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PDBsum entry 2wm1

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protein ligands metals links
Lyase PDB id
2wm1
Jmol
Contents
Protein chain
332 a.a. *
Ligands
13P
GOL
Metals
_ZN
Waters ×216
* Residue conservation analysis
PDB id:
2wm1
Name: Lyase
Title: The crystal structure of human alpha-amino-beta- carboxymuconate-epsilon-semialdehyde decarboxylase in complex with 1,3- dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis
Structure: 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase. Chain: a. Synonym: alpha-amino-beta-carboxymuconate-epsilon- semialdehyde decarboxylase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: pichia pastoris. Expression_system_taxid: 4922. Expression_system_cell_line: gs115.
Resolution:
2.01Å     R-factor:   0.197     R-free:   0.256
Authors: S.Garavaglia,S.Perozzi,L.Galeazzi,N.Raffaelli,M.Rizzi
Key ref: S.Garavaglia et al. (2009). The crystal structure of human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase in complex with 1,3-dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis. FEBS J, 276, 6615-6623. PubMed id: 19843166 DOI: 10.1111/j.1742-4658.2009.07372.x
Date:
29-Jun-09     Release date:   03-Nov-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q8TDX5  (ACMSD_HUMAN) -  2-amino-3-carboxymuconate-6-semialdehyde decarboxylase
Seq:
Struc:
336 a.a.
332 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.4.1.1.45  - Aminocarboxymuconate-semialdehyde decarboxylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
(later stages)
      Reaction: 2-amino-3-(3-oxoprop-1-en-1-yl)but-2-enedioate = 2-aminomuconate semialdehyde + CO2
2-amino-3-(3-oxoprop-1-en-1-yl)but-2-enedioate
= 2-aminomuconate semialdehyde
+ CO(2)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular vesicular exosome   2 terms 
  Biological process     metabolic process   5 terms 
  Biochemical function     catalytic activity     5 terms  

 

 
    reference    
 
 
DOI no: 10.1111/j.1742-4658.2009.07372.x FEBS J 276:6615-6623 (2009)
PubMed id: 19843166  
 
 
The crystal structure of human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase in complex with 1,3-dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis.
S.Garavaglia, S.Perozzi, L.Galeazzi, N.Raffaelli, M.Rizzi.
 
  ABSTRACT  
 
The enzyme alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) is a zinc-dependent amidohydrolase that participates in picolinic acid (PA), quinolinic acid (QA) and NAD homeostasis. Indeed, the enzyme stands at a branch point of the tryptophan to NAD pathway, and determines the final fate of the amino acid, i.e. transformation into PA, complete oxidation through the citric acid cycle, or conversion into NAD through QA synthesis. Both PA and QA are key players in a number of physiological and pathological conditions, mainly affecting the central nervous system. As their relative concentrations must be tightly controlled, modulation of ACMSD activity appears to be a promising prospect for the treatment of neurological disorders, including cerebral malaria. Here we report the 2.0 A resolution crystal structure of human ACMSD in complex with the glycolytic intermediate 1,3-dihydroxyacetonephosphate (DHAP), refined to an R-factor of 0.19. DHAP, which we discovered to be a potent enzyme inhibitor, resides in the ligand binding pocket with its phosphate moiety contacting the catalytically essential zinc ion through mediation of a solvent molecule. Arg47, Asp291 and Trp191 appear to be the key residues for DHAP recognition in human ACMSD. Ligand binding induces a significant conformational change affecting a strictly conserved Trp-Met couple, and we propose that these residues are involved in controlling ligand admission into ACMSD. Our data may be used for the design of inhibitors with potential medical interest, and suggest a regulatory link between de novo NAD biosynthesis and glycolysis.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21292315 M.A.Nalls, V.Plagnol, D.G.Hernandez, M.Sharma, U.M.Sheerin, M.Saad, J.Simón-Sánchez, C.Schulte, S.Lesage, S.Sveinbjörnsdóttir, K.Stefánsson, M.Martinez, J.Hardy, P.Heutink, A.Brice, T.Gasser, A.B.Singleton, N.W.Wood, M.A.Nalls, V.Plagnol, D.G.Hernandez, M.Sharma, U.M.Sheerin, M.Saad, J.Simón-Sánchez, C.Schulte, S.Lesage, S.Sveinbjörnsdóttir, S.Arepalli, R.Barker, Y.Ben-Shlomo, H.W.Berendse, D.Berg, K.Bhatia, R.M.de Bie, A.Biffi, B.Bloem, Z.Bochdanovits, M.Bonin, J.M.Bras, K.Brockmann, J.Brooks, D.J.Burn, G.Charlesworth, H.Chen, P.F.Chinnery, S.Chong, C.E.Clarke, M.R.Cookson, M.Cooper, J.C.Corvol, C.Counsell, P.Damier, J.F.Dartigues, P.Deloukas, G.Deuschl, D.T.Dexter, K.D.van Dijk, A.Dillman, F.Durif, A.Dürr, S.Edkins, J.R.Evans, T.Foltynie, J.Gao, M.Gardner, J.R.Gibbs, A.Goate, E.Gray, R.Guerreiro, ..Gústafsson, C.Harris, J.J.van Hilten, A.Hofman, A.Hollenbeck, M.Hu, X.Huang, H.Huber, G.Hudson, S.E.Hunt, J.Huttenlocher, T.Illig, P.V.Jónsson, J.C.Lambert, C.Langford, A.Lees, P.Lichtner, P.Limousin, G.Lopez, D.Lorenz, A.McNeill, C.Moorby, M.Moore, H.R.Morris, K.E.Morrison, E.Mudanohwo, S.O'Sullivan, J.Pearson, J.S.Perlmutter, and H.Pétursson (2011).
Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies.
  Lancet, 377, 641-649.  
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.