1li4 › Citations

Catalytic strategy of S-adenosyl-L-homocysteine hydrolase: transition-state stabilization and the avoidance of abortive reactions.

Yang X, Hu Y, Yin DH, Turner MA, Wang M, Borchardt RT, Howell PL, Kuczera K, Schowen RL
Biochemistry 42 1900-9 (2003)
Cited: 60 times
EuropePMC logo PMID: 12590576

Abstract

S-Adenosylhomocysteine hydrolase (AdoHcy hydrolase) crystallizes from solutions containing the intermediate analogue neplanocin A with the analogue bound in its 3'-keto form at the active sites of all of its four subunits and the four tightly bound cofactors in their reduced (NADH) state. The enzyme is in the closed conformation, which corresponds to the structure in which the catalytic chemistry occurs. Examination of the structure in the light of available, very detailed kinetic studies [Porter, D. J., Boyd, F. L. (1991) J. Biol. Chem. 266, 21616-21625. Porter, D. J., Boyd, F. L. (1992) J. Biol. Chem. 267, 3205-3213. Porter, D. J. (1998) J. Biol. Chem. 268, 66-73] suggests elements of the catalytic strategy of AdoHcy hydrolase for acceleration of the reversible conversion of AdoHcy to adenosine (Ado) and homocysteine (Hcy). The enzyme, each subunit of which possesses a substrate-binding domain that in the absence of substrate is in rapid motion relative to the tetrameric core of the enzyme, first binds substrate and ceases motion. Probably concurrently with oxidation of the substrate to its 3'-keto form, the closed active site is "sealed off" from the environment, as indicated by a large (10(8)(-)(9)-fold) reduction in the rate of departure of ligands, a feature that prevents exposure of the labile 3'-keto intermediates to the aqueous environment. Elimination of the 5'-substituent (Hcy in the hydrolytic direction, water in the synthetic direction) generates the central intermediate 4',5'-didehydro-5'-deoxy-3'-ketoadenosine. Abortive 3'-reduction of the central intermediate is prevented by a temporary suspension of all or part of the redox catalytic power of the enzyme during the existence of the central intermediate. The abortive reduction is 10(4)-fold slower than the productive reductions at the ends of the catalytic cycle and has a rate constant similar to those of nonenzymic intramolecular model reactions. The mechanism for suspending the redox catalytic power appears to be a conformationally induced increase in the distance across which hydride transfer must occur between cofactor and substrate, the responsible conformational change again being that which "seals" the active site. The crystal structure reveals a well-defined chain of three water molecules leading from the active site to the subunit surface, which may serve as a relay for proton exchange between solvent and active site in the closed form of the enzyme, permitting maintenance of active-site functional groups in catalytically suitable protonation states.

Reviews - 1li4 mentioned but not cited (2)

  1. S-adenosyl-L-homocysteine hydrolase and methylation disorders: yeast as a model system. Tehlivets O, Malanovic N, Visram M, Pavkov-Keller T, Keller W. Biochim Biophys Acta 1832 204-215 (2013)
  2. S-adenosyl-l-homocysteine Hydrolase: A Structural Perspective on the Enzyme with Two Rossmann-Fold Domains. Brzezinski K. Biomolecules 10 E1682 (2020)

Articles - 1li4 mentioned but not cited (20)

  1. Crystal structures of Mycobacterium tuberculosis S-adenosyl-L-homocysteine hydrolase in ternary complex with substrate and inhibitors. Reddy MC, Kuppan G, Shetty ND, Owen JL, Ioerger TR, Sacchettini JC. Protein Sci 17 2134-2144 (2008)
  2. Regulation of S-adenosylhomocysteine hydrolase by lysine acetylation. Wang Y, Kavran JM, Chen Z, Karukurichi KR, Leahy DJ, Cole PA. J Biol Chem 289 31361-31372 (2014)
  3. Structural insights into the reaction mechanism of S-adenosyl-L-homocysteine hydrolase. Kusakabe Y, Ishihara M, Umeda T, Kuroda D, Nakanishi M, Kitade Y, Gouda H, Nakamura KT, Tanaka N. Sci Rep 5 16641 (2015)
  4. A single mutation at Tyr143 of human S-adenosylhomocysteine hydrolase renders the enzyme thermosensitive and affects the oxidation state of bound cofactor nicotinamide-adenine dinucleotide. Beluzić R, Cuk M, Pavkov T, Fumić K, Barić I, Mudd SH, Jurak I, Vugrek O. Biochem J 400 245-253 (2006)
  5. High-resolution structures of complexes of plant S-adenosyl-L-homocysteine hydrolase (Lupinus luteus). Brzezinski K, Dauter Z, Jaskolski M. Acta Crystallogr D Biol Crystallogr 68 218-231 (2012)
  6. Purification, crystallization and preliminary crystallographic studies of plant S-adenosyl-L-homocysteine hydrolase (Lupinus luteus). Brzezinski K, Bujacz G, Jaskolski M. Acta Crystallogr Sect F Struct Biol Cryst Commun 64 671-673 (2008)
  7. Crystallographic and SAXS studies of S-adenosyl-l-homocysteine hydrolase from Bradyrhizobium elkanii. Manszewski T, Szpotkowski K, Jaskolski M. IUCrJ 4 271-282 (2017)
  8. Methylation deficiency disrupts biological rhythms from bacteria to humans. Fustin JM, Ye S, Rakers C, Kaneko K, Fukumoto K, Yamano M, Versteven M, Grünewald E, Cargill SJ, Tamai TK, Xu Y, Jabbur ML, Kojima R, Lamberti ML, Yoshioka-Kobayashi K, Whitmore D, Tammam S, Howell PL, Kageyama R, Matsuo T, Stanewsky R, Golombek DA, Johnson CH, Kakeya H, van Ooijen G, Okamura H. Commun Biol 3 211 (2020)
  9. The rationale for targeting the NAD/NADH cofactor binding site of parasitic S-adenosyl-L-homocysteine hydrolase for the design of anti-parasitic drugs. Cai S, Li QS, Fang J, Borchardt RT, Kuczera K, Middaugh CR, Schowen RL. Nucleosides Nucleotides Nucleic Acids 28 485-503 (2009)
  10. Metal-cation regulation of enzyme dynamics is a key factor influencing the activity of S-adenosyl-L-homocysteine hydrolase from Pseudomonas aeruginosa. Czyrko J, Sliwiak J, Imiolczyk B, Gdaniec Z, Jaskolski M, Brzezinski K. Sci Rep 8 11334 (2018)
  11. Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba. Tillery L, Barrett K, Goldstein J, Lassner JW, Osterhout B, Tran NL, Xu L, Young RM, Craig J, Chun I, Dranow DM, Abendroth J, Delker SL, Davies DR, Mayclin SJ, Calhoun B, Bolejack MJ, Staker B, Subramanian S, Phan I, Lorimer DD, Myler PJ, Edwards TE, Kyle DE, Rice CA, Morris JC, Leahy JW, Manetsch R, Barrett LK, Smith CL, Van Voorhis WC. PLoS One 16 e0241738 (2021)
  12. Correlation between Virtual Screening Performance and Binding Site Descriptors of Protein Targets. Shamsara J. Int J Med Chem 2018 3829307 (2018)
  13. Comparative kinetics of cofactor association and dissociation for the human and trypanosomal S-adenosylhomocysteine hydrolases. 3. Role of lysyl and tyrosyl residues of the C-terminal extension. Cai S, Fang J, Li QS, Borchardt RT, Kuczera K, Middaugh CR, Schowen RL. Biochemistry 49 8434-8441 (2010)
  14. Crystallization of mouse S-adenosyl-L-homocysteine hydrolase. Ishihara M, Kusakabe Y, Ohsumichi T, Tanaka N, Nakanishi M, Kitade Y, Nakamura KT. Acta Crystallogr Sect F Struct Biol Cryst Commun 66 313-315 (2010)
  15. Discovery-2: an interactive resource for the rational selection and comparison of putative drug target proteins in malaria. Mpangase PT, Szolkiewicz MJ, le Grange M, Smit JH, Burger PB, Joubert F. Malar J 12 116 (2013)
  16. S-adenosyl-L-homocysteine hydrolase from a hyperthermophile (Thermotoga maritima) is expressed in Escherichia coli in inactive form - Biochemical and structural studies. Brzezinski K, Czyrko J, Sliwiak J, Nalewajko-Sieliwoniuk E, Jaskolski M, Nocek B, Dauter Z. Int J Biol Macromol 104 584-596 (2017)
  17. Structural insight into binding mode of inhibitor with SAHH of Plasmodium and human: interaction of curcumin with anti-malarial drug targets. Singh DB, Dwivedi S. J Chem Biol 9 107-120 (2016)
  18. Contribution to the prediction of the fold code: application to immunoglobulin and flavodoxin cases. Banach M, Prudhomme N, Carpentier M, Duprat E, Papandreou N, Kalinowska B, Chomilier J, Roterman I. PLoS One 10 e0125098 (2015)
  19. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  20. Validation of Deep Learning-Based DFCNN in Extremely Large-Scale Virtual Screening and Application in Trypsin I Protease Inhibitor Discovery. Zhang H, Lin X, Wei Y, Zhang H, Liao L, Wu H, Pan Y, Wu X. Front Mol Biosci 9 872086 (2022)


Reviews citing this publication (4)

  1. Trans-methylation reactions in plants: focus on the activated methyl cycle. Rahikainen M, Alegre S, Trotta A, Pascual J, Kangasjärvi S. Physiol Plant 162 162-176 (2018)
  2. Functional and Pathological Roles of AHCY. Vizán P, Di Croce L, Aranda S. Front Cell Dev Biol 9 654344 (2021)
  3. [Structural biology for developing antimalarial compounds]. Tanaka N, Umeda T, Kusakabe Y, Nakanishi M, Kitade Y, Nakamura KT. Yakugaku Zasshi 133 527-537 (2013)
  4. [Structural and functional studies on proteins as potential drug discovery targets]. Tanaka N. Yakugaku Zasshi 127 1673-1683 (2007)

Articles citing this publication (34)

  1. A method for the analysis of domain movements in large biomolecular complexes. Poornam GP, Matsumoto A, Ishida H, Hayward S. Proteins 76 201-212 (2009)
  2. Anti-HIV-1 activity of 3-deaza-adenosine analogs. Inhibition of S-adenosylhomocysteine hydrolase and nucleotide congeners. Gordon RK, Ginalski K, Rudnicki WR, Rychlewski L, Pankaskie MC, Bujnicki JM, Chiang PK. Eur J Biochem 270 3507-3517 (2003)
  3. Crystal structure of S-adenosyl-L-homocysteine hydrolase from the human malaria parasite Plasmodium falciparum. Tanaka N, Nakanishi M, Kusakabe Y, Shiraiwa K, Yabe S, Ito Y, Kitade Y, Nakamura KT. J Mol Biol 343 1007-1017 (2004)
  4. QM/MM simulation of liquid water with an adaptive quantum region. Bernstein N, Várnai C, Solt I, Winfield SA, Payne MC, Simon I, Fuxreiter M, Csányi G. Phys Chem Chem Phys 14 646-656 (2012)
  5. Identification of Proteins Differentially Expressed by Quercetin Treatment in a Middle Cerebral Artery Occlusion Model: A Proteomics Approach. Shah FA, Park DJ, Koh PO. Neurochem Res 43 1608-1623 (2018)
  6. Synthesis, Activity and Metabolic Stability of Non-Ribose Containing Inhibitors of Histone Methyltransferase DOT1L. Deng L, Zhang L, Yao Y, Wang C, Redell MS, Dong S, Song Y. Medchemcomm 4 822-826 (2013)
  7. Catalytic mechanism of S-adenosylhomocysteine hydrolase: roles of His 54, Asp130, Glu155, Lys185, and Aspl89. Yamada T, Takata Y, Komoto J, Gomi T, Ogawa H, Fujioka M, Takusagawa F. Int J Biochem Cell Biol 37 2417-2435 (2005)
  8. S-adenosylhomocysteine hydrolase (AHCY) deficiency: two novel mutations with lethal outcome. Vugrek O, Beluzić R, Nakić N, Mudd SH. Hum Mutat 30 E555-65 (2009)
  9. Docking and in silico ADMET studies of noraristeromycin, curcumin and its derivatives with Plasmodium falciparum SAH hydrolase: a molecular drug target against malaria. Singh DB, Gupta MK, Singh DV, Singh SK, Misra K. Interdiscip Sci 5 1-12 (2013)
  10. The antiviral drug ribavirin is a selective inhibitor of S-adenosyl-L-homocysteine hydrolase from Trypanosoma cruzi. Cai S, Li QS, Borchardt RT, Kuczera K, Schowen RL. Bioorg Med Chem 15 7281-7287 (2007)
  11. Ethanol exposure modulates hepatic S-adenosylmethionine and S-adenosylhomocysteine levels in the isolated perfused rat liver through changes in the redox state of the NADH/NAD(+) system. Watson WH, Song Z, Kirpich IA, Deaciuc IV, Chen T, McClain CJ. Biochim Biophys Acta 1812 613-618 (2011)
  12. Analyzing S-adenosylhomocysteine hydrolase gene sequences in deuterostome genomes. Zhao JN, Wang Y, Zhao BS, Chen LL. J Biomol Struct Dyn 27 371-380 (2009)
  13. Structure and function of eritadenine and its 3-deaza analogues: potent inhibitors of S-adenosylhomocysteine hydrolase and hypocholesterolemic agents. Yamada T, Komoto J, Lou K, Ueki A, Hua DH, Sugiyama K, Takata Y, Ogawa H, Takusagawa F. Biochem Pharmacol 73 981-989 (2007)
  14. Beyond the survival and death of the deltamethrin-threatened pollen beetle Meligethes aeneus: An in-depth proteomic study employing a transcriptome database. Erban T, Harant K, Chalupnikova J, Kocourek F, Stara J. J Proteomics 150 281-289 (2017)
  15. Antioxidant molecular mechanism of adenosyl homocysteinase from cyanobacteria and its wound healing process in fibroblast cells. Sarkar P, Stefi RV, Pasupuleti M, Paray BA, Al-Sadoon MK, Arockiaraj J. Mol Biol Rep 47 1821-1834 (2020)
  16. Inhibitory effect of Epimedium extract on S-adenosyl-L-homocysteine hydrolase and biomethylation. Zhang X, Li Y, Yang X, Wang K, Ni J, Qu X. Life Sci 78 180-186 (2005)
  17. Mutational analyses of Plasmodium falciparum and human S-adenosylhomocysteine hydrolases. Nakanishi M, Yabe S, Tanaka N, Ito Y, Nakamura KT, Kitade Y. Mol Biochem Parasitol 143 146-151 (2005)
  18. S-adenosylhomocysteine hydrolase from the archaeon Pyrococcus furiosus: biochemical characterization and analysis of protein structure by comparative molecular modeling. Porcelli M, Moretti MA, Concilio L, Forte S, Merlino A, Graziano G, Cacciapuoti G. Proteins 58 815-825 (2005)
  19. Varroa destructor parasitism has a greater effect on proteome changes than the deformed wing virus and activates TGF-β signaling pathways. Erban T, Sopko B, Kadlikova K, Talacko P, Harant K. Sci Rep 9 9400 (2019)
  20. An enzyme captured in two conformational states: crystal structure of S-adenosyl-L-homocysteine hydrolase from Bradyrhizobium elkanii. Manszewski T, Singh K, Imiolczyk B, Jaskolski M. Acta Crystallogr D Biol Crystallogr 71 2422-2432 (2015)
  21. Synthesis and biological evaluation of immunosuppressive agent DZ2002 and its stereoisomers. Zhang YM, Ding Y, Tang W, Luo W, Gu M, Lu W, Tang J, Zuo JP, Nan FJ. Bioorg Med Chem 16 9212-9216 (2008)
  22. Adenosine analogue inhibitors of S-adenosylhomocysteine hydrolase. Converso A, Hartingh T, Fraley ME, Garbaccio RM, Hartman GD, Huang SY, Majercak JM, McCampbell A, Na SJ, Ray WJ, Savage MJ, Wolffe C, Yeh S, Yu Y, White R, Zhang R. Bioorg Med Chem Lett 24 2737-2740 (2014)
  23. Design, synthesis, and molecular modeling studies of 5'-deoxy-5'-ureidoadenosine: 5'-ureido group as multiple hydrogen bonding donor in the active site of S-adenosylhomocysteine hydrolase. Wang T, Lee HJ, Tosh DK, Kim HO, Pal S, Choi S, Lee Y, Moon HR, Zhao LX, Lee KM, Jeong LS. Bioorg Med Chem Lett 17 4456-4459 (2007)
  24. S-adenosylhomocysteine analogues with the carbon-5' and sulfur atoms replaced by a vinyl unit. Andrei D, Wnuk SF. Org Lett 8 5093-5096 (2006)
  25. Separation and identification of HSP-associated protein complexes from pancreatic cancer cell lines using 2D CN/SDS-PAGE coupled with mass spectrometry. Zhao Z, Liu H, Wang X, Wang X, Li Z. J Biomed Biotechnol 2011 193052 (2011)
  26. Evaluation of NAD(H) analogues as selective inhibitors for Trypanosoma cruzi S-adenosylhomocysteine hydrolase. Li QS, Cai S, Fang J, Borchardt RT, Kuczera K, Middaugh CR, Schowen RL. Nucleosides Nucleotides Nucleic Acids 28 473-484 (2009)
  27. Synthesis of 5'-functionalized nucleosides: S-Adenosylhomocysteine analogues with the carbon-5' and sulfur atoms replaced by a vinyl or halovinyl unit. Wnuk SF, Sacasa PR, Lewandowska E, Andrei D, Cai S, Borchardt RT. Bioorg Med Chem 16 5424-5433 (2008)
  28. A Tribute to Ronald T. Borchardt--Teacher, Mentor, Scientist, Colleague, Leader, Friend, and Family Man. Schowen KB, Schowen RL, Borchardt SE, Borchardt PM, Artursson P, Audus KL, Augustijns P, Nicolazzo JA, Raub TJ, Schöneich C, Siahaan TJ, Takakura Y, Thakker DR, Wolfe MS. J Pharm Sci 105 370-385 (2016)
  29. A coupled photometric assay for characterization of S-adenosyl-l-homocysteine hydrolases in the physiological hydrolytic direction. Kailing LL, Bertinetti D, Herberg FW, Pavlidis IV. N Biotechnol 39 11-17 (2017)
  30. Crystallization and preliminary X-ray diffraction analysis of the S-adenosylhomocysteine hydrolase (SAHH) from Thermotoga maritima. He M, Zheng Y, Huang CH, Qian G, Xiao X, Ko TP, Shao W, Guo RT. Acta Crystallogr F Struct Biol Commun 70 1563-1565 (2014)
  31. Molecular Response to High Hydrostatic Pressure: Time-Series Transcriptomic Analysis of Shallow-Water Sea Cucumber Apostichopus japonicus. Chen J, Liang L, Li Y, Zhang H. Front Genet 11 355 (2020)
  32. Discovery and structural analyses of S-adenosyl-L-homocysteine hydrolase inhibitors based on non-adenosine analogs. Nakao A, Suzuki H, Ueno H, Iwasaki H, Setsuta T, Kashima A, Sunada S. Bioorg Med Chem 23 4952-4969 (2015)
  33. Identification of proteins regulated by chlorogenic acid in an ischemic animal model: a proteomic approach. Shah MA, Kang JB, Koh PO. Lab Anim Res 39 12 (2023)
  34. Ocimum Sanctum Linn: A Potential Adjunct Therapy for Hyperhomocysteinemia-Induced Vascular Dementia. Pasangulapati JP, Ravula AR, Kanala DR, Boyina S, Gangarapu K, Boyina HK. Adv Exp Med Biol 1195 213-225 (2020)


Quick links