeting Fatty Acid Biosynthesis for the Development of Novel Chemotherapeutics against Mycobacterium tuberculosis: Evaluation of A-Ring-Modified Diphenyl Ethers as High-Affinity Inha Inhibitors. Medline
28. Kruh, N. A.; Rawat, R.; Ruzsicska, B. P.; Tonge, P. J. (2007) Protein Sci. 16, 1617-27. Probing mechanisms of resistance to the tuberculosis drug isoniazid: Conformational changes caused by inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis. Medline
29. Bonnac, L.; Gao, G. Y.; Chena, L.; Felczaka, K.; Bennetta, E. M.; Xub, H.; Kim, T. S.; Liu, N.; Oh, H. W.; Tonge, P. J.; Pankiewicz, K. W. (2007) Bioorg. Med. Chem. Lett. 17, 4588-91. Synthesis of 4-phenoxybenzamide adenine dinucleotide as NAD analogue with inhibitory activity against enoyl-ACP reductase (InhA) of Mycobacterium tuberculosis. Medline
30. Bell, A. F.; Stratton, C. F.; Zhang, X.; Novichenok, P.; Jaye, A. A.; Nair, P. A.; Parikh, S.; Rawat, R.; Tonge, P. J. (2007) J. Am. Chem. Soc. 129, 6425-31. Evidence from Raman spectroscopy that InhA, the mycobacterial enoyl reductase, modulates the conformation of the NADH cofactor to promote catalysis. Medline
31. Tonge, P.J., Kisker, C., and Slayden, R.A. (2006) Current Topics in Medicinal Chemistry, 7, 489-98 . Development of Modern InhA Inhibitors to Combat Drug Resistant Strains of Mycobacterium tuberculosis . Medline
32. Huang, Q., Tonge, P.J. Slayden, R.A., Kirikae, T. and Ojima, I. (2006) Current Topics in Medicinal Chemistry, 7, 527-43 . FtsZ, a Novel Target for Anti-TB Drug Discovery. Medline
33. Kolappan, S. Zwahlen, J., Zhou, R., Truglio, J., Tonge, P.J. and Kisker, C. (2007) Biochemistry 46, 946-53. . Lysine 190 is the Catalytic Base in MenF, the Menaquinone-Specific Isochorismate Synthase from E. Coli: Implications for an Enzyme Family. Medline
34. Zwahlen, J., Kolappan, S., Zhou, R., Kisker, C. and Tonge, P.J. (2007) Biochemistry 46, 954-64 . Structure and Mechanism of MbtI, the Salicylate Synthase from Mycobacterium tuberculosis. Medline
2006
35. Kondo, M.; Nappa, J.; Ronayne, K. L.; Stelling, A. L.; Tonge, P. J.; Meech, S. R. (2006) J. Phys. Chem. B. 110, 20107-10 . Ultrafast Vibrational Spectroscopy of the Flavin Chromophore. Medline
36. Stoner-Ma, D.; Melief, E. H.; Nappa, J.; Ronayne, K. L.; Tonge, P. J.; Meech, S. R. (2006) J. Phys. Chem. B. 110, 22009-18 . Proton Relay Reaction in Green Fluorescent Protein (GFP): Polarization-Resolved Ultrafast Vibrational Spectroscopy of Isotopically Edited GFP. Medline
37. Rafi, S., Novichenok, P., Kolappan, S., Zhang, X., Stratton, C.F., Rawat, R., Kisker, C., Simmerling, C. and Tonge, P.J. (2006) J. Biol. Chem. 281, 39285-93 . Structure of Acyl Carrier Protein Bound to FabI, the FASII Enoyl Reductase from Escherichia coli. Medline
38. Huang, Q., Kirikae, F., Kirikiae, T., Pepe, A., Amina, A., Respicio, L., Slayden, R.A., Tonge, P.J. and Ojima, I. (2006) J. Med. Chem. 49, 463-6. Targeting FtsZ for Antituberculosis Drug Discovery: Noncytotoxic Taxanes as Novel Antituberculosis Agents. Medline
39. Jaye, A.A., Stoner-Ma, D., Matousek, P., Towrie, M., Tonge, P.J. and Meech, S.R. (2006) Photochem. Photobiol. 82, 373-9. Time Resolved Emission Spectra of the Green Fluorescent Protein. Medline
40. Sullivan, T.J., Truglio, J.J., Boyne, M.E., Novichenok, P., Zhang, X., Stratton, C.F., Li, H-J., Kaur, T., Amin, A., Johnson, F., Slayden, R.A., Kisker, C. and Tonge, P.J. (2006) ACS Chemical Biology, 1, 43-53. High Affinity InhA Inhibitors With Activity Against Drug Resistant Strains of Mycobacterium Tuberculosis. Medline
41. Callahan, B.P., Bell, A.F., Tonge, P.J. and Wolfenden, R. (2006) Bioorganic Chemistry, 34, 59-65. A Raman-active competitive inhibitor of OMP decarboxylase. Medline
42. Rafi, S., Cui, G., Song, K., Tonge, P.J. and Simmerling, C. (2006) J. Med. Chem. 49, 4574-80. Predicting the Binding Affinity of Triclosan and Three Triclosan Analogs for FabI, the E. Coli Enoyl Reductase, Using MM-PBSA Calculations. Medline
2005
43. Stoner-Ma, D., Jaye, A.A., Matousek, P., Towrie, M., Meech, S.R. and Tonge, P.J. (2005) J. Am. Chem. Soc. 127, 2864-5. Observation of Excited State Proton Transfer in Green Fluorescent Protein Using Ultrafast Vibrational Spectroscopy. Medline
44. Wu, J., Bell, A.F. and Tonge, P.J. (2005) J. Am. Chem. Soc. 127, 8424-32. Ring Current Effects in the Active Site of Medium-Chain Acyl-CoA Dehydrogenase Revealed by NMR Spectroscopy. Medline
45. Doll, C., Bell, A.F., Power, N., Tonge, P.J. and Tipton, P.A. (2005) Biochemistry 44, 11440-6. Procatalytic Ligand Strain. Ionization and Perturbation of 8-Nitroxanthine at the Urate Oxidase Active Site. Medline
46. Carlisle-Moore, L., Gordon, C.R., Machutta, C.A., Miller, W.T. and Tonge, P.J. (2005) J. Biol. Chem. 280, 42612-8. Substrate recognition by the human fatty acid synthase. Medline
2004
47. Vengris, m., van Stokkum, I.H.M., He, X., Bell, A.F., Tonge, P.J., van Grondelle, R. and Larsen, D.S. (2004) J. Phys. Chem. A. 108, 4587-4598. Ultrafast Excited and Ground-State Dynamics of the Green Fluorescent Protein Chromophore in Solution.
48. Sivaraman, S., Sullivan, T., Johnson, F., Novichenok, P., Cui, G., Simmerling, C. and Tonge, P.J. (2004) J. Med. Chem., 47, 509-518.Inhibition of the Bacterial Enoyl Reductase FabI by Triclosan: A Structure-Reactivity Analysis of FabI Inhibition by Triclosan Analogs. Medline
2003
49. Rawat, R., Whitty, A. and Tonge, P.J. (2003) Proc. Natl. Acad. Sci. U.S.A., 100, 13881-13886. The Isoniazid-NAD Adduct is a Slow, Tight-Binding Inhibitor of InhA, the Mycobacterium Tuberculosis Enoyl Reductase; Adduct Affinity and Drug Resistance. Medline
50. Boye, S., Nielsen, S.B., Krogh, H., Nielsen, I.B., Pedersen, U.V., Bell, A.F., He X, Tonge, P.J.and Andersen, L.H. (2003) Phys. Chem. Chem. Phys., 5, 3021-3026. Gas-Phase Absorption Properties of DsRed Model Chromophores
51. Wu,J., Bell, A. F., Luo, L., Stephens, A.W., Stankovich, M. T. and Tonge,P.J. (2003) Biochemistry, 42, 11846-11856. Probing Hydrogen Bonding Interactions in the Active Site of Medium-Chain Acyl-CoA Dehydrogenase using Raman Spectroscopy. Medline
52. Truglio, J.J., Theis, K., Feng, Y., Gajda, R., Machutta, C., Tonge, P.J. and Kisker, C. (2003) J. Biol. Chem., 278, 42352-42360. Crystal Structure of Mycobacterium tuberculosis MenB, a Key Enzyme in Vitamin K2 Biosynthesis. Medline
53. Sivaraman, S., Hedstrom, L. and Tonge, P.J.+ (2003) Biochemistry, 42, 4406-13. Structure-Activity Studies of the Inhibition of FabI, the Enoyl Reductase from Escherichia coli, by Triclosan: Kinetic Analysis of Mutant FabIs. Medline
54. Bell, A.F., Stoner-Ma, D., Wachter, R.M. and Tonge, P.J.+ (2003) J. Am. Chem. Soc. 125, 6919-6926. Light Driven Decarboxylation of Wild-type Green Fluorescent Protein. Medline
55. He, X., Bell, A.F. and Tonge, P.J.+ (2003) FEBS Lett. 549, 35-38. Ground state isomerization of a model green fluorescent protein chromophore. Medline.
56. Boye, S., Krogh, H., Nielsen, S.B., Pedersen, S.U., Pedersen, U.V., Andersen, L.H.+, Bell, A.F., He, X. and Tonge, P.J. (2003) Phys. Rev. Lett. 90, 118103. Vibrationally resolved photoabsorption spectroscopy of red fluorescent protein chromophore anions. Medline.
2002
57. Bell, A.F., Feng, Y., Hofstein, H.A., Parikh, S., Wu, J., Rudolph, M.J., Kisker, C., Whitty, A. and Tonge, P.J. (2002) Chemistry & Biology, 9, 1247-1255. Stereoselectivity of Enoyl-CoA Hydratase Results from Preferential Activation of One of Two Bound Substrate Conformers. Medline
58. Feng, Y., Hofstein, H.A., Zwahlen, J. and Tonge, P.J. (2002) Biochemistry,41, 12883-90. Effect of Mutagenesis on the Stereochemistry of Enoyl-CoA Hydratase. Medline
59. He, X., Bell, A.F. and Tonge, P.J. (2002) Organic Letters, 4, 1523-1526. Synthesis and Spectroscopic Studies of Model Red Fluorescent Protein Chromophores. Medline.
60. He, X., Bell, A.F. and Tonge, P.J. (2002) J. Phys. Chem ., B106, 6056-6066. Isotopic Labeling and Normal Mode Analysis of a Model Green Fluorescent Protein Chromophore.
2001
61. Bell, A.F., Wu, J., Feng, Y. and Tonge, P.J. (2001) Biochemistry, 40, 1725-1733. Involvement of G141 in substrate activation by enoyl-CoA hydratase. Medline.
62. Dai, M., Feng, Y. and Tonge, P.J. (2001) J. Am. Chem. Soc., 123, 506-507. Synthesis of crotonyl-oxyCoA: A mechanistic probe of the reaction catalyzed by enoyl-CoA hydratase. Medline.
63. Bell, A.F., He, X., Ridge, J.P., Hanson, G.R., McEwan, A.G. and Tonge, P.J. (2001) Biochemistry, 40, 440-448. Active site heterogeneity in DMSO Reductase from Rhodobacter capsulatus revealed by Raman spectroscopy. Medline
2000
64. Pellett, J.D., Sabaj, K.M., Stephens, A.W., Bell, A.F., Wu, J., Tonge, P.J. and Stankovich, M.T. (2000) Biochemistry, 39, 13982-13992. Medium-Chain Acyl-Coenzyme A Dehydrogenase Bound to a Product Analogue, Hexadienoyl-Coenzyme A: Effects on Reduction Potential, pKa, and Polarization. Medline.
65. Gawlita, E., Lantz, M., Paneth, P., Bell, A.F., Tonge, P.J. and Anderson, V.E. (2000) J. Am. Chem. Soc., 122, 11660-11669. H-Bonding in Alcohols Is Reflected in the C-H Bond Strength: Variation of C-D Vibrational Frequency and Fractionation Factor
66. Parikh, S.L., Xiao, G. and Tonge, P.J. (2000) Biochemistry, 39, 7645-7650. Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid. Medline.
67. Wu, W., Feng, Y., He, X., Hofstein, H.S., Raleigh, D.P. and Tonge, P.J. (2000) J. Am. Chem. Soc. 122, 3987-3994. Stereospecificity of the reaction catalyzed by enoyl-CoA hydratase.
68. Bell, A.F., Xiang, H., Wachter, R.M. and Tonge, P.J. (2000) Biochemistry, 39, 4423-4431. Probing the ground state structure of the green fluorescent protein chromophore using Raman spectroscopy. Medline.
69. Tonge, P.J. (2000) Nat. Struct. Biol., 7, 94-96. Another brick in the wall. Medline.
70. Rudik, I., Bell, A.F., Tonge, P.J. and Thorpe, C. (2000) Biochemistry, 39, 92-101. 4-Hydroxycinnamoyl-CoA: An ionizable probe of the active site of acyl-CoA dehydrogenase. Medline.
1999
71. Stankovich, M.T., Sabaj, K.M. and Tonge, P.J. (1999) Arch. Biochem. Biophys., 370, 16-21. Structure/function of medium chain acyl-CoA dehydrogenase: The importance of substrate polarization.
72. Parikh, S., Moynihan, D.P., Xiao, G. and Tonge, P.J. (1999) Biochemistry, 38, 13623-13634. Roles of tyrosine 158 and lysine 165 in the catalytic mechanism of InhA, the enoyl-ACP reductase from Mycobacterium Tuberculosis. Medline.
73. Hofstein, H.S., Feng, Y., Anderson, V.E. and Tonge, P.J. (1999) Biochemistry, 38, 9508-9516. Role of glutamate 144 and glutamate 164 in the catalytic mechanism of enoyl-CoA hydratase. Medline.
74. Stewart, M., Parikh, S., Xiao, G., Tonge, P.J. and Kisker, C. (1999) J. Mol. Biol.,290, 859-865. Structural basis for the mechanism of action of triclosan. Medline.
1998
75. Wu, W-J., Tonge, P.J. and Raleigh, D.P. (1998) J. Am. Chem. Soc., 120, 9988-9994. Stereospecific 1H and 13C NMR assignments of crotonyl-coenzyme A and hexadienoyl-coenzyme A: conformational analysis and comparison with protein:CoA complexes.
1997
76. Tonge, P.J., Carey, P.R. and Fausto, R . (1997) J. Chem. Soc. Faraday Trans., 93, 3619-3625. Molecular structure of S-ethyl thioacrylate. Combined vibrational spectroscopic and ab initio SCF-MO study.
77. Clarkson, J., Tonge, P.J., Taylor, K.L., Dunaway-Mariano, D. and Carey, P.R. (1997) Biochemistry, 36, 10192-10199. A Raman study of the polarizing forces promoting catalysis in 4-chlorobenzoate-CoA dehalogenase.
78. Wu, W-J., Anderson, V.E., Raleigh, D.P. and Tonge, P.J. (1997) Biochemistry, 36, 2211-2220. Structure of hexadienoyl-CoA bound to enoyl-CoA hydratase determined by transferred NOE measurements: mechanistic predictions based on the X-ray structure of 4-chlorobenzoyl-CoA dehalogenase. Medline.
1996
79. P opov, S., Dubrovsky, L., Lee, M-A., Pennathur, S., Haffer, O., Al-Abed, Y., Tonge, P.J., Ulrich, P., Rexach, M., Blobel, G., Cerami, A.C. and Bukrinsky, M. (1996) Proc. Natl. Acad. Sci. USA, 93, 11859-11864. Critical role of reverse transcriptase in the inhibitory mechanism of CNI-H0294 on HIV-1 nuclear translocation
80. Doran, J.D., Tonge, P.J., Mort, J.S. and Carey, P.R. (1996) Biochemistry, 35, 12487-12494. Deacylation and reacylation for a series of acyl cysteine proteases, including acyl groups derived from novel chromophoric substrates.
81. Tonge, P.J., Fausto, R. and Carey, P.R. (1996) J. Mol. Struct., 379, 135-142. FTIR studies of hydrogen bonding between a ,b -unsaturated esters and alcohols.
82. Moore A.N.J, Vakos H, Neville T.A.M, Tonge P.J., Arya P, Burton G.W. (1996) Biotechnology Techniques, 10, 523-528. A quick method for purifying bile salt-activated lipases.
1995
83. Tonge, P.J., Anderson, V.E., Fausto, R., Kim, M., Pusztai-Carey, M. and Carey, P.R. (1995) Biospectroscopy, 1, 387-394. Localized electron polarization in a substrate analog binding to the active site of enoyl-CoA hydratase: Raman spectroscopic and conformational analyses of rotamers of hexadienoyl thiolesters.
84. Doran, J.D., Tonge, P.J., Carey, P.R. and Arya, P. (1995) Bioorganic and Medicinal Chemistry Letters, 5, 2381-2384. Synthesis of chromophoric dipeptides as substrates for papain.
85. Taylor, K.L., Liu, R.Q., Liang, P.H., Price, J., Dunaway-Mariano, D., Tonge, P.J., Clarkson, J. and Carey, P.R. (1995) Biochemistry, 34, 13881-13888. Evidence for electrophilic catalysis in the 4-chlorobenzoyl-CoA dehalogenase reaction: UV, Raman and 13C-NMR spectral studies of dehalogenase complexes of benzoyl-CoA adducts.
86. Carey, P.R. and Tonge, P.J. (1995) Acc. Chem. Res., 28, 8-13. Unlocking the secrets of enzyme power using Raman spectroscopy.
1994
87. Fausto, R., Tonge, P.J. and Carey, P.R. (1994) J. Chem. Soc. Faraday Trans., 90, 3491-3503. Molecular structures of cis- and trans-S-ethyl thiocrotonate.
88. D'Ordine, R.L., Bahnson, B.J., Tonge, P.J. and Anderson, V.E. (1994) Biochemistry, 33, 14733-14742. Enoyl-CoA hydratase catalyzed exchange of the a -protons of CoA thiolesters: A model for an enolized intermediate in the enzyme catalyzed elimination?
89. D'Ordine, R.L., Tonge, P.J., Carey, P.R. and Anderson, V.E. (1994) Biochemistry, 33, 12635-12643. Electronic rearrangement induced by substrate analog binding to the enoyl-CoA hydratase active site: Evidence for substrate activation.
90. Doran, J.D., Tonge, P.J., Kim, M. and Carey, P.R. (1994) Photochemistry and Photobiology, 60, 432-434. Facile characterization of the spectra of cis and trans photoisomers in a mixture of acyl-enzymes by raman difference spectroscopy.
91. Fausto, R., Martins, A.G., Teixeira-Dias, J.J.C., Tonge, P.J. and Carey, P.R. (1994) J. Phys. Chem. 98, 3592-3596. Rotational isomerism in CH3CH2C(=S)SR (R=CH3, C2H5): a combined vibrational spectroscopic and ab initio study.
92. Fausto, R., Teixeira-Dias, J.J.C., Tonge, P.J. and Carey, P.R. (1994) J. Mol. Struct. 324, 113-122. Rotational isomers of N-(b -phenylpropionyl)alanine ethyl dithioester: a Raman spectroscopic and MO study.
93. Fausto, R., Martins, A.G., Teixeira-Dias, J.J.C., Tonge, P.J. and Carey, P.R. (1994) J. Mol. Struct. 323, 59-69. Rotational isomerism in CH3C(=S)SCH3 and CH3(C=S)SC2H5: a combined vibrational spectroscopic and ab initio study.
1993
94. Tonge, P.J., Carey, P.R., Callender, R., Deng, H., Ekiel, I. and Muhandiram, D.D. (1993) J. Am. Chem. Soc. 115, 8757-8762. Characterization of trans and cis-5-methylthienylacryloylchymotrypsin using Raman difference spectroscopy, NMR and kinetics: Carbonyl environment and reactivity.
95. Tonge, P.J. and Carey, P.R. (1993) Advances in Spectroscopy 20, 129-161. Biomolecular Spectroscopy Part A, ed. Clark, R.J.H. and Hester, R.E. Raman, resonance Raman and FTIR spectroscopic studies of enzyme-substrate complexes.
96. Curtis, R.D., Tonge, P.J., Smith, I.C.P. and Jarrell, H.C. (1993) J. Magn. Reson. 102A, 110-113. DePakeing of dipolar-chemical shift NMR spectra.
1992
97. Tonge, P.J, and Carey, P.R. (1992) Biochemistry 31, 9122-9125. Forces, bond lengths and reactivity; fundamental insight into the mechanism of enzyme catalysis.
98. Tonge, P.J., Carey, P.R. and Anderson V.E. (1992) J. Am. Chem. Soc. 114, 8738-8739. Multiple forms of acetyldithio-coenzyme A binding to citrate synthase; resonance Raman evidence.
99. Tonge, P.J., Gour-Salin, B., Lachance, P., Storer, A.C. and Carey, P.R. (1992) Biophys. J. 63, 191-196. Resonance Raman spectroscopic and kinetic consequences of a nitrogen-sulphur enzyme-substrate contact in a series of dithioacylpapains.
1991
100. Tonge, P.J., Pusztai, M., White, A.J., Wharton, C.W. and Carey, P.R. (1991) Biochemistry 30, 4790-4795. Resonance Raman and FTIR spectroscopic studies of the acyl carbonyl group in [3-(5-Methyl-2-thienyl)acryloyl]-chymotrypsin: evidence for artifacts in the spectra obtained by both techniques.
101. Tonge, P.J., Menard, R., Storer, A.C., Ruzsicska, B.P. and Carey, P.R. (1991) J. Am. Chem. Soc. 113, 4297-4303. Markedly different acyl-papain structures deacylate at similar rates: Resonance Raman spectroscopic and kinetic evidence.
1990
102. Tonge, P.J. and Carey, P.R. (1990) Biochemistry 29, 10723-10727. Length of the acyl carbonyl bond in acyl-serine proteases correlates with reactivity.
103. Carey, P.R. and Tonge. P.J. (1990) Chem. Soc. Rev. 19, 97-120. Chemistry of enzyme-substrate complexes revealed by resonance Raman spectroscopy.
1989
104. Tonge, P.J. and Carey, P.R. (1989) Biochemistry 28, 6701-6709. Direct observation of the titration of substrate carbonyl groups in the active site of a-chymotrypsin by resonance Raman spectroscopy.
105. Tonge, P.J., Lee, H., Sans Cartier, L.R., Ruzsicska, B.P. and Carey, P.R. (1989) J. Am. Chem. Soc. 111, 1496-1497. Striking changes observed in key acyl-enzyme linkages by resonance Raman experiments near 77 K.
106. Sans Cartier, L.R., Tonge, P.J. and Carey, P.R. (1989) Indian Journal of Physics. 63, 5170-5179. Resonance Raman studies of enzyme-substrate intermediates at cryogenic temperatures: construction of a cryostat-based U.V. resonance Raman system.
107. Tonge, P.J. and Carey, P.R. (1989) J. Mol. Liquids. 42, 195-212. Resonance Raman and absorption spectroscopic characterization of the chemically engineered enzyme thiolsubtilisin: comparison with a natural thiolenzyme.
108. Tonge, P.J., Moore, G.R. and Wharton, C.W. (1989) Biochem. J. 258, 599-605. Fourier-Transform infra-red studies of the alkaline isomerization of mitochondrial cytochrome c and the ionization of carboxylic acids.
1985
109. Tonge, P.J. and Wharton, C.W. (1985) Biochem. Soc. Trans. 13, 929-930. Observation of carbonyl stretch vibrations in acyl-chymotrypsins by using Fourier-Transform infra-red spectroscopy.
110. Tonge, P.J., Wharton, C.W., Szawelski, R.J., Killough, P.M. and Hester, R.E. (1985) Biochem. Soc. Trans. 13, 930-931. Ultra-violet resonance Raman spectroscopy of a highly specific acyl-papain.
