Quantum mechanics and molecular mechanics study of the reaction mechanism of quorum quenching enzyme: N-acyl homoserine lactonase with C6-HSL

Zhang, Shujun; Su, Hao; Ma, Guangcai; Liu, Yongjun

doi:10.1039/c6ra00328a

Cited by 3 publications

(3 citation statements)

References 42 publications

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“…Therefore, we manually adjusted the position of W2. Generally, the movement of a free small molecule is not very difficult, we did not simulate this process . The QM/MM optimized structure (IM3′) is shown in Figure .…”

Section: Resultsmentioning

confidence: 72%

Comparative studies of the catalytic mechanisms of two chorismatases: CH‐fkbo and CH‐Hyg5

Dong

Liu

2017

Proteins

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Chorismatase is an important enzyme involved in Shikimate pathway, which catalyzes the conversion of chorismate into pyruvate and (dihydro)-benzoic acid derivatives. According to the outcomes of catalytic reactions, chorismatases can be divided into three subfamilies: CH-Fkbo, CH-Hyg5 and CH-XanB2. Recently, the crystal structures of CH-Fkbo and CH-Hyg5 from Streptomyces hygroscopicus have been successfully obtained, allowing us to perform QM/MM calculations to explore the reaction details. Our calculation results support the proposal that CH-Fkbo and CH-Hyg5 employ different catalytic mechanisms and gave the mechanistic details. Fkbo follows a typical hydrolytic mechanism, which contains three consecutive steps, including the protonation step of the methylene group of substrate, the nucleophilic attack of the resulted carbocation by activated water and cleavage of C2'-O8 bond of tetrahedral intermediate (hemiketal). The protonation of methylene group and the C2'-O8 cleavage correspond to similar energy barriers (26.5 and 24.8 kcal/mol), suggesting both steps to be rate-limiting. Whereas Hyg5 employs an intramolecular mechanism, in which the oxygen from C4 migrates to C3 via an arene oxide intermediate. The first step of Hyg5, which corresponds to the concerted protonation of methylene group and the cleavage of C3-O8, is calculated to be rate-limiting with an energy barrier of 26.3 kcal/mol. The nonconserved active site residue G240 (or A244 °) is suggested to be responsible for leading to different reaction mechanism in CH-Fkbo and CH-Hyg5. During the catalytic reaction, residue C327 plays an important role in directing the product selectivity in Hyg5 enzyme. Proteins 2017; 85:1146-1158. © 2017 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 72%

Comparative studies of the catalytic mechanisms of two chorismatases: CH‐fkbo and CH‐Hyg5

Dong

Liu

2017

Proteins

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“…The optimized structure is denoted as IM1′, in which W2 forms two strong hydrogen bonds with the O8 (1.82 Å) and hydroxyl (1.57 Å) of the substrate. The relative energy of IM1′ is only 4.3 kcal/mol higher than IM1, implying the movement of W2 in the active site to be quite easy . With the assistance of W2, the protonated pyruvate carboxylic acid transfers the proton to O8 via a seven-membered ring transition state, corresponding to an energy barrier of 12.1 kcal/mol.…”

Section: Resultsmentioning

confidence: 99%

“…The relative energy of IM1′ is only 4.3 kcal/mol higher than IM1, implying the movement of W2 in the active site to be quite easy. 53 With the assistance of W2, the protonated pyruvate carboxylic acid transfers the proton to O8 via a seven-membered ring transition state, corresponding to an energy barrier of 12.1 kcal/mol. From IM1′ to TS2, the C2′−O8 bond length increases from 1.44 to 1.57 Å; simultaneously, the distance of the H W2 −O8 bond decreases from 1.82 to 1.12 Å.…”

Section: How S86 and N17 Steer The Reaction Activity Of Mqnamentioning

confidence: 99%

Exploring the Substrate-Assisted Dehydration of Chorismate Catalyzed by Dehydratase MqnA from QM/MM Calculations: The Role of Pocket Residues and the Hydrolysis Mechanism of N17D Mutant

Dong,

Liu

2023

J. Chem. Inf. Model.

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MqnA is the first enzyme on the futalosine pathway to menaquinone, which catalyzes the dehydration of chorismate to yield 3-enolpyruvyl-benzoate (3-EPB). MqnA is also the only chorismate dehydratase known so far. In this work, based on the recently determined crystal structures, we constructed the enzyme–substrate complex models and conducted quantum mechanics/molecular mechanics (QM/MM) calculations to elucidate the reaction details of MqnA and the critical roles of pocket residues. The calculation results confirm that the MqnA-catalyzed dehydration of chorismate follows the substrate-assisted E1cb mechanism, in which the enol carboxylate in the side chain of the substrate is responsible for deprotonating the C3 of chorismate. This proton transfer process is much slower than C4-OH departure. Calculations on different mutants reveal that S86 and N17 are important for anchoring the enol carboxylate of the substrate in a favorable conformation to extract the C3-proton. The strong H-bonds formed between the enol carboxylate of chorismate and S86/N17 play a key role in stabilizing the reaction intermediate. Consistent with the experimental observations, our calculations demonstrate that the MqnA N17D mutant also shows hydrolase activity and the typical enzyme-catalyzed hydrolysis mechanism is elucidated. The protonated D17 is responsible for saturating the methylene group of chorismate to start the hydrolysis reaction. The orientation of the carboxyl group of D17 is key in determining MqnA to be a dehydratase or hydrolase.

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Enzymatic Quorum Quenching for Virulence Attenuation of Phytopathogenic Bacteria

Vesuna

Nerurkar

2018

Biotechnological Applications of Quorum Sensing Inhibitors

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Quantum mechanics and molecular mechanics study of the reaction mechanism of quorum quenching enzyme: N-acyl homoserine lactonase with C6-HSL

Abstract: N-Acyl-homoserine lactonase fromOchrobactrumsp. strain (AidH) is a novel AHL (N-acyl-homoserine lactone)-lactonase that hydrolyzes the ester bond of the homoserine lactone ring of AHLs.

Cited by 3 publications

References 42 publications

Comparative studies of the catalytic mechanisms of two chorismatases: CH‐fkbo and CH‐Hyg5

Comparative studies of the catalytic mechanisms of two chorismatases: CH‐fkbo and CH‐Hyg5

Exploring the Substrate-Assisted Dehydration of Chorismate Catalyzed by Dehydratase MqnA from QM/MM Calculations: The Role of Pocket Residues and the Hydrolysis Mechanism of N17D Mutant

Enzymatic Quorum Quenching for Virulence Attenuation of Phytopathogenic Bacteria

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