Pericyclic Reactions Catalyzed by Chorismate-Utilizing Enzymes

Abstract

One of the fundamental questions of enzymology is how catalytic power is derived. This review focuses on recent developments in the structure-function relationships of chorismate-utilizing enzymes involved in siderophore biosynthesis to provide insight into the biocatalysis of pericyclic reactions. Specifically, salicylate synthesis by the two-enzyme pathway in Pseudomonas aeruginosa is examined. The isochorismate-pyruvate lyase is discussed in the context of its homologues, the chorismate mutases, and the isochorismate synthase is compared to its homologues in the MST-family (menaquinone, siderophore or tryptophan biosynthesis) of enzymes. The tentative conclusion is that the activities observed cannot be reconciled by inspection of the active site participants alone. Instead, individual activities must arise from unique dynamic properties of each enzyme that are tuned to promote specific chemistries.

The Remarkable Pliability and Promiscuity of Specialized Metabolism

“…Whereas the isochorismate-pyruvate lyase activity of PchB involves the transfer of a hydrogen from C2 to C9 with pyruvate elimination, the latent chorismate mutase activity catalyzes C-C bond formation between C1 and C9 with fission of the C-O bond between C3 and its ether oxygen (Fig. 4C) (Lamb 2011). PchB is structurally related to bacterial chorismate mutase, and its ability to catalyze two different pericyclic reactions arises from an elastic catalytic mechanism, wherein the same enzyme active site stabilizes alternative transition states (Lamb 2011).…”

“…4C) (Lamb 2011). PchB is structurally related to bacterial chorismate mutase, and its ability to catalyze two different pericyclic reactions arises from an elastic catalytic mechanism, wherein the same enzyme active site stabilizes alternative transition states (Lamb 2011). Notably, the mechanistic elasticity of PchB may also help to uncover the long-sought-after enzyme that catalyzes the conversion of isochorismate to SA in plants by using comparative phylogenetic and biochemical analyses (Dempsey et al 2011).…”

Expanding the results of a high throughput screen against an isochorismate-pyruvate lyase to enzymes of a similar scaffold or mechanism

“…The generation of the siderophore pyochelin by P. aeruginosa requires two enzymes, an isochorismate synthase (PchA) and an isochorismate-pyruvate lyase (PchB). Interestingly, PchA, Irp9 and MbtI are all structural homologues in the MST (menaquinone, siderophore and tryptophan biosynthesis) family, but as yet it is unknown why PchA cannot perform the pericyclic lyase reaction [17]. There are homologues of PchA that are isochorismate synthases, which also cannot perform the pericyclic lyase reaction.…”

“…E. coli MenF [18, 19] is involved in menaquinone biosynthesis whereas EntC [20–23] from E. coli and VibC [24, 25] from Vibrio cholera are found in the biosynthetic pathways for dihydroxybenzoate capped siderophores. For MenF, EntC and VibC, the inability to perform the lyase reaction is biologically logical, since isochorismate is required for the formation of the biosynthetic products whereas salicylate is not [17]. …”

“…EcCM is the N-terminal domain of the well-studied bifunctional P-protein [29], the terminal enzyme of the shikimate biosynthetic pathway that is the branch point for the production of aromatic amino acids [30]. Both PchB and EcCM perform pericyclic reactions with similar transition states, differing in the alignment of the enolpyruvyl tail over the ring and thus the atomic composition of the cyclic transition state (Figure 2) [17]. The shikimate pathway is also recognized as an attractive target for antimicrobial drug design, since mammals do not synthesize aromatic amino acids.…”