Mechanistic promiscuity

What is seen for this series of inhibitors is that small structural modifications of the inhibitor can completely change the mechanism of inhibition. Clearly, structure-activity conclusions are very difficult to draw correctly in the absence of structural data in such a case. In general, the need to assess this type of mechanistic promiscuity by crystallography and/or mass spectrometry can become an excessively demanding resource drain in a medicinal chemistry project. 

In the Organophosphate Phosphate Antiporter (OPA) family (2. A. 1.4), most members preferentially catalyze substrate substrate antiport, but they can also catalyze substrate H symport, and some preferentially seem to use a symport rather than an antiport mechanism. Also, in the Nitrate/ Nitrite Porter (NNP) family (2.A. 1.8), members of similar sequence can catalyze either uptake, efflux, or NO j NO exchange. Finally, members of the Organocation Transporter (OCT) family in animals (2.A.1.19) appear to be mechanistically promiscuous, catalyzing substrate uptake, export, exchange, and/or uniport. Sometimes the mechanism and substrate H stoichiometry depends on... 

Decarboxylases are one of the members of the enolase superfamily. The most important and interesting point of this class of enzymes is that they are mechanistically diverse and catalyze different overall reactions. However, each enzyme shares a partial reaction in which an active site base abstracts a proton to form a nucleophile. The intermediates are directed to different products in the different active sites of different members. However, some enzymes of this class exhibit catalytic promiscuity in their natural form. ° This fact is considered to be strongly related to the evolution of enzymes. Reflecting the similarity of the essential step of the total reaction, there are some successful examples of artificial-directed evolution of these enzymes to catalyze distinctly different chemical transformation. The changing of decarboxylase to racemase described in Section 2.5 is also one of these examples. 

Khersonsky O, Roodveldt C, Tawfik DS (2006) Enzyme promiscuity evolutionary and mechanistic aspects. Curr Opin Chem Biol 10 498-508... 

In another study, the promiscuous chorismate mutase activity of isochorismate pyruvate-lyase (PchB) was used to derive mechanistic insights into its native activity (isochorismate pyruvate lyase). Presumed key active-site residues were randomized, and the resulting variants of PchB were selected for the promiscuous chorismate mutase activity. Consequently, a common mechanism was proposed for both functions of PchB, with the rare [l,5]-sigmatropic rearrangement for the lyase activity, being distinct from other pyruvate lyases. 

Mechanistic Origins of Differences in the Catalytic Parameters for Native Versus Promiscuous Functions... 

Enzyme superfamiiies include numerous enzymes that although distant in sequence, share the same fold and the same catalytic mechanism. Members of such diverse superfamiiies catalyze different chemical transformations of many different substrates, but share a common motive of catalysis. Analysis of enzyme families and superfamiiies provides the most solid and convincing body of evidence for the role of promiscuity in the evolution of new functions. Specifically, the identification of promiscuous activities, or cross-reactivities, between different members of the same enzyme family or superfamily, and the directed evolution of these activities, provide important hints regarding evolutionary, structural, and mechanistic relationships within enzyme families (Figure 5). 

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