Mechanistic imperative for the evolution of a metalloglutathione transferase of the vicinal oxygen chelate superfamily.
A number of glutathione (GSH) transferases are now known in prokaryotes and eukaryotes. The enzymes appear to be primarily involved in the metabolism of foreign compounds. At least six distinct classes of soluble GSH transferases have been identified in eukaryotes and named alpha, mu, pi, sigma, theta and kappa. Sequences and the known three-dimensional structures of the soluble enzymes suggest that these proteins share a common ancestry, though the precise details of their evolution remain obscure. A second distinct family of GSH transferases are the microsomal or membrane-bound enzymes that include leukotriene C4 synthase. A third family is represented by a bacterial GSH transferase (FosA) responsible for conferring resistance to the antibiotic fosfomycin, reported some years ago by Suarez and co-workers (Arca et al., Antimicrob. Agents Chemother. 34 (1990) 1552-1556). The enzyme is quite specific for fosfomycin, which contains a very stable epoxide moiety. Evidence is presented that FosA is a metalloprotein related to iron- and manganese-dependent dioxygenases and to glyoxalase I. These enzymes are members of a previously unrecognized group of enzymes; the vicinal oxygen chelate superfamily. The mechanistic imperative driving the evolution of FosA and its relatives, which are enzymes catalyzing quite diverse chemical reactions, is proposed to be the electrophilic assistance provided by the metal through chelation of a substrate or intermediate.
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
L T
LT
Laughlin
B A
BA
Bernat
R N
RN
Armstrong
D000818:Animals; D001426:Bacterial Proteins; D001665:Binding Sites; D002413:Cations, Divalent / Q000494:pharmacology; D002614:Chelating Agents / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D019143:Evolution, Molecular; D005982:Glutathione Transferase / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008667:Metalloproteins / Q000145:classification / Q000235:genetics / Q000378:metabolism; D008670:Metals / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism
D001426:Bacterial Proteins; D002413:Cations, Divalent; D002614:Chelating Agents; D008667:Metalloproteins; D008670:Metals; D005982:Glutathione Transferase; D010100:Oxygen