2017
DOI: 10.1021/acs.biochem.7b00248
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Mechanism of Formation of the Nonstandard Product in the Prenyltransferase Reaction of the G115T Mutant of FtmPT1: A Case of Reaction Dynamics Calling the Shots?

Abstract: FtmPT1 is a fungal indole prenyltransferase that affords Tryprostatin B from Brevianamide F and dimethylallyl pyrophosphate; however, when a single residue in the active site is mutated (Gly115Thr), a novel five-membered ring compound is obtained as the major product with Tryprostatin B as the minor product. Herein, we describe detailed studies of the catalysis of the Gly115Thr mutant of FtmPT1 with a focus on the observed regioselectivity of the reaction. We employ one- and two-dimensional potential of mean f… Show more

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Cited by 4 publications
(5 citation statements)
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“…While the SCC-DFTB method is known to underestimate absolute barriers in many cases, this approach has been satisfactorily applied to elucidate the effects of mutations on several enzyme-catalyzed reactions; it provides useful and predictive relative barriers. 36 …”
Section: Resultsmentioning
confidence: 99%
“…While the SCC-DFTB method is known to underestimate absolute barriers in many cases, this approach has been satisfactorily applied to elucidate the effects of mutations on several enzyme-catalyzed reactions; it provides useful and predictive relative barriers. 36 …”
Section: Resultsmentioning
confidence: 99%
“…This group includes FgaPT2, 23,24 FtmPT1 (ref. [25][26][27] and CdpNPT 27,28 from Aspergillus fumigatus, AnaPT 29 from Neosartoria fischeri, AtaPT 30 from Aspergillus terreus. All these enzymes have been identified through genome mining and characterised in vitro making it difficult, in some cases, to identify their in vivo substrates and metabolic products with certainty; however, all can mediate the transfer of DMAPP onto the indole core of at least one indole containing substrate.…”
Section: Discussionmentioning
confidence: 99%
“…30,31 Whereas FgaPT1 and FgaPT2 appear to demonstrate high substrate specificity and regioselectivity, CdpNPT, AnaPT and AtaPT are able to utilise a variety of indole containing substrates and even appear to catalyse both head and tail prenylations. [23][24][25][26][27][28]32 AtaPT also has been shown to mediate C-and/or O-prenylation on non-indole containing substrates. 30,31 The low level of sequence identity seen between the IDT PTs and the other fungal aromatic PTs for which structures are known is consistent with the low level of sequence similarity that exists in the αββα PTs, despite their apparent common architecture and shared patterns of catalytic function.…”
Section: Discussionmentioning
confidence: 99%
“…Natural Product Reports different binding modes. 67,[73][74][75][76][77][78][79][80][81][82][83][84] Although there has been recent evidence to suggest that the particular mechanism may depend on the individual PT or the substrate, 61,65,85 any mechanistic explanation at present remains speculative. The continued effort of determining and examining the atomic structures of DMATSs will be essential for resolving this uncertainty.…”
Section: Reviewmentioning
confidence: 99%
“…The chemical and biochemical rationale for both mechanisms are plausible in many situations, and the utilization of different substrates and/or mutants calls into question whether the results can be attributed to different binding modes. 67,73–84 Although there has been recent evidence to suggest that the particular mechanism may depend on the individual PT or the substrate, 61,65,85 any mechanistic explanation at present remains speculative. The continued effort of determining and examining the atomic structures of DMATSs will be essential for resolving this uncertainty.…”
Section: Introductionmentioning
confidence: 99%