The chemistry of protein catalysis

Gemma L. Holliday, Daniel E. Almonacid, John Blayney Owen Mitchell, Janet M. Thornton

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

We report, for the first time, on the statistics of chemical mechanisms and amino acid residue functions that occur in enzyme reaction sequences using the MAGE database of 202 distinct enzyme reaction mechanisms as a knowledge base. MAGE currently holds representatives from each Enzyme Commission sub-subclass where there is an available crystal structure and sufficient evidence in the primary literature for a mechanism. Each catalytic step of every reaction sequence in MAGE is fully annotated, so that it includes the function of the catalytic residues involved in the reaction and the chemical mechanisms by which substrates are transformed into products. We show that the most catalytic amino acid residues are histidine, cysteine and aspartate, which are also the residues whose side-chains are more likely to serve as reactants, and that have the greatest versatility of function. We show that electrophilic reactions in enzymes are very rare, and the majority of enzyme reactions rely upon nucleophilic and general acid/base chemistry. However, although rare, radical (homolytic) reactions are much more common than electrophilic reactions. Thus, the majority of amino acid residues perform stabilisation roles (as spectators) or proton shuttling roles (as reactants). The analysis presented provides a better understanding of the mechanisms of enzyme catalysis and may act as an initial step in the validation and prediction of mechanism in an enzyme active site. (c) 2007 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)1261-1277
Number of pages17
JournalJournal of Molecular Biology
Volume372
Issue number5
DOIs
Publication statusPublished - 5 Oct 2007

Keywords

  • enzyme reaction mechanism
  • catalytic residue
  • amino acid residue function
  • enzyme chemistry
  • Ingold mechanisms
  • PYRUVATE FORMATE-LYASE
  • OROTIDINE 5'-MONOPHOSPHATE DECARBOXYLASE
  • CRYSTAL-STRUCTURE
  • SUBSTRATE-SPECIFICITY
  • ANGSTROM RESOLUTION
  • NAD(+) SYNTHETASE
  • ENZYME DATABASE
  • DATA-BANK
  • MECHANISM
  • RESIDUES

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