Structural highlights
Function
AMACR_MYCTU Catalyzes the epimerization of (2R)- and (2S)-methylacyl-coenzyme A (CoA) thioesters (PubMed:15632186, PubMed:19854148, PubMed:26348625). Accepts as substrates a wide range of alpha-methylacyl-CoAs, including (2R)-2-methylmyristoyl-CoA and (2S)-2-methylmyristoyl-CoA, (2R)-pristanoyl-CoA and (2S)-pristanoyl-CoA, and the cholesterol esters (25R)-3-oxo-cholest-4-en-26-oyl-CoA and (25S)-3-oxo-cholest-4-en-26-oyl-CoA (PubMed:15632186, PubMed:26348625). Can also catalyze the interconversion of the non-physiologic substrates (2R)-ibuprofenoyl-CoA and (2S)-ibuprofenoyl-CoA, which are potential competitive inhibitors of the enzyme (PubMed:19854148).[1] [2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
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.,Bhaumik P, Schmitz W, Hassinen A, Hiltunen JK, Conzelmann E, Wierenga RK J Mol Biol. 2007 Apr 6;367(4):1145-61. Epub 2007 Jan 27. PMID:17320106[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Savolainen K, Bhaumik P, Schmitz W, Kotti TJ, Conzelmann E, Wierenga RK, Hiltunen JK. Alpha-methylacyl-CoA racemase from Mycobacterium tuberculosis. Mutational and structural characterization of the active site and the fold. J Biol Chem. 2005 Apr 1;280(13):12611-20. Epub 2005 Jan 4. PMID:15632186 doi:10.1074/jbc.M409704200
- ↑ Ouazia D, Bearne SL. A continuous assay for alpha-methylacyl-coenzyme A racemase using circular dichroism. Anal Biochem. 2010 Mar 1;398(1):45-51. PMID:19854148 doi:10.1016/j.ab.2009.10.039
- ↑ Lu R, Schmitz W, Sampson NS. α-Methyl Acyl CoA Racemase Provides Mycobacterium tuberculosis Catabolic Access to Cholesterol Esters. Biochemistry. 2015 Sep 22;54(37):5669-72. PMID:26348625 doi:10.1021/acs.biochem.5b00911
- ↑ Bhaumik P, Schmitz W, Hassinen A, Hiltunen JK, Conzelmann E, Wierenga RK. 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. 2007 Apr 6;367(4):1145-61. Epub 2007 Jan 27. PMID:17320106 doi:http://dx.doi.org/10.1016/j.jmb.2007.01.062
