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Understanding epoxide hydrolase regiospecificity: towards the discovery and design of highly selective biocatalysts (LB133)
Author(s) -
Horsman Geoff,
Aliwalas Mark
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.lb133
Subject(s) - regioselectivity , enediyne , diol , chemistry , epoxide hydrolase , stereochemistry , biosynthesis , natural product , enzyme , computational biology , biochemistry , biology , organic chemistry , microsome , catalysis
The ever‐increasing quantity of genomic data continues to reveal a great deal about microbial natural product biosynthesis and has enabled new molecule and biocatalyst discovery. However, predicting chemical structures from gene sequences remains challenging because even enzymes with high sequence similarity may catalyze unexpectedly different reactions. This information gap between genes and chemical structure can be narrowed by careful comparison of related biosynthetic enzymes. For example, epoxide hydrolases (EHs) of very high sequence similarity from related enediyne biosynthetic pathways can have different regiospecificities, resulting in opposite stereochemical configuration in the products. Specifically, “inverting” EHs hydrolyze an (S)‐epoxide substrate to generate an (R)‐vicinal diol while “retaining” EHs yield an (S)‐vicinal diol. Intriguingly, the inverting EHs possess only one of the two canonical Tyr residues present in EHs. Biochemical characterization of several EH mutants suggests that Tyr substitution may direct EH regioselectivity. Indeed, genome mining has identified additional enediyne biosynthesis‐associated EHs that further the predictive utility of the Tyr substitution, thereby setting the stage for understanding EH regioselectivity.