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Sub-ångström-resolution crystallography reveals physical distortions that enhance reactivity of a covalent enzymatic intermediate.

Lüdtke S, Neumann P, Erixon KM, Leeper F, Kluger R, Ficner R, Tittmann K
Nat Chem 5 762-7 (2013)
Related entries: 4kxu, 4kxw, 4kxx, 4kxy

Cited: 33 times
EuropePMC logo PMID: 23965678

Abstract

It is recognized widely that enzymes promote reactions by providing a pathway that proceeds through a transition state of lower energy. In principle, further rate enhancements could be achieved if intermediates are prevented from relaxing to their lowest energy state, and thereby reduce the barrier to the subsequent transition state. Here, we report sub-ångström-resolution crystal structures of genuine covalent reaction intermediates of transketolase. These structures reveal a pronounced out-of-plane distortion of over 20° for the covalent bond that links cofactor and substrate, and a specific elongation of the scissile substrate carbon-carbon bond (d > 1.6 Å). To achieve these distortions, the protein's conformation appears to prevent relaxation of a substrate-cofactor intermediate. The results implicate a reduced barrier to the subsequent step that is consistent with an intermediate of raised energy and leads to a more efficient overall process.

Articles - 4kxv mentioned but not cited (2)

  1. How the Destabilization of a Reaction Intermediate Affects Enzymatic Efficiency: The Case of Human Transketolase. Prejanò M, Medina FE, Ramos MJ, Russo N, Fernandes PA, Marino T. ACS Catal 10 2872-2881 (2020)
  2. QM/MM Study of Human Transketolase: Thiamine Diphosphate Activation Mechanism and Complete Catalytic Cycle. Nauton L, Hecquet L, Théry V. J Chem Inf Model 61 3502-3515 (2021)


Reviews citing this publication (5)

  1. Transition metal catalysis in confined spaces. Leenders SH, Gramage-Doria R, de Bruin B, Reek JN. Chem Soc Rev 44 433-448 (2015)
  2. Experimental observation of thiamin diphosphate-bound intermediates on enzymes and mechanistic information derived from these observations. Jordan F, Nemeria NS. Bioorg Chem 33 190-215 (2005)
  3. Sweet siblings with different faces: the mechanisms of FBP and F6P aldolase, transaldolase, transketolase and phosphoketolase revisited in light of recent structural data. Tittmann K. Bioorg Chem 57 263-280 (2014)
  4. Marvels of enzyme catalysis at true atomic resolution: distortions, bond elongations, hidden flips, protonation states and atom identities. Neumann P, Tittmann K. Curr Opin Struct Biol 29 122-133 (2014)
  5. Low barrier hydrogen bonds in protein structure and function. Kemp MT, Lewandowski EM, Chen Y. Biochim Biophys Acta Proteins Proteom 1869 140557 (2021)

Articles citing this publication (26)

  1. Akt phosphorylation and regulation of transketolase is a nodal point for amino acid control of purine synthesis. Saha A, Connelly S, Jiang J, Zhuang S, Amador DT, Phan T, Pilz RB, Boss GR. Mol Cell 55 264-276 (2014)
  2. A lysine-cysteine redox switch with an NOS bridge regulates enzyme function. Wensien M, von Pappenheim FR, Funk LM, Kloskowski P, Curth U, Diederichsen U, Uranga J, Ye J, Fang P, Pan KT, Urlaub H, Mata RA, Sautner V, Tittmann K. Nature 593 460-464 (2021)
  3. Low-barrier hydrogen bonds in enzyme cooperativity. Dai S, Funk LM, von Pappenheim FR, Sautner V, Paulikat M, Schröder B, Uranga J, Mata RA, Tittmann K. Nature 573 609-613 (2019)
  4. Substrate Distortion and the Catalytic Reaction Mechanism of 5-Carboxyvanillate Decarboxylase. Vladimirova A, Patskovsky Y, Fedorov AA, Bonanno JB, Fedorov EV, Toro R, Hillerich B, Seidel RD, Richards NG, Almo SC, Raushel FM. J Am Chem Soc 138 826-836 (2016)
  5. Validation of a homology model of Mycobacterium tuberculosis DXS: rationalization of observed activities of thiamine derivatives as potent inhibitors of two orthologues of DXS. Masini T, Lacy B, Monjas L, Hawksley D, de Voogd AR, Illarionov B, Iqbal A, Leeper FJ, Fischer M, Kontoyianni M, Hirsch AK. Org Biomol Chem 13 11263-11277 (2015)
  6. Enzymatic control of cycloadduct conformation ensures reversible 1,3-dipolar cycloaddition in a prFMN-dependent decarboxylase. Bailey SS, Payne KAP, Saaret A, Marshall SA, Gostimskaya I, Kosov I, Fisher K, Hay S, Leys D. Nat Chem 11 1049-1057 (2019)
  7. A thermostable transketolase evolved for aliphatic aldehyde acceptors. Yi D, Saravanan T, Devamani T, Charmantray F, Hecquet L, Fessner WD. Chem Commun (Camb) 51 480-483 (2015)
  8. Structural Views along the Mycobacterium tuberculosis MenD Reaction Pathway Illuminate Key Aspects of Thiamin Diphosphate-Dependent Enzyme Mechanisms. Jirgis EN, Bashiri G, Bulloch EM, Johnston JM, Baker EN. Structure 24 1167-1177 (2016)
  9. Tuning and Switching Enantioselectivity of Asymmetric Carboligation in an Enzyme through Mutational Analysis of a Single Hot Spot. Wechsler C, Meyer D, Loschonsky S, Funk LM, Neumann P, Ficner R, Brodhun F, Müller M, Tittmann K. Chembiochem 16 2580-2584 (2015)
  10. Heme-binding enables allosteric modulation in an ancient TIM-barrel glycosidase. Gamiz-Arco G, Gutierrez-Rus LI, Risso VA, Ibarra-Molero B, Hoshino Y, Petrović D, Justicia J, Cuerva JM, Romero-Rivera A, Seelig B, Gavira JA, Kamerlin SCL, Gaucher EA, Sanchez-Ruiz JM. Nat Commun 12 380 (2021)
  11. On the reliability of peptide nonplanarity seen in ultra-high resolution crystal structures. Brereton AE, Karplus PA. Protein Sci 25 926-932 (2016)
  12. The human transketolase-like proteins TKTL1 and TKTL2 are bona fide transketolases. Deshpande GP, Patterton HG, Faadiel Essop M. BMC Struct Biol 19 2 (2019)
  13. Gold(I)-catalysed synthesis of a furan analogue of thiamine pyrophosphate. Iqbal A, Sahraoui el-H, Leeper FJ. Beilstein J Org Chem 10 2580-2585 (2014)
  14. Mechanical insights of oxythiamine compound as potent inhibitor for human transketolase-like protein 1 (TKTL1 protein). Mariadasse R, Biswal J, Jayaprakash P, Rao GR, Choubey SK, Rajendran S, Jeyakanthan J. J Recept Signal Transduct Res 36 233-242 (2016)
  15. Structural basis for antibiotic action of the B1 antivitamin 2'-methoxy-thiamine. Rabe von Pappenheim F, Aldeghi M, Shome B, Begley T, de Groot BL, Tittmann K. Nat Chem Biol 16 1237-1245 (2020)
  16. Demystifying DPP III Catalyzed Peptide Hydrolysis-Computational Study of the Complete Catalytic Cycle of Human DPP III Catalyzed Tynorphin Hydrolysis. Tomić A, Tomić S. Int J Mol Sci 23 1858 (2022)
  17. Phage Display on the Anti-infective Target 1-Deoxy-d-xylulose-5-phosphate Synthase Leads to an Acceptor-Substrate Competitive Peptidic Inhibitor. Marcozzi A, Masini T, Zhu D, Pesce D, Illarionov B, Fischer M, Herrmann A, Hirsch AKH. Chembiochem 19 58-65 (2018)
  18. A 'Split-Gene' Transketolase From the Hyper-Thermophilic Bacterium Carboxydothermus hydrogenoformans: Structure and Biochemical Characterization. James P, Isupov MN, De Rose SA, Sayer C, Cole IS, Littlechild JA. Front Microbiol 11 592353 (2020)
  19. Assessing the Thiamine Diphosphate Dependent Pyruvate Dehydrogenase E1 Subunit for Carboligation Reactions with Aliphatic Ketoacids. Marsden SR, McMillan DGG, Hanefeld U. Int J Mol Sci 21 E8641 (2020)
  20. Evidence of Diradicals Involved in the Yeast Transketolase Catalyzed Keto-Transferring Reactions. Hsu NS, Wang YL, Lin KH, Chang CF, Ke SC, Lyu SY, Hsu LJ, Li YS, Chen SC, Wang KC, Li TL. Chembiochem 19 2395-2402 (2018)
  21. The Mesomeric Effect of Thiazolium on non-Kekulé Diradicals in Pichia stipitis Transketolase. Hsu NS, Wang YL, Lin KH, Chang CF, Lyu SY, Hsu LJ, Liu YC, Chang CY, Wu CJ, Li TL. Angew Chem Int Ed Engl 57 1802-1807 (2018)
  22. The Need for an Alternative to Radicals as the Cause of Fragmentation of a Thiamin-Derived Breslow Intermediate. Bielecki M, Kluger R. Angew Chem Int Ed Engl 56 6321-6323 (2017)
  23. Unravelling Enzymatic Features in a Supramolecular Iridium Catalyst by Computational Calculations. Tomasini M, Caporaso L, Trouvé J, Poater J, Gramage-Doria R, Poater A. Chemistry 28 e202201970 (2022)
  24. New Role of Water in Transketolase Catalysis. Solovjeva ON. Int J Mol Sci 24 2068 (2023)
  25. Normal mode analysis calculation for a full-atom model with a smaller number of degrees of freedom for huge protein molecules. Endo S, Wako H. Biophys Physicobiol 16 205-212 (2019)
  26. Search for Inhibitors of Mycobacterium tuberculosis Transketolase in a Series of Sulfo-Substituted Compounds. Gushchina IV, Nilov DK, Shcherbakova TA, Baldin SM, Švedas VK. Acta Naturae 15 81-83 (2023)


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