<i>Streptococcus pneumoniae</i> Isoprenoid Biosynthesis Is Downregulated by Diphosphomevalonate:  An Antimicrobial Target

Andreassi, John L.; Dabovic, Kristina; Leyh, Thomas S.

doi:10.1021/bi048075t

Cited by 30 publications

(45 citation statements)

References 18 publications

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“…However, when S. pneumoniae MVK and PMK were present at the initiation of the reaction, the velocity of mevalonate conversion significantly decreased (Fig. 3C), verifying the inhibition of S. pneumoniae MVK by diphosphomevalonate (2).…”

Section: Resultsmentioning

confidence: 56%

“…The effect of diphosphomevalonate on the rate of MVK reactions was analyzed using a pyruvate kinase and lactate dehydrogenase coupling system, as previously described (2). Briefly, the addition of mevalonate to the reaction mixture containing MVK resulted in the quantitative conversion of the substrate to phosphomevalonate.…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of MVKs by diphosphomevalonate. The inhibition of three MVKs by diphosphomevalonate was investigated using a spectrophotometric pyruvate kinase-and lactate dehydrogenase-coupled assay, as previously described (2). This approach couples two reactions of the mevalonate pathway, the initial phosphorylation of mevalonate by MVK and the subsequent conversion of phosphomevalonate to diphosphomevalonate by PMK.…”

Section: Methodsmentioning

confidence: 99%

“…Interestingly, DMAPP, IPP, GPP, and FPP were not feedback inhibitors of the Gram-positive bacterium S. pneumoniae MVK at concentrations of up to 12 M; however, diphosphomevalonate inhibited S. pneumoniae MVK at nanomolar concentrations (2).…”

mentioning

confidence: 89%

“…Organisms manage these tasks through the intricate regulation of isoprenoid-producing pathways (15). MVK was demonstrated to be an important regulatory point in the mevalonate pathway in both bacteria (1,2,31) and eukaryotes (4,9,13,16,18). Previously the small-molecule regulation of MVKs could be divided into two classes.…”

mentioning

confidence: 99%

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Characterization of a Feedback-Resistant Mevalonate Kinase from the Archaeon Methanosarcina mazei

Primak¹,

Du²,

Miller³

et al. 2011

Appl Environ Microbiol

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The mevalonate pathway is utilized for the biosynthesis of isoprenoids in many bacterial, eukaryotic, and archaeal organisms. Based on previous reports of its feedback inhibition, mevalonate kinase (MVK) may play an important regulatory role in the biosynthesis of mevalonate pathway-derived compounds. Here we report the purification, kinetic characterization, and inhibition analysis of the MVK from the archaeon Methanosarcina mazei. The inhibition of the M. mazei MVK by the following metabolites derived from the mevalonate pathway was explored: dimethylallyl diphosphate (DMAPP), geranyl pyrophosphate (GPP), farnesyl pyrophosphate (FPP), isopentenyl monophosphate (IP), and diphosphomevalonate. M. mazei MVK was not inhibited by DMAPP, GPP, FPP, diphosphomevalonate, or IP, a proposed intermediate in an alternative isoprenoid pathway present in archaea. Our findings suggest that the M. mazei MVK represents a distinct class of mevalonate kinases that can be differentiated from previously characterized MVKs based on its inhibition profile.

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Section: Resultsmentioning

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 89%

mentioning

confidence: 99%

See 3 more Smart Citations

Characterization of a Feedback-Resistant Mevalonate Kinase from the Archaeon Methanosarcina mazei

Primak¹,

Du²,

Miller³

et al. 2011

Appl Environ Microbiol

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Rational questing for potential novel inhibitors of FabK from Streptococcus pneumoniae by combining FMO calculation, CoMFA 3D-QSAR modeling and virtual screening

Zhang

Min

et al. 2010

J Mol Model

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Enoyl-acyl carrier protein (ACP) reductase (ENR) is an attractive and potential target for developing selective antibacterial agents. Recent studies showed that FabK is the sole isoform of ENR in Streptococcus pneumoniae, and at the same time an X-ray crystallographic study of FabK from S. pneumoniae (SpFabK) was reported for the first time. Based on above information, the interaction mechanism and pair interaction energies between ligand and the active site of SpFabK were analyzed with the ab initio fragment molecular orbital (FMO) calculation based on the FlexX docking model at the FMO-RHF/6-31G* level. Subsequently, the first molecular docking-based 3D-QSAR model with comparative molecular field analysis (CoMFA) was established with cross-validated coefficients (q(2)) up to 0.511 and regression coefficients (r(2)) up to 0.986. Then integrating the 3D-QSAR CoMFA predicted model, molecular docking, and FMO pair interaction analysis structure-based virtual screening was performed, six novel and potential lead compounds were sorted out for further study.

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Active site binding modes of inhibitors of Staphylococcus aureus mevalonate diphosphate decarboxylase from docking and molecular dynamics simulations

2015

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Bacterial mevalonate diphosphate decarboxylase (MDD) is an attractive therapeutic target for antibacterial drug development. In this work, we discuss a combined docking and molecular dynamics strategy toward inhibitor binding to bacterial MDD. The docking parameters utilized in this study were first validated with observations for the inhibitors 6-fluoromevalonate diphosphate (FMVAPP) and diphosphoglycolylproline (DPGP) using existing structures for the Staphylococcus epidermidis enzyme. The validated docking protocol was then used to predict structures of the inhibitors bound to Staphylococcus aureus MDD using the unliganded crystal structure of Staphylococcus aureus MDD. We also investigated a possible interactions improvement by combining this docking method with molecular dynamics simulations. Thus, the predicted docking structures were analyzed in a molecular dynamics trajectory to generate dynamic models and reinforce the predicted binding modes. FMVAPP is predicted to make more extensive contacts with S. aureus MDD, forming stable hydrogen bonds with Arg144, Arg193, Lys21, Ser107, and Tyr18, as well as making stable hydrophobic interactions with Tyr18, Trp19, and Met196. The differences in predicted binding are supported by experimentally determined Ki values of 0.23 ± 0.02 and 34 ± 8 μM, for FMVAPP and DPGP, respectively. The structural information coupled with the kinetic characterization obtained from this study should be useful in defining the requirements for inhibition as well as in guiding the selection of active compounds for inhibitor optimization.

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Streptococcus pneumoniae Isoprenoid Biosynthesis Is Downregulated by Diphosphomevalonate: An Antimicrobial Target

Cited by 30 publications

References 18 publications

Characterization of a Feedback-Resistant Mevalonate Kinase from the Archaeon Methanosarcina mazei

Characterization of a Feedback-Resistant Mevalonate Kinase from the Archaeon Methanosarcina mazei

Rational questing for potential novel inhibitors of FabK from Streptococcus pneumoniae by combining FMO calculation, CoMFA 3D-QSAR modeling and virtual screening

Active site binding modes of inhibitors of Staphylococcus aureus mevalonate diphosphate decarboxylase from docking and molecular dynamics simulations

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