1jc5 Citations

Crystal structure of methylmalonyl-coenzyme A epimerase from P. shermanii: a novel enzymatic function on an ancient metal binding scaffold.

Structure 9 637-46 (2001)
Cited: 21 times
EuropePMC logo PMID: 11470438

Abstract

Background

Methylmalonyl-CoA epimerase (MMCE) is an essential enzyme in the breakdown of odd-numbered fatty acids and of the amino acids valine, isoleucine, and methionine. Present in many bacteria and in animals, it catalyzes the conversion of (2R)-methylmalonyl-CoA to (2S)-methylmalonyl-CoA, the substrate for the B12-dependent enzyme, methylmalonyl-CoA mutase. Defects in this pathway can result in severe acidosis and cause damage to the central nervous system in humans.

Results

The crystal structure of MMCE from Propionibacterium shermanii has been determined at 2.0 A resolution. The MMCE monomer is folded into two tandem betaalphabetabetabeta modules that pack edge-to-edge to generate an 8-stranded beta sheet. Two monomers then pack back-to-back to create a tightly associated dimer. In each monomer, the beta sheet curves around to create a deep cleft, in the floor of which His12, Gln65, His91, and Glu141 provide a binding site for a divalent metal ion, as shown by the binding of Co2+. Modeling 2-methylmalonate into the active site identifies two glutamate residues as the likely essential bases for the epimerization reaction.

Conclusion

The betaalphabetabetabeta modules of MMCE correspond with those found in several other proteins, including bleomycin resistance protein, glyoxalase I, and a family of extradiol dioxygenases. Differences in connectivity are consistent with the evolution of these very different proteins from a common precursor by mechanisms of gene duplication and domain swapping. The metal binding residues also align precisely, and striking structural similarities between MMCE and glyoxalase I suggest common mechanisms in their respective epimerization and isomerization reactions.

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  1. The genomic enzymology of antibiotic resistance. Morar M, Wright GD. Annu. Rev. Genet. 44 25-51 (2010)
  2. The ins and outs of ring-cleaving dioxygenases. Vaillancourt FH, Bolin JT, Eltis LD. Crit. Rev. Biochem. Mol. Biol. 41 241-267 (2006)

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  2. Cryptic chlorination by a non-haem iron enzyme during cyclopropyl amino acid biosynthesis. Vaillancourt FH, Yeh E, Vosburg DA, O'Connor SE, Walsh CT. Nature 436 1191-1194 (2005)
  3. Catalysing new reactions during evolution: economy of residues and mechanism. Bartlett GJ, Borkakoti N, Thornton JM. J. Mol. Biol. 331 829-860 (2003)
  4. Structural and functional analysis of A-type ketoreductases from the amphotericin modular polyketide synthase. Zheng J, Taylor CA, Piasecki SK, Keatinge-Clay AT. Structure 18 913-922 (2010)
  5. Functional annotation by identification of local surface similarities: a novel tool for structural genomics. Ferrè F, Ausiello G, Zanzoni A, Helmer-Citterich M. BMC Bioinformatics 6 194 (2005)
  6. Using reaction mechanism to measure enzyme similarity. O'Boyle NM, Holliday GL, Almonacid DE, Mitchell JB. J. Mol. Biol. 368 1484-1499 (2007)
  7. 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. 367 1145-1161 (2007)
  8. Structural variation in bacterial glyoxalase I enzymes: investigation of the metalloenzyme glyoxalase I from Clostridium acetobutylicum. Suttisansanee U, Lau K, Lagishetty S, Rao KN, Swaminathan S, Sauder JM, Burley SK, Honek JF. J. Biol. Chem. 286 38367-38374 (2011)
  9. Structural insight into gene duplication, gene fusion and domain swapping in the evolution of PLP-independent amino acid racemases. Liu L, Iwata K, Yohda M, Miki K. FEBS Lett. 528 114-118 (2002)
  10. Functional analysis of the methylmalonyl-CoA epimerase from Caenorhabditis elegans. Kühnl J, Bobik T, Procter JB, Burmeister C, Höppner J, Wilde I, Lüersen K, Torda AE, Walter RD, Liebau E. FEBS J. 272 1465-1477 (2005)
  11. Biosynthetic gene cluster of cetoniacytone A, an unusual aminocyclitol from the endosymbiotic Bacterium Actinomyces sp. Lu 9419. Wu X, Flatt PM, Xu H, Mahmud T. Chembiochem 10 304-314 (2009)
  12. Epimerase (Msed_0639) and mutase (Msed_0638 and Msed_2055) convert (S)-methylmalonyl-coenzyme A (CoA) to succinyl-CoA in the Metallosphaera sedula 3-hydroxypropionate/4-hydroxybutyrate cycle. Han Y, Hawkins AS, Adams MW, Kelly RM. Appl. Environ. Microbiol. 78 6194-6202 (2012)
  13. Molecular basis of mitomycin C resistance in streptomyces: structure and function of the MRD protein. Martin TW, Dauter Z, Devedjiev Y, Sheffield P, Jelen F, He M, Sherman DH, Otlewski J, Derewenda ZS, Derewenda U. Structure 10 933-942 (2002)
  14. Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: a novel cause of mild methylmalonic aciduria. Dobson CM, Gradinger A, Longo N, Wu X, Leclerc D, Lerner-Ellis J, Lemieux M, Belair C, Watkins D, Rosenblatt DS, Gravel RA. Mol. Genet. Metab. 88 327-333 (2006)
  15. Expression of Xhdsi-1VOC, a novel member of the vicinal oxygen chelate (VOC) metalloenzyme superfamily, is up-regulated in leaves and roots during desiccation in the resurrection plant Xerophyta humilis (Bak) Dur and Schinz. Mulako I, Farrant JM, Collett H, Illing N. J. Exp. Bot. 59 3885-3901 (2008)
  16. Toxoflavin lyase requires a novel 1-His-2-carboxylate facial triad. Fenwick MK, Philmus B, Begley TP, Ealick SE. Biochemistry 50 1091-1100 (2011)
  17. Conserved protein YecM from Escherichia coli shows structural homology to metal-binding isomerases and oxygenases. Zhang RG, Duke N, Laskowski R, Evdokimova E, Skarina T, Edwards A, Joachimiak A, Savchenko A. Proteins 51 311-314 (2003)
  18. A study on the chiral inversion of mandelic acid in humans. Yevglevskis M, Bowskill CR, Chan CC, Heng JH, Threadgill MD, Woodman TJ, Lloyd MD. Org. Biomol. Chem. 12 6737-6744 (2014)
  19. Crystal structure of a putative methylmalonyl-coenzyme A epimerase from Thermoanaerobacter tengcongensis at 2.0 A resolution. Shi L, Gao P, Yan XX, Liang DC. Proteins 77 994-999 (2009)


Related citations provided by authors (1)

  1. Expression, Crystallization and Preliminary Characterization of Methylmalonyl Coenzyme A Epimerase from Propionibacterium shermanii. Mc Carthy AA, Baker HM, Shewry SC, Kagawa TF, Saafi E, Patchett ML, Baker EN Acta Crystallogr. D Biol. Crystallogr. 57 706-708 (2001)