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PDBsum entry 1b3r

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
1b3r
Jmol
Contents
Protein chains
428 a.a. *
Ligands
NAD ×4
Waters ×1239
* Residue conservation analysis
PDB id:
1b3r
Name: Hydrolase
Title: Rat liver s-adenosylhomocystein hydrolase
Structure: Protein (s-adenosylhomocysteine hydrolase). Chain: a, b, c, d. Fragment: catalytic domain (1 - 181 & 352 - 402). Engineered: yes. Other_details: each subunit contains one NAD+ molecule.
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Strain: mv1304. Organ: liver. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
Resolution:
2.80Å     R-factor:   0.199     R-free:   0.269
Authors: Y.Hu,J.Komoto,Y.Huang,F.Takusagawa,T.Gomi,H.Ogawa,Y.Takata, M.Fujioka
Key ref:
Y.Hu et al. (1999). Crystal structure of S-adenosylhomocysteine hydrolase from rat liver. Biochemistry, 38, 8323-8333. PubMed id: 10387078 DOI: 10.1021/bi990332k
Date:
14-Dec-98     Release date:   23-Dec-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P10760  (SAHH_RAT) -  Adenosylhomocysteinase
Seq:
Struc:
432 a.a.
428 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.3.1.1  - Adenosylhomocysteinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Adenosylhomocysteinase
      Reaction: S-adenosyl-L-homocysteine + H2O = L-homocysteine + adenosine
S-adenosyl-L-homocysteine
+ H(2)O
= L-homocysteine
+ adenosine
      Cofactor: NAD(+)
NAD(+)
Bound ligand (Het Group name = NAD) corresponds exactly
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     neuron projection   6 terms 
  Biological process     homocysteine biosynthetic process   8 terms 
  Biochemical function     hydrolase activity     5 terms  

 

 
    reference    
 
 
DOI no: 10.1021/bi990332k Biochemistry 38:8323-8333 (1999)
PubMed id: 10387078  
 
 
Crystal structure of S-adenosylhomocysteine hydrolase from rat liver.
Y.Hu, J.Komoto, Y.Huang, T.Gomi, H.Ogawa, Y.Takata, M.Fujioka, F.Takusagawa.
 
  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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21119889 F.Coppedè (2010).
One-carbon metabolism and Alzheimer's disease: focus on epigenetics.
  Curr Genomics, 11, 246-260.  
19177456 O.Vugrek, R.Beluzić, N.Nakić, and S.H.Mudd (2009).
S-adenosylhomocysteine hydrolase (AHCY) deficiency: two novel mutations with lethal outcome.
  Hum Mutat, 30, E555-E565.  
19201949 R.P.Matthews, K.Lorent, R.Mañoral-Mobias, Y.Huang, W.Gong, I.V.Murray, I.A.Blair, and M.Pack (2009).
TNFalpha-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish S-adenosylhomocysteine hydrolase.
  Development, 136, 865-875.  
18536033 B.Devogelaere, E.Sammels, and H.De Smedt (2008).
The IRBIT domain adds new functions to the AHCY family.
  Bioessays, 30, 642-652.  
17932938 C.Hu, J.Fang, R.T.Borchardt, R.L.Schowen, and K.Kuczera (2008).
Molecular dynamics simulations of domain motions of substrate-free S-adenosyl- L-homocysteine hydrolase in solution.
  Proteins, 71, 131-143.  
  18607106 K.Brzezinski, G.Bujacz, and M.Jaskolski (2008).
Purification, crystallization and preliminary crystallographic studies of plant S-adenosyl-L-homocysteine hydrolase (Lupinus luteus).
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 671-673.  
17334902 M.A.Grillo, and S.Colombatto (2008).
S-adenosylmethionine and its products.
  Amino Acids, 34, 187-193.  
18815415 M.C.Reddy, G.Kuppan, N.D.Shetty, J.L.Owen, T.R.Ioerger, and J.C.Sacchettini (2008).
Crystal structures of Mycobacterium tuberculosis S-adenosyl-L-homocysteine hydrolase in ternary complex with substrate and inhibitors.
  Protein Sci, 17, 2134-2144.
PDB codes: 2ziz 2zj0 2zj1 3ce6 3dhy
18457953 S.F.Wnuk, P.R.Sacasa, E.Lewandowska, D.Andrei, S.Cai, and R.T.Borchardt (2008).
Synthesis of 5'-functionalized nucleosides: S-Adenosylhomocysteine analogues with the carbon-5' and sulfur atoms replaced by a vinyl or halovinyl unit.
  Bioorg Med Chem, 16, 5424-5433.  
17335583 C.H.Tung, J.W.Huang, and J.M.Yang (2007).
Kappa-alpha plot derived structural alphabet and BLOSUM-like substitution matrix for rapid search of protein structure database.
  Genome Biol, 8, R31.  
17180248 J.O.Rosado, M.Salvador, and D.Bonatto (2007).
Importance of the trans-sulfuration pathway in cancer prevention and promotion.
  Mol Cell Biochem, 301, 1.  
16996649 M.L.Selley (2007).
A metabolic link between S-adenosylhomocysteine and polyunsaturated fatty acid metabolism in Alzheimer's disease.
  Neurobiol Aging, 28, 1834-1839.  
17917424 N.Tanaka (2007).
[Structural and functional studies on proteins as potential drug discovery targets]
  Yakugaku Zasshi, 127, 1673-1683.  
17559404 V.Ctrnáctá, F.Stejskal, J.S.Keithly, and I.Hrdý (2007).
Characterization of S-adenosylhomocysteine hydrolase from Cryptosporidium parvum.
  FEMS Microbiol Lett, 273, 87-95.  
17048851 D.Andrei, and S.F.Wnuk (2006).
S-adenosylhomocysteine analogues with the carbon-5' and sulfur atoms replaced by a vinyl unit.
  Org Lett, 8, 5093-5096.  
16736098 N.R.Buist, B.Glenn, O.Vugrek, C.Wagner, S.Stabler, R.H.Allen, I.Pogribny, A.Schulze, S.H.Zeisel, I.Barić, and S.H.Mudd (2006).
S-adenosylhomocysteine hydrolase deficiency in a 26-year-old man.
  J Inherit Metab Dis, 29, 538-545.  
16601863 R.Castro, I.Rivera, H.J.Blom, C.Jakobs, and I.Tavares de Almeida (2006).
Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: an overview.
  J Inherit Metab Dis, 29, 3.  
15645450 M.Porcelli, M.A.Moretti, L.Concilio, S.Forte, A.Merlino, G.Graziano, and G.Cacciapuoti (2005).
S-adenosylhomocysteine hydrolase from the archaeon Pyrococcus furiosus: biochemical characterization and analysis of protein structure by comparative molecular modeling.
  Proteins, 58, 815-825.  
16061414 T.Yamada, Y.Takata, J.Komoto, T.Gomi, H.Ogawa, M.Fujioka, and F.Takusagawa (2005).
Catalytic mechanism of S-adenosylhomocysteine hydrolase: roles of His 54, Asp130, Glu155, Lys185, and Aspl89.
  Int J Biochem Cell Biol, 37, 2417-2435.
PDB code: 1xwf
15165742 D.Kloor, and H.Osswald (2004).
S-Adenosylhomocysteine hydrolase as a target for intracellular adenosine action.
  Trends Pharmacol Sci, 25, 294-297.  
12525476 H.Ando, A.Mizutani, T.Matsu-ura, and K.Mikoshiba (2003).
IRBIT, a novel inositol 1,4,5-trisphosphate (IP3) receptor-binding protein, is released from the IP3 receptor upon IP3 binding to the receptor.
  J Biol Chem, 278, 10602-10612.  
14527954 J.Kindrachuk, J.Parent, G.F.Davies, M.Dinsmore, S.Attah-Poku, and S.Napper (2003).
Overexpression of L-isoaspartate O-methyltransferase in Escherichia coli increases heat shock survival by a mechanism independent of methyltransferase activity.
  J Biol Chem, 278, 50880-50886.  
12910461 J.M.Bujnicki, S.T.Prigge, D.Caridha, and P.K.Chiang (2003).
Structure, evolution, and inhibitor interaction of S-adenosyl-L-homocysteine hydrolase from Plasmodium falciparum.
  Proteins, 52, 624-632.  
12919315 R.K.Gordon, K.Ginalski, W.R.Rudnicki, L.Rychlewski, M.C.Pankaskie, J.M.Bujnicki, and P.K.Chiang (2003).
Anti-HIV-1 activity of 3-deaza-adenosine analogs. Inhibition of S-adenosylhomocysteine hydrolase and nucleotide congeners.
  Eur J Biochem, 270, 3507-3517.  
11741948 Y.Huang, J.Komoto, Y.Takata, D.R.Powell, T.Gomi, H.Ogawa, M.Fujioka, and F.Takusagawa (2002).
Inhibition of S-adenosylhomocysteine hydrolase by acyclic sugar adenosine analogue D-eritadenine. Crystal structure of S-adenosylhomocysteine hydrolase complexed with D-eritadenine.
  J Biol Chem, 277, 7477-7482.
PDB code: 1k0u
11927587 Y.Takata, T.Yamada, Y.Huang, J.Komoto, T.Gomi, H.Ogawa, M.Fujioka, and F.Takusagawa (2002).
Catalytic mechanism of S-adenosylhomocysteine hydrolase. Site-directed mutagenesis of Asp-130, Lys-185, Asp-189, and Asn-190.
  J Biol Chem, 277, 22670-22676.
PDB codes: 1ky4 1ky5
11453979 M.Medina, J.L.Urdiales, and M.I.Amores-Sánchez (2001).
Roles of homocysteine in cell metabolism: old and new functions.
  Eur J Biochem, 268, 3871-3882.  
10933798 D.Yin, X.Yang, Y.Hu, K.Kuczera, R.L.Schowen, R.T.Borchardt, and T.C.Squier (2000).
Substrate binding stabilizes S-adenosylhomocysteine hydrolase in a closed conformation.
  Biochemistry, 39, 9811-9818.  
11106503 X.Yang, D.Yin, S.F.Wnuk, M.J.Robins, and R.T.Borchardt (2000).
Mechanisms of inactivation of human S-adenosylhomocysteine hydrolase by 5',5',6',6'-tetradehydro-6'-deoxy-6'-halohomoadenosines.
  Biochemistry, 39, 15234-15241.  
  10588658 N.Radomski, C.Kaufmann, and C.Dreyer (1999).
Nuclear accumulation of S-adenosylhomocysteine hydrolase in transcriptionally active cells during development of Xenopus laevis.
  Mol Biol Cell, 10, 4283-4298.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.