PDBsum entry 2gd2

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Isomerase PDB id
Protein chains
354 a.a. *
CAA ×4
GOL ×2
Waters ×1554
* Residue conservation analysis
PDB id:
Name: Isomerase
Title: The 1,1-proton transfer reaction mechanism by alpha-methylac racemase is catalyzed by an aspartate/histidine pair and in smooth, methionine-rich surface for binding the fatty acyl
Structure: Probable alpha-methylacyl-coa racemase mcr. Chain: a, b, c, d. Synonym: 2-methylacyl-coa racemase, 2-arylpropionyl-coa epi engineered: yes
Source: Mycobacterium tuberculosis. Organism_taxid: 1773. Gene: cab09031. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.70Å     R-factor:   0.208     R-free:   0.250
Authors: P.Bhaumik,R.K.Wierenga
Key ref:
P.Bhaumik et al. (2007). The catalysis of the 1,1-proton transfer by alpha-methyl-acyl-CoA racemase is coupled to a movement of the fatty acyl moiety over a hydrophobic, methionine-rich surface. J Mol Biol, 367, 1145-1161. PubMed id: 17320106 DOI: 10.1016/j.jmb.2007.01.062
15-Mar-06     Release date:   20-Feb-07    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
O06543  (O06543_MYCTU) -  Alpha-methylacyl-CoA racemase Mcr
360 a.a.
354 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     acyl-CoA metabolic process   1 term 
  Biochemical function     catalytic activity     3 terms  


DOI no: 10.1016/j.jmb.2007.01.062 J Mol Biol 367:1145-1161 (2007)
PubMed id: 17320106  
The catalysis of the 1,1-proton transfer by alpha-methyl-acyl-CoA racemase is coupled to a movement of the fatty acyl moiety over a hydrophobic, methionine-rich surface.
P.Bhaumik, W.Schmitz, A.Hassinen, J.K.Hiltunen, E.Conzelmann, R.K.Wierenga.
Alpha-methylacyl-CoA racemases are essential enzymes for branched-chain fatty acid metabolism. Their reaction mechanism and the structural basis of their wide substrate specificity are poorly understood. High-resolution crystal structures of Mycobacterium tuberculosis alpha-methylacyl-CoA racemase (MCR) complexed with substrate molecules show the active site geometry required for catalysis of the interconversion of (2S) and (2R)-methylacyl-CoA. The thioester oxygen atom and the 2-methyl group are in a cis-conformation with respect to each other. The thioester oxygen atom fits into an oxyanion hole and the 2-methyl group points into a hydrophobic pocket. The active site geometry agrees with a 1,1-proton transfer mechanism in which the acid/base-pair residues are His126 and Asp156. The structures of the complexes indicate that the acyl chains of the S-substrate and the R-substrate bind in an S-pocket and an R-pocket, respectively. A unique feature of MCR is a large number of methionine residues in the acyl binding region, located between the S-pocket and the R-pocket. It appears that the (S) to (R) interconversion of the 2-methylacyl chiral center is coupled to a movement of the acyl group over this hydrophobic, methionine-rich surface, when moving from its S-pocket to its R-pocket, whereas the 2-methyl moiety and the CoA group remain fixed in their respective pockets.
  Selected figure(s)  
Figure 1.
Figure 1. (a) The substrate molecules of mammalian Amacr. The covalent structures of pristanoyl-CoA, 3,7,12-trihydroxycoprostanoyl-CoA and ibuprofenoyl-CoA are shown. The methyl group attached to the chiral C^α atom is referred to as the 2-methyl moiety. Amacr interconverts the chirality of this C^α atom. (b) The covalent structures of the substrate analogues acetyl-CoA and acetoacetyl-CoA. The conformation of the acetoacetyl moiety shown at the left concerns the conformation that allows for internal hydrogen bonding. The rotamer at the right visualizes the observed mode of binding in the structure of the acetoacetyl-CoA MCR complex. (c) The reaction catalyzed by MCR. The catalytic interconversion of the two enantiomers takes place in the enzyme active site by a 1,1-proton transfer involving a catalytic acid/base-pair, which in MCR is His126 (base B[1]) and Asp156 (base B[2]). In the anionic intermediate, the C^α atom is planar and a negative charge develops on the thioester oxygen atom.
Figure 9.
Figure 9. The reaction mechanism of the interconversion of (2S)-methylacyl-CoA to (2R)-methylacyl-CoA by MCR, as suggested from the crystal structure and kinetic data. In this enzymatic conversion, His126 acts as a general base (abstracting a proton from the α-carbon atom of the (S)-compound) and Asp156 acts as a general acid (donating a proton to the α-carbon atom of the (S)-compound). Dotted lines highlight important stabilizing interactions. The oxyanion of the reaction intermediate is stabilized by hydrogen bonding interactions with the main-chain NH group of Asp127, as well as with the protonated side-chains of His126 and Asp156.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2007, 367, 1145-1161) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20442897 F.A.Sattar, D.J.Darley, F.Politano, T.J.Woodman, M.D.Threadgill, and M.D.Lloyd (2010).
Unexpected stereoselective exchange of straight-chain fatty acyl-CoA alpha-protons by human alpha-methylacyl-CoA racemase 1A (P504S).
  Chem Commun (Camb), 46, 3348-3350.  
19156321 D.J.Darley, D.S.Butler, S.J.Prideaux, T.W.Thornton, A.D.Wilson, T.J.Woodman, M.D.Threadgill, and M.D.Lloyd (2009).
Synthesis and use of isotope-labelled substrates for a mechanistic study on human alpha-methylacyl-CoA racemase 1A (AMACR; P504S).
  Org Biomol Chem, 7, 543-552.  
18279392 M.D.Lloyd, D.J.Darley, A.S.Wierzbicki, and M.D.Threadgill (2008).
Alpha-methylacyl-CoA racemase--an 'obscure' metabolic enzyme takes centre stage.
  FEBS J, 275, 1089-1102.  
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.