Catalytic mechanism of mevalonate kinase revisited, a QM/MM study

McClory, James; Lin, Juntang; Timson, David J.; Zhang, Jian; Huang, Meilan

doi:10.1039/c8ob03197e

Cited by 10 publications

(5 citation statements)

References 41 publications

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“…Lactic acid concentrations are closely related to bacterial pyruvate metabolism, which regulates bacterial acetic acid production and propionic acid metabolism ( Gaspar et al, 2014 )0.5-methyltetrahydropteroyltriglutamate–homocysteine methyltransferase (metE) can increase the tolerance of Escherichia coli to acetic acid and increase the concentration of acetic acid in the environment ( Mordukhova and Pan, 2013 ). Mevalonate kinase (mvk) is an ATP-dependent rate-limiting enzyme in mevalonate biosynthesis, the down-regulation of which promotes the synthesis of mevalonate ( McClory et al, 2019 ). In the metabolic pathway of butyric acid production, PS promoted the expression of aldehyde-alcohol dehydrogenase 2 (adh2), which was annotated to butanoate metabolism pathway (map00650).…”

Section: Discussionmentioning

confidence: 99%

Influence of Polysaccharides From Polygonatum kingianum on Short-Chain Fatty Acid Production and Quorum Sensing in Lactobacillus faecis

Yang

Meng

et al. 2021

Front. Microbiol.

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Polysaccharide is one of the main active ingredients of Polygonatum kingianum, which has been proven to regulate the balance of gut microbiota. For the first time, this study focused on the regulation of polysaccharides from Polygonatum kingianum (PS) on Lactobacillus faecis, a specific probiotic in the intestinal tract. PS effectively promoted the biomass, biofilm and acetic acid production in L. faecis 2-84, and enhanced quorum sensing (QS) signaling. The characteristics of gene sequence were analyzed using genomics approaches, and L. faecis 2-84 was found to encode 18 genes that are closely related to QS and 10 genes related to short-chain fatty acids (SCFAs). Additionally, transcriptome and proteome analysis demonstrated that PS could promote the QS system of L. faecis by enhancing the transcription of oppA gene and expression of oppD protein. PS also regulated the production and metabolism of SCFAs of L. faecis by upregulating the expression of ldh and metE gene and adh2 protein, and downregulating the expression of mvK gene. In conclusion, it was speculated that PS could affect intestinal SCFAs production by affecting the QS system and SCFAs production in L. faecis. The present study implied that PS might have a role in promoting the growth of intestinal probiotics, where the QS system and SCFAs might be two of the important mechanisms for the probiotic activity of PS.

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Section: Discussionmentioning

confidence: 99%

Influence of Polysaccharides From Polygonatum kingianum on Short-Chain Fatty Acid Production and Quorum Sensing in Lactobacillus faecis

Yang

Meng

et al. 2021

Front. Microbiol.

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“…The RDs also confirm the role of ARG129 and Mg 2+ cation, which were thought to be crucial for catalysis according to experimental studies. 55 We did not found any record of QC/MM simulations of these reaction coordinates, although a similar system was treated by McClory and co-workers, 56 the catalysis of mavalonate-5-phosphate by the mavalonate kinase. The reaction that occurs holds significant resemblance with AKs and involves the transfer of a phosphoryl group from an ATP molecule to the mavalonate, with a Mg 2+ cation as a cofactor and a charged arginine and lysine amino-acid residue stabilizing the phosphoryl group in the TS geometry, which also holds remarkable similarities with AKs' TS.…”

Section: ∑ ∑mentioning

confidence: 99%

Elucidating Enzymatic Catalysis Using Fast Quantum Chemical Descriptors

Grillo

Urquiza-Carvalho

Bachega

et al. 2020

J. Chem. Inf. Model.

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In general, computational simulations of enzymatic catalysis processes are thermodynamic and structural surveys to complement experimental studies, requiring high level computational methods to match accurate energy values. In the present work, we propose the usage of reactivity descriptors, theoretical quantities calculated from the electronic structure, to characterize enzymatic catalysis outlining its reaction profile using low-level computational methods, such as semiempirical Hamiltonians. We simulate three enzymatic reactions paths, one containing two reaction coordinates and without prior computational study performed, and calculate the reactivity descriptors for all obtained structures. We observed that the active site local hardness does not change substantially, even more so for the amino-acid residues that are said to stabilize the reaction structures. This corroborates with the theory that activation energy lowering is caused by the electrostatic environment of the active sites. Also, for the quantities describing the atom electrophilicity and nucleophilicity, we observed abrupt changes along the reaction coordinates, which also shows the enzyme participation as a reactant in the catalyzed reaction. We expect that such electronic structure analysis allows the expedient proposition and/or prediction of new mechanisms, providing chemical characterization of the enzyme active sites, thus hastening the process of transforming the resolved protein three-dimensional structures in catalytic information.

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“…However, computer simulations employing quantum mechanics/molecular mechanics approaches suggest that this mechanism does not occur in any of the GHMP kinases studied to date. Instead, these simulations predict direct transfer of the phosphate group from ATP, most likely assisted by stabilisation of the transition state [44][45][46].…”

Section: Challenge 4: Understand Catalysismentioning

confidence: 92%

Four Challenges for Better Biocatalysts

Timson

2019

Fermentation

Self Cite

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Biocatalysis (the use of biological molecules or materials to catalyse chemical reactions) has considerable potential. The use of biological molecules as catalysts enables new and more specific syntheses. It also meets many of the core principles of “green chemistry”. While there have been some considerable successes in biocatalysis, the full potential has yet to be realised. This results, partly, from some key challenges in understanding the fundamental biochemistry of enzymes. This review summarises four of these challenges: the need to understand protein folding, the need for a qualitative understanding of the hydrophobic effect, the need to understand and quantify the effects of organic solvents on biomolecules and the need for a deep understanding of enzymatic catalysis. If these challenges were addressed, then the number of successful biocatalysis projects is likely to increase. It would enable accurate prediction of protein structures, and the effects of changes in sequence or solution conditions on these structures. We would be better able to predict how substrates bind and are transformed into products, again leading to better enzyme engineering. Most significantly, it may enable the de novo design of enzymes to catalyse specific reactions.

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Catalytic mechanism of mevalonate kinase revisited, a QM/MM study

Abstract: Catalytically active structure of Mevalonate kinase in complex with the ATP and the mevalonate substrate.

Cited by 10 publications

References 41 publications

Influence of Polysaccharides From Polygonatum kingianum on Short-Chain Fatty Acid Production and Quorum Sensing in Lactobacillus faecis

Influence of Polysaccharides From Polygonatum kingianum on Short-Chain Fatty Acid Production and Quorum Sensing in Lactobacillus faecis

Elucidating Enzymatic Catalysis Using Fast Quantum Chemical Descriptors

Four Challenges for Better Biocatalysts

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