Mechanistic Diversity in a Metalloenzyme Superfamily

Abstract

It is now appreciated that the relationships of proteins, particularly enzymes, within a protein superfamily can be understood not only in terms of their sequence similarities and three-dimensional structures but also by chemical threads that relate their functional attributes. The mechanistic ties among superfamily members can often be traced to a common transition state for the rate-limiting step of the reactions being catalyzed. This paper presents an analysis of a metalloenzyme superfamily, the members of which catalyze a very diverse set of reactions with unrelated transition states but a more general common mechanistic imperative. The vicinal oxygen chelate (VOC) superfamily is composed of structurally related proteins with paired beta alpha beta beta beta motifs that provide a metal coordination environment with two or three open or readily accessible coordination sites to promote direct electrophilic participation of the metal ion in catalysis. The known types of reactions that are catalyzed include isomerizations (glyoxalase I), epimerizations (methylmalonyl-CoA epimerase), oxidative cleavage of C-C bonds (extradiol dioxygenase), and nucleophilic substitutions (fosfomycin resistance proteins). The remarkable access to mechanism space that is provided by the VOC superfamily appears to derive from a simple, pseudosymmetric structural fold that maximizes the catalytic versatility of the metal center.

Determinants of Regioselectivity and Chemoselectivity in Fosfomycin Resistance Protein FosA from QM/MM Calculations

“…15−17 Amino acid sequence comparisons have demonstrated that these three enzymes are members of the vicinal oxygen chelate (VOC) superfamily of metalloenzymes. 18 The structural hallmark of this superfamily is a paired βαβββ motif that offers coordination sites to the metal, which in turn help substrate binding through direct coordination. 18 The X-ray structures of FosA from Pseudomonas aeruginosa 13,19 and transposon Tn2921 20 have been solved.…”

Gentisate 1,2-Dioxygenase fromXanthobacter polyaromaticivorans127W

“…5) The third group enzyme is apparently different from the two former groups because it degrades 1,4-or 2,5-dihydroxylated substrates such as gentisate (2,5-dihydroxybenzoate), homogentisate, and hydroquinone. Gentisate 1,2-dioxygenase (GDO, EC1.13.11.4) is included in this group, which cleaves the aromatic ring between the carboxyl and proximal hydroxyl groups in the aromatic ring to yield maleylpyruvate.…”

Glutationa e enzimas relacionadas: papel biológico e importância em processos patológicos

“…Outras famílias de glutationa transferases (GSTs), ausentes em mamíferos, são descritas na literatura. 27,28 O sistema de nomenclatura para as GSTs citossólicas e mitocondriais é bem estabelecido 23,29 e prevê que: as glutationa transferases são divididas de acordo com a seqüência de aminoácidos e/ou nucleotídeos, propriedades imunológicas, parâmetros de cinética enzimática e/ou estrutura terciária e quaternária; as sub-unidades devem ser agrupadas segundo a seqüência de seus genes e designadas por algarismos hindu-árabicos numa ordem crescente, em função da data de sua identificação; as sub-unidades codificadas pelo mesmo locus de um gene devem ser designadas pelo mesmo algarismo, sendo as variações alélicas, se observadas, indicadas por letras minúsculas do alfabeto romano em subscrito. 29 Para distinguir enzimas de diferentes espécies, deve-se utilizar a inicial do nome do organismo (termo em inglês) em letra minúscula e em itálico.…”

“…Estes compostos são denominados xenobióticos e podem interagir de maneira dele- (26) e da progesterona (28) téria ao organismo. A detoxificação enzimática de xenobióticos pode ser classificada em três fases distintas, porém estritamente relacionadas: fase I, II e III.…”

“…-pregnen-3,20-diona (27), e a isomerização da ligação dupla pela ação da GST A3-3, resultando na produção de progesterona (28 …”