ChemInform Abstract: Chorismate Mutase Inhibitors: Synthesis and Evaluation of Some Potential Transition‐State Analogues.

Bartlett, P. A.; Nakagawa, Y.; Johnson, Charles R.; Reich, Siegfried; Luis, A Echegoyen

doi:10.1002/chin.198851208

Cited by 5 publications

(7 citation statements)

References 1 publication

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“…A milestone in the elucidation of the enzyme reaction mechanism was reached when the crystal structure of CM was solved by Lipscomb and coworkers in 1993, and refined to 2.2 Å resolution . The active site structure in complex with Bartlett's TS analog (TSA) and reaction product ( 2 ) strongly suggested that the enzymatic mechanism proceeds as a pericyclic process, similar to the uncatalyzed reaction. The structure provided the basis for the first quantum and molecular mechanics (QM/MM) study on CM, which suggested that substrate conversion may involve a combination of substrate strain and TS stabilization .…”

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confidence: 99%

Quantum chemical modeling of the reaction path of chorismate mutase based on the experimental substrate/product complex

et al. 2017

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Chorismate mutase is a well‐known model enzyme, catalyzing the Claisen rearrangement of chorismate to prephenate. Recent high‐resolution crystal structures along the reaction coordinate of this enzyme enabled computational analyses at unprecedented detail. Using quantum chemical simulations, we investigated how the catalytic reaction mechanism is affected by electrostatic and hydrogen‐bond interactions. Our calculations showed that the transition state (TS) was mainly stabilized electrostatically, with Arg90 playing the leading role. The effect was augmented by selective hydrogen‐bond formation to the TS in the wild‐type enzyme, facilitated by a small‐scale local induced fit. We further identified a previously underappreciated water molecule, which separates the negative charges during the reaction. The analysis includes the wild‐type enzyme and a non‐natural enzyme variant, where the catalytic arginine was replaced with an isosteric citrulline residue.

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confidence: 99%

Quantum chemical modeling of the reaction path of chorismate mutase based on the experimental substrate/product complex

et al. 2017

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“…The literature reports inhibition of this and similar compounds as I 50 / K m 1 , with a value of 0.008 for the TSA [34, 35]. Similar calculations were performed for compounds 6 and 10 versus EcCM, and values of 0.05 and 0.053 were determined, better than all of the reported compounds save the TSA.…”

Section: Discussionmentioning

confidence: 52%

“…The shikimate pathway is also recognized as an attractive target for antimicrobial drug design, since mammals do not synthesize aromatic amino acids. Rational design of inhibitors has been conducted for the chorismate mutases [31–38], including the TSA (transition state analogue), an oxabicyclic acid generated by Bartlett [34, 35]. EcCM is refractory to screening, because it lacks a good spectrophotometric handle and is difficult to make in sufficient quantities.…”

Section: Introductionmentioning

confidence: 99%

“… 1 Bartlett and colleagues reported inhibition of chorismate mutase/prephenate dehydrogenase by their transition state analogues as I 50 / K m values [34, 35], where they defined I 50 as “the concentration of inhibitor giving 50% inhibition when the substrate concentration equals K m ” [34]. For the sake of direct comparison, we likewise make these calculations.…”

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confidence: 99%

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

Meneely

Luo

Riley

et al. 2014

Bioorganic & Medicinal Chemistry

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Antibiotic resistance is a growing health concern, and new avenues of antimicrobial drug design are being actively sought. One suggested pathway to be targeted for inhibitor design is that of iron scavenging through siderophores. Here we present a high throughput screen to the isochorismatepyruvate lyase of Pseudomonas aeruginosa, an enzyme required for the production of the siderophore pyochelin. Compounds identified in the screen are high nanomolar to low micromolar inhibitors of the enzyme and produce growth inhibition in PAO1 P. aeruginosa in the millimolar range under iron-limiting conditions. The identified compounds were also tested for enzymatic inhibition of E. coli chorismate mutase, a protein of similar fold and similar chemistry, and of Y. enterocolitica salicylate synthase, a protein of differing fold but catalyzing the same lyase reaction. In both cases, subsets of the inhibitors from the screen were found to be inhibitory to enzymatic activity (mutase or synthase) in the micromolar range and capable of growth inhibition in their respective organisms (E. coli or Y. enterocolitica).

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“…Several groups have synthesized inhibitors of selected aromatic pathway enzymes in the hope they would have herbicidal activity. Enzymes for which no herbicidal activity of synthetic inhibitors was reported include shikimate dehydrogenase (Baille et al 1972;Bugg et al 1988a), dehydroquinase (Bugg et al 1988b), and chorismate mutase (Bartlett et al 1988;Clarke et al 1990). Ambiguous results were reported for 3-dehydroquinate synthase.…”

Section: Targeting the Aromatic Pathway For Herbicide Designmentioning

confidence: 99%

Evaluating anthranilate synthase as a herbicide target

et al. 1997

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Attempts to discover new active ingredients and target sites within the aromatic pathway have resulted in the synthesis of potent enzyme inhibitors, but no herbicides. As an aid in identifying a new target for inhibitor design and screening, we have determined the mode of action of a compound (6-methyl anthranilate) that exhibits noncommercial levels of herbicidal activity. Our evidence suggests that 6-methyl anthranilate is converted in vivo, by traversing the tryptophan biosynthetic sequence, to 4-methyl tryptophan, which inhibits anthranilate synthase. Inhibitors synthesized by design and those found by target-based screening converged on analogs of tryptophan and anthranilate. None, however, was more herbicidal than 6-methyl anthranilate.

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ChemInform Abstract: Chorismate Mutase Inhibitors: Synthesis and Evaluation of Some Potential Transition‐State Analogues.

Cited by 5 publications

References 1 publication

Quantum chemical modeling of the reaction path of chorismate mutase based on the experimental substrate/product complex

Quantum chemical modeling of the reaction path of chorismate mutase based on the experimental substrate/product complex

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

Evaluating anthranilate synthase as a herbicide target

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