Enzymes in the enolase superfamily are related by their ability to catalyze the abstraction of a proton alpha to a carboxylic acid to form an enolate anion intermediate. This conserved partial reaction is mediated by conserved residues in the active site, including three residues used to bind a divalent metal involved in stabilization of the common intermediate.
Reactions catalyzed by these enzymes include racemization, beta-elimination of OH- or NH3, and cycloisomerization. Each member has two structural domains, an N-terminal “capping” domain and a C-terminal beta8/alpha8-barrel domain, both of which are required for function. In general, the catalytic residues can be found at ends of the beta strands in the C-terminal barrel domain, while the residues required for substrate specificity are contained in the N-terminal domain. Although the beta8/alpha8-barrel fold is common to many other superfamilies, none of these superfamilies show a significant level of sequence or functional similarity to the enolase superfamily.
Networks curated for the enolase SF in the SFLD are available for download via the Download Archived Data tab. An additional set of networks that include structure and sequence similarity networks, chemical similarity networks, and additional networks from the MEERCat infrastructure paper are available for download here. The MEERCat paper links enzyme reactions and ligands to their associated proteins using the Enolase superfamily as a detailed example.
Babbitt, P.C., et al.
The enolase superfamily: a general strategy for enzyme-catalyzed abstraction of the alpha-protons of carboxylic acids
▸ Abstract
We have discovered a superfamily of enzymes related by their ability to catalyze the abstraction of the alpha-proton of a carboxylic acid to form an enolic intermediate. Although each reaction catalyzed by these enzymes is initiated by this common step, their overall reactions (including racemization, beta-elimination of water, beta-elimination of ammonia, and cycloisomerization) as well as the stereochemical consequences (syn vs anti) of the beta-elimination reactions are diverse. Analysis of sequence and structural similarities among these proteins suggests that all of their chemical reactions are mediated by a common active site architecture modified through evolution to allow the enolic intermediates to partition to different products in their respective active sites via different overall mechanisms. All of these enzymes retain the ability to catalyze the thermodynamically difficult step of proton abstraction. These homologous proteins, designated the "enolase superfamily", include enolase as well as more metabolically specialized enzymes: mandelate racemase, galactonate dehydratase, glucarate dehydratase, muconate-lactonizing enzymes, N-acylamino acid racemase, beta-methylaspartate ammonia-lyase, and o-succinylbenzoate synthase. Comparative analysis of structure-function relationships within the superfamily suggests that carboxyphosphonoenolpyruvate synthase, another member of the superfamily, does not catalyze the reaction proposed in the literature but catalyzes an enolase-like reaction instead. The established and deduced structure-function relationships in the superfamily allow the prediction that other apparent members of the family for which no catalytic functions have yet been assigned will also perform chemistry involving abstraction of the alpha-protons of carboxylic acids.
