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Catalytic mechanism of S-adenosylhomocysteine hydrolase. Site-directed mutagenesis of Asp-130, Lys-185, Asp-189, and Asn-190.

Takata Y, Yamada T, Huang Y, Komoto J, Gomi T, Ogawa H, Fujioka M, Takusagawa F
J Biol Chem 277 22670-6 (2002)
Cited: 32 times
EuropePMC logo PMID: 11927587

Abstract

S-Adenosylhomocysteine hydrolase (AdoHcyase) catalyzes the hydrolysis of S-adenosylhomocysteine to form adenosine and homocysteine. On the bases of crystal structures of the wild type enzyme and the D244E mutated enzyme complexed with 3'-keto-adenosine (D244E.Ado*), we have identified the important amino acid residues, Asp-130, Lys-185, Asp-189, and Asn-190, for the catalytic reaction and have proposed a catalytic mechanism (Komoto, J., Huang, Y., Gomi, T., Ogawa, H., Takata, Y., Fujioka, M., and Takusagawa, F. (2000) J. Biol. Chem. 275, 32147-32156). To confirm the proposed catalytic mechanism, we have made the D130N, K185N, D189N, and N190S mutated enzymes and measured the catalytic activities. The catalytic rates (k(cat)) of D130N, K185N, D189N, and N190S mutated enzymes are reduced to 0.7%, 0.5%, 0.1%, and 0.5%, respectively, in comparison with the wild type enzyme, indicating that Asp-130, Lys-185, Asp-189, and Asn-190 are involved in the catalytic reaction. K(m) values of the mutated enzymes are increased significantly, except for the N190S mutation, suggesting that Asp-130, Lys-185, and Asp-189 participate in the substrate binding. To interpret the kinetic data, the oxidation states of the bound NAD molecules of the wild type and mutated enzymes were measured during the catalytic reaction by monitoring the absorbance at 340 nm. The crystal structures of the WT and D244E.Ado*, containing four subunits in the crystallographic asymmetric unit, were re-refined to have the same subunit structures. A detailed catalytic mechanism of AdoHcyase has been revealed based on the oxidation states of the bound NAD and the re-refined crystal structures of WT and D244E.Ado*. Lys-185 and Asp-130 abstract hydrogen atoms from 3'-OH and 4'-CH, respectively. Asp-189 removes a proton from Lys-185 and produces the neutral N zeta (-NH(2)), and Asn-190 facilitates formation of the neutral Lys-185. His-54 and His-300 hold and polarize a water molecule, which nucleophilically attacks the C5'- of 3'-keto-4',5'-dehydroadenosine to produce 3'-keto-Ado.

Reviews - 1ky4 mentioned but not cited (1)

  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)

Articles - 1ky4 mentioned but not cited (3)

  1. Molecular docking screens using comparative models of proteins. Fan H, Irwin JJ, Webb BM, Klebe G, Shoichet BK, Sali A. J Chem Inf Model 49 2512-2527 (2009)
  2. 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)
  3. 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)


Reviews citing this publication (1)

  1. Metabolism and regulation of glycerolipids in the yeast Saccharomyces cerevisiae. Henry SA, Kohlwein SD, Carman GM. Genetics 190 317-349 (2012)

Articles citing this publication (27)

  1. 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)
  2. 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)
  3. 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)
  4. Historical Article John Montgomery's legacy: carbocyclic adenosine analogues as SAH hydrolase inhibitors with broad-spectrum antiviral activity. De Clercq E. Nucleosides Nucleotides Nucleic Acids 24 1395-1415 (2005)
  5. S-adenosyl-l-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling. Greco CM, Cervantes M, Fustin JM, Ito K, Ceglia N, Samad M, Shi J, Koronowski KB, Forne I, Ranjit S, Gaucher J, Kinouchi K, Kojima R, Gratton E, Li W, Baldi P, Imhof A, Okamura H, Sassone-Corsi P. Sci Adv 6 eabc5629 (2020)
  6. 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)
  7. 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)
  8. Molecular insights of SAH enzyme catalysis and implication for inhibitor design. Wei H, Zhang R, Wang C, Zheng H, Li A, Chou KC, Wei DQ. J Theor Biol 244 692-702 (2007)
  9. Adenosine binding sites at S-adenosylhomocysteine hydrolase are controlled by the NAD+/NADH ratio of the enzyme. Kloor D, Lüdtke A, Stoeva S, Osswald H. Biochem Pharmacol 66 2117-2123 (2003)
  10. 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)
  11. 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)
  12. 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)
  13. 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)
  14. 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)
  15. Crystallographic and SAXS studies of S-adenosyl-l-homocysteine hydrolase from Bradyrhizobium elkanii. Manszewski T, Szpotkowski K, Jaskolski M. IUCrJ 4 271-282 (2017)
  16. Functional analysis of human S-adenosylhomocysteine hydrolase isoforms SAHH-2 and SAHH-3. Fumić K, Beluzić R, Cuk M, Pavkov T, Kloor D, Barić I, Mijić I, Vugrek O. Eur J Hum Genet 15 347-351 (2007)
  17. 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)
  18. Crystal structures of S-adenosylhomocysteine hydrolase from the thermophilic bacterium Thermotoga maritima. Zheng Y, Chen CC, Ko TP, Xiao X, Yang Y, Huang CH, Qian G, Shao W, Guo RT. J Struct Biol 190 135-142 (2015)
  19. S-Adenosylhomocysteine hydrolase (AdoHcyase) deficiency: enzymatic capabilities of human AdoHcyase are highly effected by changes to codon 89 and its surrounding residues. Beluzić R, Cuk M, Pavkov T, Barić I, Vugrek O. Biochem Biophys Res Commun 368 30-36 (2008)
  20. Molecular dynamics simulations of domain motions of substrate-free S-adenosyl- L-homocysteine hydrolase in solution. Hu C, Fang J, Borchardt RT, Schowen RL, Kuczera K. Proteins 71 131-143 (2008)
  21. 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)
  22. Determinants for the cAMP-binding site at the S-adenosylhomocysteine-hydrolase. Kloor D, Hermes M, Kirschler J, Müller M, Hagen N, Kalbacher H, Stevanovic S, Osswald H. Naunyn Schmiedebergs Arch Pharmacol 380 215-222 (2009)
  23. Enzymatic synthesis of S-adenosylhomocysteine: immobilization of recombinant S-adenosylhomocysteine hydrolase from Corynebacterium glutamicum (ATCC 13032). Lozada-Ramírez JD, Sánchez-Ferrer A, García-Carmona F. Appl Microbiol Biotechnol 93 2317-2325 (2012)
  24. S-Inosyl-L-Homocysteine Hydrolase, a Novel Enzyme Involved in S-Adenosyl-L-Methionine Recycling. Miller D, Xu H, White RH. J Bacteriol 197 2284-2291 (2015)
  25. 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)
  26. Efficient biosynthesis of nucleoside cytokinin angustmycin A containing an unusual sugar system. Yu L, Zhou W, She Y, Ma H, Cai YS, Jiang M, Deng Z, Price NPJ, Chen W. Nat Commun 12 6633 (2021)
  27. 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)


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