Importance of Tetrahedral Intermediate Formation in the Catalytic Mechanism of the Serine Proteases Chymotrypsin and Subtilisin

Petrillo, Teodolinda; O'Donohoe, Catrina A; Howe, Nicole; Malthouse, J. Paul G.

doi:10.1021/bi300688k

Cited by 15 publications

(31 citation statements)

References 50 publications

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“…Z-Ala-Ala-Phe-H (Scheme 1A) was synthesized as described by Petrillo et al [4]. Z-Ala-Ala-Phe-13 COOCH 3 and Z-Ala-Ala-Phe-13 COCHO (Scheme 1D) were synthesized as described by Cosgrove et al, [18].…”

Section: Synthesis Of Z-ala-ala-phe-h Z-ala-ala-phe-cooch 3 and Z-almentioning

confidence: 99%

“…We have recently developed an approach which enables us to quantify how much a peptide warhead contributes to inhibitor potency [4]. This has been used to determine how the glyoxylate group and the carboxylate group contribute to inhibitor potency with the serine protease chymotrypsin.…”

Section: Introductionmentioning

confidence: 99%

“…Recently we have developed a procedure that allows us to quantify hemiketal formation in chymotrypsin-glyoxal inhibitor complexes and to determine the effective molarity of the hydroxyl group of the catalytic serine residue in these complexes [4]. In this study we use a similar approach to quantify hemiacetal formation in a chymotrypsinaldehyde inhibitor complex and to determine the effective molarity of the hydroxyl group of the catalytic serine residue in this complex.…”

Section: Introductionmentioning

confidence: 99%

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Hemiacetal stabilization in a chymotrypsin inhibitor complex and the reactivity of the hydroxyl group of the catalytic serine residue of chymotrypsin

Cleary

Doherty

Evans

et al. 2014

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Section: Synthesis Of Z-ala-ala-phe-h Z-ala-ala-phe-cooch 3 and Z-almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hemiacetal stabilization in a chymotrypsin inhibitor complex and the reactivity of the hydroxyl group of the catalytic serine residue of chymotrypsin

Cleary

Doherty

Evans

et al. 2014

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…In serine proteases, the hydroxyl of the active site serine acts as a nucleophile in a well-established global pathway [55]. Those enzymes utilize serine to add to the amide of proteins and form an intermediate that leads to production of an acyl enzyme derivative.…”

Section: Introductionmentioning

confidence: 99%

Catalyzing decarboxylation by taming carbon dioxide

Kluger

2015

Pure and Applied Chemistry

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Decarboxylation reactions on enzymes are consistently much faster than their nonenzymic counterparts. Examination of the potential for catalysis in the nonenzymic reactions revealed that the reaction is slowed by the failure of CO 2 to be launched into solution upon C-C bond cleavage. Catalysts can facilitate the reaction by weakening the C-CO 2 H bond but this is not sufficient. Converting the precursor of CO 2 into a precursor of bicarbonate facilitates the forward reaction as does protonation of the nascent carbanion.

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“…The catalytic reaction mechanism of trypsin consists of the acylation process, which yields an acylenzyme (EA) complex, followed by the deacylation process (not shown in Figure 1). The formation and breakdown of EA are thought to proceed via a tetrahedral intermediate (TET) 9. Kawai et al 10.…”

Section: Introductionmentioning

confidence: 99%

Connecting Classical QSAR and LERE Analyses Using Modern Molecular Calculations, LERE‐QSAR (VI): Hydrolysis of Substituted Hippuric Acid Phenyl Esters by Trypsin

Mashima

Kurahashi

Sasahara

et al. 2014

Molecular Informatics

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The reaction mechanism of trypsin was studied by applying DFT and ab initio molecular orbital (MO) calculations to complexes of trypsin with a congeneric series of eight para-substituted hippuric acid phenyl esters, for which a previous quantitative structureactivity relationship (QSAR) study revealed nice linearity of Hammett substitution constant σ(-) with logarithmic values of the MichaelisMenten and catalytic rate constants. Based on the LERE procedure, we performed QSAR analyses on each elementary reaction step during the acylation process. The present calculations showed that the rate-determining step during the acylation process is the transition state (TS) between the enzymesubstrate complex (ES) and tetrahedral intermediate (TET), and that the proton transfer occurs from Ser195 to His57, not between His57 and Asp102. The LERE-QSAR analysis statistically suggested that the variation of overall free-energy changes leading to formation of TS is governed mostly by that of activation energies required to form TS from ES. In spite of a very limited number of congeneric ligands in the current work, it is critically essential to clarify and verify physicochemical meanings of a typical QSAR/Chemoinformatics parameter, Hammett σ(-) based on quantum chemical calculations on the proteinligand kinetics; how Hammett σ(-) behaves in terms of proteinligand interaction energies.

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Importance of Tetrahedral Intermediate Formation in the Catalytic Mechanism of the Serine Proteases Chymotrypsin and Subtilisin

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Cited by 15 publications

References 50 publications

Hemiacetal stabilization in a chymotrypsin inhibitor complex and the reactivity of the hydroxyl group of the catalytic serine residue of chymotrypsin

Hemiacetal stabilization in a chymotrypsin inhibitor complex and the reactivity of the hydroxyl group of the catalytic serine residue of chymotrypsin

Catalyzing decarboxylation by taming carbon dioxide

Connecting Classical QSAR and LERE Analyses Using Modern Molecular Calculations, LERE‐QSAR (VI): Hydrolysis of Substituted Hippuric Acid Phenyl Esters by Trypsin

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