Wikipedia

John P. Richard

John P. Richard is a chemist and academic. He is a SUNY Distinguished Professor at the University at Buffalo.[1]

John P. Richard
Occupation(s)Chemist and academic
Academic background
EducationB.S., Biochemistry (1974)
Ph.D., Chemistry (1979)
Alma materOhio State University
Academic work
InstitutionsUniversity at Buffalo, SUNY

Richard has studied problems related to the mechanisms for organic reactions and their catalysis by enzymes, and has worked to test different theories to explain how enzymes achieve their rate accelerations.[2] He has edited or co-edited 17 books and has published more than 250 articles and book chapters on his research. He is the recipient of the numerous awards, including UB Sustained Achievement Award,[3] Jacob Schoellkopf Medal,[4][5] and NIH MIRA Award.[6]

Richard is a Fellow of the American Chemical Society (ACS),[7] and was Secretary of the ACS Division of Biological Chemistry from 2003 to 2008.

Education and early career

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Richard earned his B.S. degree in biochemistry from The Ohio State University in 1974. He pursued his graduate studies at the same university, working with Perry A. Frey.[8] Following this, he served as a Postdoctoral Fellow with William Jencks at Brandeis University from 1979 to 1982.[5]

Career

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Richard began his academic career in 1985 as an assistant professor in the University of Kentucky, where he was promoted to associate professor in 1990. In 1993, he joined the University at Buffalo, SUNY as an associate professor. He was promoted to Professor in 1995 and to SUNY Distinguished Professor in 2019.[1]

Richard served as the co-chair for GRC on Enzymes, Coenzymes & Metabolic Pathways in 2006,[9] the Chair of the GRC on Isotopes in Biological & Chemical Sciences in 2010,[10] and the co-chair of the Winter Enzyme Mechanisms Conference in 2011.[5] He was a member of the Organizing Committee for Reaction Mechanisms VII (2005), the 12th Kyushu International Symposium on Physical Organic Chemistry (2009), and the Winter Enzyme Mechanisms Conferences in 2015 and 2017.[11]

Research

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Richard has conducted parallel studies on the mechanisms for organic reactions in aqueous solution and at enzyme active sites in order to define the root causes for enzymatic rate accelerations. The focus of many of these studies has been on the characterization of the lifetimes and thermodynamic stability for carbocation and carbanion intermediates of organic reactions in water and the determination of the mechanisms for their stabilization by enzyme catalysts.[12][13]

Formation and stability of carbocations and carbanions in water

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Richard's postdoctoral work described the use of an azide anion clock to determine the lifetimes of carbocation intermediates of solvolysis reactions.[14] He showed that these lifetimes sometimes enforce the mechanisms for nucleophilic substitution at aliphatic carbon.[15][16][17] Richard and Amyes next reported novel methods for determination of the pKas of weak carbon acids in water,[18] and their application in the determination of the effect of a spectrum of organic functional groups on carbon acid pKa.[19] His work has focused on creating a model to rationalize the large effects of resonance electron-donating or accepting substituents on the lifetimes of carbocation and carbanion intermediates of organic reactions.[20][21]

Formation and stability of carbocations and carbanions at enzyme active sites

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Richard has worked to draw comparisons between the mechanisms for the formation of carbocations and carbanions in water and at enzyme active sites. His application of the azide ion clock to the characterization of the oxocarbocation intermediate of ß-galactosidase-catalyzed hydrolysis of lactose showed that the intermediate is stabilized by interactions with the protein catalyst.[22] His comparison of the pKas for the weakly acidic C-6 hydrogen of uridine monophosphate in water and at the active site of orotidine 5'-monophosphate decarboxylate demonstrated that there is a large stabilization of the UMP carbanion reaction intermediate by interactions with the protein catalyst.[23] This was one key result from studies to characterize the mechanism of action of an enzyme that operates at peak catalytic efficiency.[24] His investigations on the glycolytic enzyme triosephosphate isomerase revealed the mechanism by which the catalyst operates to increase the driving force for proton transfer from the enzyme-bound carbon acid to the protein.[25]

Bioorganic and bioinorganic reaction mechanisms

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Richard's investigations on the nonenzymatic isomerization and elimination reactions of triosephosphates have shed light on the origin of cellular methylglyoxal, a toxic compound that is neutralized by the action of glyoxalase I and II.[26] His work has led to the identification of novel nonenzymatic Claisen and aldol condensation reactions of pyridoxal cofactor analogs, and results from collaborative studies with Crugeiras and Rios provide a characterization of the kinetics and thermodynamics for proton transfer reactions at pyridoxal-amino acid adducts.[27] In collaboration with Richard Nagorski, it was demonstrated that Zn2+ catalyzes aldose-ketose isomerization through competing proton and hydride transfer mechanisms. This finding was predicted because the two mechanisms are followed by enzymes such as triosephosphate isomerase (proton transfer) and xylose isomerase (hydride transfer).[28] Alongside Janet Morrow, Richard investigated small molecule metal-ion catalysts of phosphate diester hydrolysis in work that characterized cooperativity in catalysis by binuclear complexes and demonstrated that these complexes achieve enzyme-like rate accelerations.[29]

Role of substrate-driven conformational changes in enzyme catalysis

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Richard and Amyes discovered that many enzyme-catalyzed reactions of phosphodianion truncated substrates are activated by phosphite dianion.[30][31] These enzymes utilize binding energy of the substrate phosphodianion to drive a change in protein conformation that traps the substrate at an active-site cage;[32] this is equivalent to the substrate-induced fits first described by Daniel Koshand.[33] The activating substrate-driven enzyme conformational changes result in the differential binding of enzymatic ground and transition states that is a required property of the most proficient enzyme catalysts.[34] This model has provided a simple rationalization for the activation of adenylate kinase-catalyzed phosphoryl group transfer from adenosine triphosphate to phosphite dianion by the substrate fragment adenosine,[35] as well as for the activation of formate dehydrogenase-catalyzed hydride transfer from formate to nicotinamide riboside by the substrate fragment ADP.[36] The latter finding confirmed a proposal by W. P. Jencks that evolution has produced cofactors composed of small reactive functionalities connected to larger nonreactive fragments that provide large intrinsic binding energies for stabilization of enzymatic transition states.[37]

Awards and honors

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  • 2003 – Walton Visitor Fellow, University College, Dublin, Ireland[12]
  • 2009 – Jacob Schoellkopf Medal, ACS Western New York Section[4]
  • 2014 – Fellow, American Chemical Society[7]
  • 2020 – MIRA Award, NIH[6]

Selected publications

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  • Richard, J. P. (1993). Mechanism for the formation of methylglyoxal from triosephosphates. Biochemical Society Transactions, 21(2), 549–553.
  • Iranzo, O., Kovalevsky, A. Y., Morrow, J. R., & Richard, J. P. (2003). Physical and kinetic analysis of the cooperative role of metal ions in catalysis of phosphodiester cleavage by a dinuclear Zn (II) complex. Journal of the American Chemical Society, 125(7), 1988–1993.
  • Amyes, T. L., Diver, S. T., Richard, J. P., Rivas, F. M., & Toth, K. (2004). Formation and stability of N-heterocyclic carbenes in water: the carbon acid p K a of imidazolium cations in aqueous solution. Journal of the American Chemical Society, 126(13), 4366–4374.
  • Richard, J. P. (2019). Protein flexibility and stiffness enable efficient enzymatic catalysis. Journal of the American Chemical Society, 141(8), 3320–3331.
  • Richard, J. P. (2022). Enabling role of ligand-driven conformational changes in enzyme evolution. Biochemistry, 61(15), 1533–1542.

References

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  1. ^ a b "Faculty Achievements". arts-sciences.buffalo.edu.
  2. ^ "John P. Richard". arts-sciences.buffalo.edu.
  3. ^ "Sustained Achievement Award". www.buffalo.edu.
  4. ^ a b "THE JACOB F. SCHOELLKOPF Medal 1931 -- 2019" (PDF).
  5. ^ a b c "UB Professor to Receive 2009 Schoellkopf Award". www.ubmd.com.
  6. ^ a b "UB chemist awarded $2 million NIH grant". arts-sciences.buffalo.edu.
  7. ^ a b "ACS Fellows". American Chemical Society.
  8. ^ "Chemistry Tree - Perry A. Frey". academictree.org.
  9. ^ "2006 Enzymes, Coenzymes and Metabolic Pathways Conference GRC". www.grc.org.
  10. ^ "2010 Isotopes in Biological and Chemical Sciences Conference GRC". www.grc.org.
  11. ^ "MEMORANDUM - March 20, 2019 - SUNY" (PDF).
  12. ^ a b "John P. Richard - Richard Research Group".
  13. ^ "John P. Richard". scholar.google.com.
  14. ^ Richard, John P.; Rothenberg, Marc E.; Jencks, William P. (March 5, 1984). "Formation and stability of ring-substituted 1-phenylethyl carbocations". Journal of the American Chemical Society. 106 (5): 1361–1372. doi:10.1021/ja00317a031 – via CrossRef.
  15. ^ Richard, John P.; Jencks, William P. (March 5, 1984). "Concerted bimolecular substitution reactions of 1-phenylethyl derivatives". Journal of the American Chemical Society. 106 (5): 1383–1396. doi:10.1021/ja00317a033 – via CrossRef.
  16. ^ Jencks, William P. (June 1, 1980). "When is an intermediate not an intermediate? Enforced mechanisms of general acid-base, catalyzed, carbocation, carbanion, and ligand exchange reaction". Accounts of Chemical Research. 13 (6): 161–169. doi:10.1021/ar50150a001 – via CrossRef.
  17. ^ Richard, John P. (February 6, 1995). "A consideration of the barrier for carbocation-nucleophile combination reactions". Tetrahedron. 51 (6): 1535–1573. doi:10.1016/0040-4020(94)01019-V – via ScienceDirect.
  18. ^ Amyes, Tina L.; Richard, John P. (December 5, 1992). "Generation and stability of a simple thiol ester enolate in aqueous solution". Journal of the American Chemical Society. 114 (26): 10297–10302. doi:10.1021/ja00052a028 – via CrossRef.
  19. ^ Amyes, Tina L.; Richard, John P. (July 5, 2017). "Substituent Effects on Carbon Acidity in Aqueous Solution and at Enzyme Active Sites". Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry. 28 (12): 2407–2421. doi:10.1055/s-0036-1588778. PMC 5630183. PMID 28993718.
  20. ^ Richard, J. P.; Amyes, T. L.; Toteva, M. M. (December 5, 2001). "Formation and stability of carbocations and carbanions in water and intrinsic barriers to their reactions". Accounts of Chemical Research. 34 (12): 981–988. doi:10.1021/ar0000556. PMID 11747416 – via PubMed.
  21. ^ Richard, J. P.; Amyes, T. L.; Williams, K. B. (October 30, 1998). "Intrinsic barriers to the formation and reaction of carbocations". Pure and Applied Chemistry. 70 (10): 2007–2014. doi:10.1351/pac199870102007.
  22. ^ Richard, J. P.; Huber, R. E.; Heo, C.; Amyes, T. L.; Lin, S. (September 24, 1996). "Structure-reactivity relationships for beta-galactosidase (Escherichia coli, lac Z). 4. Mechanism for reaction of nucleophiles with the galactosyl-enzyme intermediates of E461G and E461Q beta-galactosidases". Biochemistry. 35 (38): 12387–12401. doi:10.1021/bi961029b. PMID 8823174 – via PubMed.
  23. ^ Tsang, Wing-Yin; Wood, B. McKay; Wong, Freeman M.; Wu, Weiming; Gerlt, John A.; Amyes, Tina L.; Richard, John P. (September 5, 2012). "Proton transfer from C-6 of uridine 5'-monophosphate catalyzed by orotidine 5'-monophosphate decarboxylase: formation and stability of a vinyl carbanion intermediate and the effect of a 5-fluoro substituent". Journal of the American Chemical Society. 134 (35): 14580–14594. doi:10.1021/ja3058474. PMC 3434256. PMID 22812629.
  24. ^ Richard, John P.; Amyes, Tina L.; Reyes, Archie C. (April 17, 2018). "Orotidine 5'-Monophosphate Decarboxylase: Probing the Limits of the Possible for Enzyme Catalysis". Accounts of Chemical Research. 51 (4): 960–969. doi:10.1021/acs.accounts.8b00059. PMC 6016548. PMID 29595949.
  25. ^ Zhai, Xiang; Reinhardt, Christopher J.; Malabanan, M. Merced; Amyes, Tina L.; Richard, John P. (July 5, 2018). "Enzyme Architecture: Amino Acid Side-Chains That Function To Optimize the Basicity of the Active Site Glutamate of Triosephosphate Isomerase". Journal of the American Chemical Society. 140 (26): 8277–8286. doi:10.1021/jacs.8b04367. PMC 6037162. PMID 29862813.
  26. ^ Richard, J. P. (May 5, 1993). "Mechanism for the formation of methylglyoxal from triosephosphates". Biochemical Society Transactions. 21 (2): 549–553. doi:10.1042/bst0210549. PMID 8359530 – via PubMed.
  27. ^ Richard, John P; Amyes, Tina L; Crugeiras, Juan; Rios, Ana (October 1, 2009). "Pyridoxal 5′-phosphate: electrophilic catalyst extraordinaire". Current Opinion in Chemical Biology. 13 (4): 475–483. doi:10.1016/j.cbpa.2009.06.023. PMC 2749917. PMID 19640775.
  28. ^ Nagorski, R. W.; Richard, J. P. (February 7, 2001). "Mechanistic imperatives for aldose-ketose isomerization in water: specific, general base- and metal ion-catalyzed isomerization of glyceraldehyde with proton and hydride transfer". Journal of the American Chemical Society. 123 (5): 794–802. doi:10.1021/ja003433a. PMID 11456612 – via PubMed.
  29. ^ Morrow, Janet R.; Amyes, Tina L.; Richard, John P. (April 1, 2008). "Phosphate Binding Energy and Catalysis by Small and Large Molecules". Accounts of Chemical Research. 41 (4): 539–548. doi:10.1021/ar7002013. PMC 2652674. PMID 18293941.
  30. ^ Fernandez, Patrick L.; Nagorski, Richard W.; Cristobal, Judith R.; Amyes, Tina L.; Richard, John P. (February 24, 2021). "Phosphodianion Activation of Enzymes for Catalysis of Central Metabolic Reactions". Journal of the American Chemical Society. 143 (7): 2694–2698. doi:10.1021/jacs.0c13423. PMC 7919737. PMID 33560827.
  31. ^ Richard, John P. (August 2, 2022). "Enabling Role of Ligand-Driven Conformational Changes in Enzyme Evolution". Biochemistry. 61 (15): 1533–1542. doi:10.1021/acs.biochem.2c00178. PMC 9354746. PMID 35829700.
  32. ^ Richard, John P. (February 27, 2019). "Protein Flexibility and Stiffness Enable Efficient Enzymatic Catalysis". Journal of the American Chemical Society. 141 (8): 3320–3331. doi:10.1021/jacs.8b10836. PMC 6396832. PMID 30703322.
  33. ^ Koshland, D. E. (February 5, 1958). "Application of a Theory of Enzyme Specificity to Protein Synthesis". Proceedings of the National Academy of Sciences of the United States of America. 44 (2): 98–104. Bibcode:1958PNAS...44...98K. doi:10.1073/pnas.44.2.98. PMC 335371. PMID 16590179.
  34. ^ Albery, W. J.; Knowles, J. R. (December 14, 1976). "Evolution of enzyme function and the development of catalytic efficiency". Biochemistry. 15 (25): 5631–5640. doi:10.1021/bi00670a032. PMID 999839 – via PubMed.
  35. ^ Fernandez, Patrick L.; Richard, John P. (December 6, 2022). "Adenylate Kinase-Catalyzed Reactions of AMP in Pieces: Specificity for Catalysis at the Nucleoside Activator and Dianion Catalytic Sites". Biochemistry. 61 (23): 2766–2775. doi:10.1021/acs.biochem.2c00531. PMC 9731266. PMID 36413937.
  36. ^ Cristobal, Judith R.; Nagorski, Richard W.; Richard, John P. (August 1, 2023). "Utilization of Cofactor Binding Energy for Enzyme Catalysis: Formate Dehydrogenase-Catalyzed Reactions of the Whole NAD Cofactor and Cofactor Pieces". Biochemistry. 62 (15): 2314–2324. doi:10.1021/acs.biochem.3c00290. PMC 10399567. PMID 37463347.
  37. ^ Jencks, William P. (January 5, 1975). "Binding Energy, Specificity, and Enzymic Catalysis: The Circe Effect". In Meister, Alton (ed.). Advances in Enzymology and Related Areas of Molecular Biology. Vol. 43. Wiley. pp. 219–410. doi:10.1002/9780470122884.ch4. ISBN 978-0-471-59178-8. PMID 892 – via CrossRef.


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