Convergence of active center geometries

Abstract

Comparisons have been made between the active center geometries of lactate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase, chymotrypsin and papain, and glyceraldehyde-3-phosphate dehydrogenase and papain. In the dehydrogenases, orientation of the nicotinamide ring about the glycosidic bond is determined by the substrate stereochemistry. The proper positioning of the carboxyamide moiety allows for the close approach of the C4 atom on the nicotinamide and the reactive carbon of the substrate. It follows that, once the conformation of the substrate or substrate intermediate has been established with respect to the functional groups in the enzyme, the A- or B-side specificity of the nicotinamide ring is predetermined. Hence, dehydrogenases which are divergently evolving from a common precursor must maintain the nicotinamide specificity if the protein fold of the catalytic domain is conserved. The tetrahedral intermediates produced during acylation of chymotrypsin and papain are found to be of opposite hand, while those of papain and glyceraldehyde-3-phosphate dehydrogenase can be regarded to be of the same hand. Thus the serine proteases, subtilisin and those of the chymotrypsin family, are of one hand while the cysteine enzymes, glyceraldehyde-3-phosphate dehydrogenase and papain, are of the other.

Three‐dimensional, sequence order‐independent structural comparison of a serine protease against the crystallographic database reveals active site similarities: Potential implications to evolution and to protein folding

“…Our method succeeded in finding the rough similarity around the active sites of these proteases automatically, without any prior knowledge of their existence. Except for the match of Cys 25 with Ser 195, the matches obtained between actinidin and trypsin differ from the ones suggested by Garavito et al (1977). We note, however, that only C, atoms were compared, whereas the active sites contain mostly side chains.…”

Electrostatic properties in the catalytic site of papain: A possible regulatory mechanism for the reactivity of the ion pair

“…These two residues together with the Asn175 form the Cys25/His159/Asn175 catalytic site motif of the cysteine proteinase superfamily analogous to the Ser/His/ Asp catalytic site motif of serine proteinases. 8 Electrostatic effects are of central importance in determining protein structure and stability and play a major role in a variety of functional mechanisms associated with proteins 9 -11 (e.g., molecular recognition, ligand specificity, catalytic mechanisms, enzyme regulation). Moreover, electrostatic effects in active sites are believed to be the most important aspect to explain the rate acceleration of enzyme catalyzed reactions, the enzymes acting like a preor-ganized "supersolvent" (i.e., active site preoriented polar environment) to provide an electrostatic stabilization of the charge distribution of transition states.…”

Structural determinants of stereospecificity in yeast alcohol dehydrogenase.

“…However, because the distinction between the Re and Si hydrogens of NADH appears subtle, many commentators (5,11,12) have rejected functional models for stereospecificity in dehydrogenases in favor of "historical" models (13,14) that assume that stereospecificity serves no selected function, but rather is a "frozen accident," a vestige of a random choice made early in the evolution of individual classes of dehydrogenases that, once made, is difficult to change.…”