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Crystal structure of S-adenosylhomocysteine hydrolase from rat liver.

Hu Y, Komoto J, Huang Y, Gomi T, Ogawa H, Takata Y, Fujioka M, Takusagawa F
Biochemistry 38 8323-33 (1999)
Cited: 66 times
EuropePMC logo PMID: 10387078

Abstract

The crystal structure of rat liver S-adenosyl-L-homocysteine hydrolase (AdoHcyase, EC 3.3.1.1) which catalyzes the reversible hydrolysis of S-adenosylhomocysteine (AdoHcy) has been determined at 2.8 A resolution. AdoHcyase from rat liver is a tetrameric enzyme with 431 amino acid residues in each identical subunit. The subunit is composed of the catalytic domain, the NAD+-binding domain, and the small C-terminal domain. Both catalytic and NAD+-binding domains are folded into an ellipsoid with a typical alpha/beta twisted open sheet structure. The C-terminal section is far from the main body of the subunit and extends into the opposite subunit. An NAD+ molecule binds to the consensus NAD+-binding cleft of the NAD+-binding domain. The peptide folding pattern of the catalytic domain is quite similar to the patterns observed in many methyltransferases. Although the crystal structure does not contain AdoHcy or its analogue, there is a well-formed AdoHcy-binding crevice in the catalytic domain. Without introducing any major structural changes, an AdoHcy molecule can be placed in the catalytic domain. In the structure described here, the catalytic and NAD+-binding domains are quite far apart from each other. Thus, the enzyme appears to have an "open" conformation in the absence of substrate. It is likely that binding of AdoHcy induces a large conformational change so as to place the ribose moiety of AdoHcy in close proximity to the nicotinamide moiety of NAD+. A catalytic mechanism of AdoHcyase has been proposed on the basis of this crystal structure. Glu155 acts as a proton acceptor from the O3'-H when the proton of C3'-H is abstracted by NAD+. His54 or Asp130 acts as a general acid-base catalyst, while Cys194 modulates the oxidation state of the bound NAD+. The polypeptide folding pattern of the catalytic domain suggests that AdoHcy molecules can travel freely to and from AdoHcyase and methyltransferases to properly regulate methyltransferase activities. We believe that the crystal structure described here can provide insight into the molecular architecture of this important regulatory enzyme.

Reviews - 1b3r 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)

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  1. Kappa-alpha plot derived structural alphabet and BLOSUM-like substitution matrix for rapid search of protein structure database. Tung CH, Huang JW, Yang JM. Genome Biol 8 R31 (2007)
  2. Identification and characterization of the Chlamydia trachomatis L2 S-adenosylmethionine transporter. Binet R, Fernandez RE, Fisher DJ, Maurelli AT. mBio 2 e00051-11 (2011)
  3. 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)
  4. Docking protein domains in contact space. Lise S, Walker-Taylor A, Jones DT. BMC Bioinformatics 7 310 (2006)
  5. Crystallographic and SAXS studies of S-adenosyl-l-homocysteine hydrolase from Bradyrhizobium elkanii. Manszewski T, Szpotkowski K, Jaskolski M. IUCrJ 4 271-282 (2017)


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  1. Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: an overview. Castro R, Rivera I, Blom HJ, Jakobs C, Tavares de Almeida I. J Inherit Metab Dis 29 3-20 (2006)
  2. Roles of homocysteine in cell metabolism: old and new functions. Medina M, Urdiales JL, Amores-Sánchez MI. Eur J Biochem 268 3871-3882 (2001)
  3. S-adenosylmethionine and its products. Grillo MA, Colombatto S. Amino Acids 34 187-193 (2008)
  4. Fluorogenic probes for disease-relevant enzymes. Zhang J, Chai X, He XP, Kim HJ, Yoon J, Tian H. Chem Soc Rev 48 683-722 (2019)
  5. S-Adenosylhomocysteine hydrolase as a target for intracellular adenosine action. Kloor D, Osswald H. Trends Pharmacol Sci 25 294-297 (2004)
  6. Importance of the trans-sulfuration pathway in cancer prevention and promotion. Rosado JO, Salvador M, Bonatto D. Mol Cell Biochem 301 1-12 (2007)
  7. IRBIT: a regulator of ion channels and ion transporters. Ando H, Kawaai K, Mikoshiba K. Biochim Biophys Acta 1843 2195-2204 (2014)
  8. The IRBIT domain adds new functions to the AHCY family. Devogelaere B, Sammels E, De Smedt H. Bioessays 30 642-652 (2008)
  9. Functional and Pathological Roles of AHCY. Vizán P, Di Croce L, Aranda S. Front Cell Dev Biol 9 654344 (2021)
  10. 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)
  11. [Structural and functional studies on proteins as potential drug discovery targets]. Tanaka N. Yakugaku Zasshi 127 1673-1683 (2007)

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  1. The geometry of domain combination in proteins. Bashton M, Chothia C. J Mol Biol 315 927-939 (2002)
  2. The Arabidopsis HOMOLOGY-DEPENDENT GENE SILENCING1 gene codes for an S-adenosyl-L-homocysteine hydrolase required for DNA methylation-dependent gene silencing. Rocha PS, Sheikh M, Melchiorre R, Fagard M, Boutet S, Loach R, Moffatt B, Wagner C, Vaucheret H, Furner I. Plant Cell 17 404-417 (2005)
  3. A metabolic link between S-adenosylhomocysteine and polyunsaturated fatty acid metabolism in Alzheimer's disease. Selley ML. Neurobiol Aging 28 1834-1839 (2007)
  4. TNFalpha-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish S-adenosylhomocysteine hydrolase. Matthews RP, Lorent K, Mañoral-Mobias R, Huang Y, Gong W, Murray IV, Blair IA, Pack M. Development 136 865-875 (2009)
  5. One-carbon metabolism and Alzheimer's disease: focus on epigenetics. Coppedè F. Curr Genomics 11 246-260 (2010)
  6. S-adenosylhomocysteine hydrolase deficiency in a 26-year-old man. Buist NR, Glenn B, Vugrek O, Wagner C, Stabler S, Allen RH, Pogribny I, Schulze A, Zeisel SH, Barić I, Mudd SH. J Inherit Metab Dis 29 538-545 (2006)
  7. 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)
  8. 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)
  9. Nuclear accumulation of S-adenosylhomocysteine hydrolase in transcriptionally active cells during development of Xenopus laevis. Radomski N, Kaufmann C, Dreyer C. Mol Biol Cell 10 4283-4298 (1999)
  10. Influence of an altered methylation potential on mRNA methylation and gene expression in HepG2 cells. Hermes M, Osswald H, Mattar J, Kloor D. Exp Cell Res 294 325-334 (2004)
  11. 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)
  12. Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency. Stender S, Chakrabarti RS, Xing C, Gotway G, Cohen JC, Hobbs HH. Mol Genet Metab 116 269-274 (2015)
  13. Structure, evolution, and inhibitor interaction of S-adenosyl-L-homocysteine hydrolase from Plasmodium falciparum. Bujnicki JM, Prigge ST, Caridha D, Chiang PK. Proteins 52 624-632 (2003)
  14. Interaction of S-adenosylhomocysteine hydrolase of Xenopus laevis with mRNA(guanine-7-)methyltransferase: implication on its nuclear compartmentalisation and on cap methylation of hnRNA. Radomski N, Barreto G, Kaufmann C, Yokoska J, Mizumoto K, Dreyer C. Biochim Biophys Acta 1590 93-102 (2002)
  15. 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)
  16. 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)
  17. 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)
  18. 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)
  19. 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)
  20. 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)
  21. 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)
  22. 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)
  23. A new structural class of S-adenosylhomocysteine hydrolase inhibitors. Kim BG, Chun TG, Lee HY, Snapper ML. Bioorg Med Chem 17 6707-6714 (2009)
  24. Molecular characterization and interactome analysis of Trypanosoma cruzi tryparedoxin II. Arias DG, Piñeyro MD, Iglesias AA, Guerrero SA, Robello C. J Proteomics 120 95-104 (2015)
  25. 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)
  26. 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)
  27. Binding of Cu2+ to S-adenosyl-L-homocysteine hydrolase. Li Y, Chen J, Liu J, Yang X, Wang K. J Inorg Biochem 98 977-983 (2004)
  28. 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)
  29. S-Adenosyl-l-Methionine Salvage Impacts Psilocybin Formation in "Magic" Mushrooms. Demmler R, Fricke J, Dörner S, Gressler M, Hoffmeister D. Chembiochem 21 1364-1371 (2020)
  30. Structure-function analysis of human TYW2 enzyme required for the biosynthesis of a highly modified Wybutosine (yW) base in phenylalanine-tRNA. Rodriguez V, Vasudevan S, Noma A, Carlson BA, Green JE, Suzuki T, Chandrasekharappa SC. PLoS One 7 e39297 (2012)
  31. 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)
  32. 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)
  33. Inactivation of S-adenosyl-L-homocysteine hydrolase with novel 5'-thioadenosine derivatives. Antiviral effects. Guillerm G, Guillerm D, Vandenplas-Vitkowski C, Glapski C, De Clercq E. Bioorg Med Chem Lett 13 1649-1652 (2003)
  34. Characterization of S-adenosylhomocysteine hydrolase from Cryptosporidium parvum. Ctrnáctá V, Stejskal F, Keithly JS, Hrdý I. FEMS Microbiol Lett 273 87-95 (2007)
  35. 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)
  36. 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)
  37. 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)
  38. 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)
  39. Synthesis of an alpha-aminophosphonate nucleoside as an inhibitor of S-adenosyl-L-homocysteine hydrolase. Steere JA, Sampson PB, Honek JF. Bioorg Med Chem Lett 12 457-460 (2002)
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  41. 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)
  42. 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)
  43. 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)
  44. Synthesis and biological activity of novel S-adenosyl-L-homocysteine hydrolase inhibitors. Steere JA, Honek JF. Bioorg Med Chem 11 3229-3236 (2003)
  45. 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)
  46. Ion Complexation Explains Orders of Magnitude Changes in the Equilibrium Constant of Biochemical Reactions in Buffers Crowded by Nonionic Compounds. Bielec K, Kowalski A, Bubak G, Witkowska Nery E, Hołyst R. J Phys Chem Lett 13 112-117 (2022)
  47. Antiparasitic activity of FLLL-32 against four Babesia species, B. bovis, B. bigemina, B. divergens and B. caballi, and one Theileria species, Theileria equi in vitro, and Babesia microti in mice. El-Sayed SAE, El-Alfy ES, Baghdadi HB, Sayed-Ahmed MZ, Alqahtani SS, Alam N, Ahmad S, Ali MS, Igarashi I, Rizk MA. Front Pharmacol 14 1278451 (2023)
  48. 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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