spacer
spacer

PDBsum entry 1do8

Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
1do8
Jmol
Contents
Protein chain
553 a.a. *
Ligands
OXL ×4
NAD ×8
Metals
_MN ×4
Waters ×959
* Residue conservation analysis
PDB id:
1do8
Name: Oxidoreductase
Title: Crystal structure of a closed form of human mitochondrial NAD(p)+-dependent malic enzyme
Structure: Malic enzyme. Chain: a, b, c, d. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
Resolution:
2.20Å     R-factor:   0.204     R-free:   0.263
Authors: Z.Yang,D.L.Floyd,G.Loeber,L.Tong
Key ref:
Z.Yang et al. (2000). Structure of a closed form of human malic enzyme and implications for catalytic mechanism. Nat Struct Biol, 7, 251-257. PubMed id: 10700286 DOI: 10.1038/73378
Date:
19-Dec-99     Release date:   06-Mar-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P23368  (MAOM_HUMAN) -  NAD-dependent malic enzyme, mitochondrial
Seq:
Struc:
 
Seq:
Struc:
584 a.a.
553 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.1.1.38  - Malate dehydrogenase (oxaloacetate-decarboxylating).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. (S)-malate + NAD+ = pyruvate + CO2 + NADH
2. Oxaloacetate = pyruvate + CO2
(S)-malate
+
NAD(+)
Bound ligand (Het Group name = NAD)
corresponds exactly
=
pyruvate
Bound ligand (Het Group name = OXL)
matches with 71.00% similarity
+ CO(2)
+ NADH
Oxaloacetate
= pyruvate
+ CO(2)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular membrane-bounded organelle   3 terms 
  Biological process     metabolic process   3 terms 
  Biochemical function     catalytic activity     8 terms  

 

 
    reference    
 
 
DOI no: 10.1038/73378 Nat Struct Biol 7:251-257 (2000)
PubMed id: 10700286  
 
 
Structure of a closed form of human malic enzyme and implications for catalytic mechanism.
Z.Yang, D.L.Floyd, G.Loeber, L.Tong.
 
  ABSTRACT  
 
Malic enzymes are widely distributed in nature and have many biological functions. The crystal structure of human mitochondrial NAD(P)+-dependent malic enzyme in a quaternary complex with NAD+, Mn++ and oxalate has been determined at 2.2 A resolution. The structures of the quaternary complex with NAD+, Mg++, tartronate or ketomalonate have been determined at 2.6 A resolution. The structures show the enzyme in a closed form in these complexes and reveal the binding modes of the cation and the inhibitors. The divalent cation is coordinated in an octahedral fashion by six ligating oxygens, two from the substrate/inhibitor, three from Glu 255, Asp 256 and Asp 279 of the enzyme, and one from a water molecule. The structural information has significant implications for the catalytic mechanism of malic enzymes and identifies Tyr 112 and Lys 183 as possible catalytic residues. Changes in tetramer organization of the enzyme are also observed in these complexes, which might be relevant for its cooperative behavior and allosteric control.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. A possible catalytic mechanism for malic enzymes. B represents the general base and HA the general acid that are required for this mechanism. Oxalate is a mimic for the enol-pyruvate intermediate in this mechanism.
Figure 4.
Figure 4. The tetramer of human malic enzyme. a, Schematic drawing of the tetramer of m-NAD-ME in the closed form. The monomers are colored in green, cyan, yellow and purple, respectively. The bound NAD^+ and oxalate molecules are shown in stick representation. b, Stereo diagram showing part of the tetramer interface in the oxalate complex involving residues 541 -544. The carbon atoms of the two monomers at this interface are shown in yellow and cyan, respectively. The location of the two-fold axis is indicated by the purple bar. c, The tetramer interface in the NAD^+ binary complex, for the same residues as those in (b). There is a large change in the relative positions of the two monomers in this region, together with a change in the side chain conformation for Tyr 543.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2000, 7, 251-257) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19091740 J.Y.Hsieh, and H.C.Hung (2009).
Engineering of the Cofactor Specificities and Isoform-specific Inhibition of Malic Enzyme.
  J Biol Chem, 284, 4536-4544.  
19236308 J.Y.Hsieh, J.H.Liu, Y.W.Fang, and H.C.Hung (2009).
Dual roles of Lys(57) at the dimer interface of human mitochondrial NAD(P)+-dependent malic enzyme.
  Biochem J, 420, 201-209.  
19416979 J.Y.Hsieh, S.H.Chen, and H.C.Hung (2009).
Functional roles of the tetramer organization of malic enzyme.
  J Biol Chem, 284, 18096-18105.  
18959763 J.Y.Hsieh, G.Y.Liu, and H.C.Hung (2008).
Influential factor contributing to the isoform-specific inhibition by ATP of human mitochondrial NAD(P)+-dependent malic enzyme: functional roles of the nucleotide binding site Lys346.
  FEBS J, 275, 5383-5392.  
18288573 M.C.Wheeler, C.L.Arias, M.A.Tronconi, V.G.Maurino, C.S.Andreo, and M.F.Drincovitch (2008).
Arabidopsis thaliana NADP-malic enzyme isoforms: high degree of identity but clearly distinct properties.
  Plant Mol Biol, 67, 231-242.  
17983264 C.H.Yeang, and D.Haussler (2007).
Detecting coevolution in and among protein domains.
  PLoS Comput Biol, 3, e211.  
17704184 H.C.Chang, L.Y.Chen, Y.H.Lu, M.Y.Li, Y.H.Chen, C.H.Lin, and G.G.Chang (2007).
Metal ions stabilize a dimeric molten globule state between the open and closed forms of malic enzyme.
  Biophys J, 93, 3977-3988.  
17566975 R.Pedreschi, E.Vanstreels, S.Carpentier, M.Hertog, J.Lammertyn, J.Robben, J.P.Noben, R.Swennen, J.Vanderleyden, and B.M.Nicolaï (2007).
Proteomic analysis of core breakdown disorder in Conference pears (Pyrus communis L.).
  Proteomics, 7, 2083-2099.  
16757477 J.Y.Hsieh, G.Y.Liu, G.G.Chang, and H.C.Hung (2006).
Determinants of the dual cofactor specificity and substrate cooperativity of the human mitochondrial NAD(P)+-dependent malic enzyme: functional roles of glutamine 362.
  J Biol Chem, 281, 23237-23245.  
16889632 S.C.Chang, K.Y.Lin, Y.J.Chen, C.H.Lai, G.G.Chang, and W.Y.Chou (2006).
Critical roles of conserved carboxylic acid residues in pigeon cytosolic NADP+-dependent malic enzyme.
  FEBS J, 273, 4072-4081.  
16143603 T.J.Merritt, D.Duvernell, and W.F.Eanes (2005).
Natural and synthetic alleles provide complementary insights into the nature of selection acting on the Men polymorphism of Drosophila melanogaster.
  Genetics, 171, 1707-1718.  
  15876562 W.Fukuda, Y.S.Ismail, T.Fukui, H.Atomi, and T.Imanaka (2005).
Characterization of an archaeal malic enzyme from the hyperthermophilic archaeon Thermococcus kodakaraensis KOD1.
  Archaea, 1, 293-301.  
14747989 C.W.Kuo, H.C.Hung, L.Tong, and G.G.Chang (2004).
Metal-Induced reversible structural interconversion of human mitochondrial NAD(P)+-dependent malic enzyme.
  Proteins, 54, 404-411.  
12562758 E.Detarsio, M.C.Wheeler, V.A.Campos Bermúdez, C.S.Andreo, and M.F.Drincovich (2003).
Maize C4 NADP-malic enzyme. Expression in Escherichia coli and characterization of site-directed mutants at the putative nucleoside-binding sites.
  J Biol Chem, 278, 13757-13764.  
14596586 G.G.Chang, and L.Tong (2003).
Structure and function of malic enzymes, a new class of oxidative decarboxylases.
  Biochemistry, 42, 12721-12733.  
12853453 G.S.Rao, D.E.Coleman, W.E.Karsten, P.F.Cook, and B.G.Harris (2003).
Crystallographic studies on Ascaris suum NAD-malic enzyme bound to reduced cofactor and identification of an effector site.
  J Biol Chem, 278, 38051-38058.
PDB code: 1o0s
12711612 H.C.Chang, and G.G.Chang (2003).
Involvement of single residue tryptophan 548 in the quaternary structural stability of pigeon cytosolic malic enzyme.
  J Biol Chem, 278, 23996-24002.  
12802505 H.Volschenk, H.J.van Vuuren, and M.Viljoen-Bloom (2003).
Malo-ethanolic fermentation in Saccharomyces and Schizosaccharomyces.
  Curr Genet, 43, 379-391.  
12577265 R.Kho, B.L.Baker, J.V.Newman, R.M.Jack, D.S.Sem, H.O.Villar, and M.R.Hansen (2003).
A path from primary protein sequence to ligand recognition.
  Proteins, 50, 589-599.  
12962632 X.Tao, Z.Yang, and L.Tong (2003).
Crystal structures of substrate complexes of malic enzyme and insights into the catalytic mechanism.
  Structure, 11, 1141-1150.
PDB codes: 1pj2 1pj3 1pj4
11739398 H.C.Chang, W.Y.Chou, and G.G.Chang (2002).
Effect of metal binding on the structural stability of pigeon liver malic enzyme.
  J Biol Chem, 277, 4663-4671.  
12192069 S.Chakraborty, N.Chakraborty, D.Jain, D.M.Salunke, and A.Datta (2002).
Active site geometry of oxalate decarboxylase from Flammulina velutipes: Role of histidine-coordinated manganese in substrate recognition.
  Protein Sci, 11, 2138-2147.  
12121650 Z.Yang, C.W.Lanks, and L.Tong (2002).
Molecular mechanism for the regulation of human mitochondrial NAD(P)+-dependent malic enzyme by ATP and fumarate.
  Structure, 10, 951-960.
PDB codes: 1gz3 1gz4
11790843 Z.Yang, H.Zhang, H.C.Hung, C.C.Kuo, L.C.Tsai, H.S.Yuan, W.Y.Chou, G.G.Chang, and L.Tong (2002).
Structural studies of the pigeon cytosolic NADP(+)-dependent malic enzyme.
  Protein Sci, 11, 332-341.
PDB code: 1gq2
11009609 D.Liu, W.E.Karsten, and P.F.Cook (2000).
Lysine 199 is the general acid in the NAD-malic enzyme reaction.
  Biochemistry, 39, 11955-11960.  
11087357 H.C.Hung, G.G.Chang, Z.Yang, and L.Tong (2000).
Slow binding of metal ions to pigeon liver malic enzyme: a general case.
  Biochemistry, 39, 14095-14102.  
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 code is shown on the right.