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Bioorg Chem. 2014 Dec;57:206-12. doi: 10.1016/j.bioorg.2014.07.001. Epub 2014 Jul 11.

Reflections on the catalytic power of a TIM-barrel.

Author information

1
Department of Chemistry, University at Buffalo, SUNY, Buffalo, NY 14260, United States. Electronic address: jrichard@buffalo.edu.
2
Department of Chemistry, University at Buffalo, SUNY, Buffalo, NY 14260, United States.

Abstract

The TIM-barrel fold is described and its propagation throughout the enzyme universe noted. The functions of the individual front loops of the eponymous TIM-barrel of triosephosphate isomerase are presented in a discussion of: (a) electrophilic catalysis, by amino acid side chains from loops 1 and 4, of abstraction of an α-carbonyl hydrogen from substrate dihydroxyacetone phosphate (DHAP) or d-glyceraldehyde 3-phosphate (DGAP). (b) The engineering of loop 3 to give the monomeric variant monoTIM and the structure and catalytic properties of this monomer. (c) The interaction between loops 6, 7 and 8 and the phosphodianion of DHAP or DGAP. (d) The mechanism by which a ligand-gated conformational change, dominated by motion of loops 6 and 7, activates TIM for catalysis of deprotonation of DHAP or DGAP. (e) The conformational plasticity of TIM, and the utilization of substrate binding energy to "mold" the distorted active site loops of TIM mutants into catalytically active enzymes. The features of the TIM-barrel fold that favor effective protein catalysis are discussed.

KEYWORDS:

Catalysis; Enolate; Enzyme; Protein structure; Proton transfer; TIM-barrel

PMID:
25092608
PMCID:
PMC4256097
DOI:
10.1016/j.bioorg.2014.07.001
[Indexed for MEDLINE]
Free PMC Article

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