Inhibition of human mevalonate kinase by allosteric inhibitors of farnesyl pyrophosphate synthase

Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring comp...

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Published inFEBS open bio Vol. 14; no. 8; pp. 1320 - 1339
Main Authors Salari, Saman, Lee, Hiu‐Fung, Tsantrizos, Youla S., Park, Jaeok
Format Journal Article
LanguageEnglish
Published England John Wiley & Sons, Inc 01.08.2024
John Wiley and Sons Inc
Wiley
Subjects
Allosteric properties
Allosteric Regulation - drug effects
Alzheimer's disease
Cancer therapies
Chromatography
Dehydrogenases
Enzyme inhibitors
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Enzyme Kinetics
Enzymes
farnesyl pyrophosphate
Farnesyl pyrophosphate synthase
Feedback
Feedback inhibition
Geranyltranstransferase - antagonists & inhibitors
Geranyltranstransferase - metabolism
Humans
isoprenoid synthesis
Kinases
Kinetics
Metabolites
Mevalonate kinase
Mevalonate pathway
Pharmacology
phosphonate compounds
Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Polyisoprenyl Phosphates - metabolism
Sesquiterpenes - chemistry
Sesquiterpenes - metabolism
Sesquiterpenes - pharmacology
Signal transduction
Software
Therapeutic targets
Canada
phosphonate compounds
isoprenoid synthesis
mevalonate pathway
mevalonate kinase
farnesyl pyrophosphate
feedback inhibition
Online AccessGet full text

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Abstract Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring compounds originally synthesized as allosteric inhibitors of farnesyl pyrophosphate synthase, we discovered mevalonate kinase inhibitors with nanomolar activity. Kinetic characterization of the two most potent inhibitors demonstrated Ki values of 3.1 and 22 nm. Structural comparison suggested features of these inhibitors likely responsible for their potency. Our findings introduce the first class of nanomolar inhibitors of human mevalonate kinase, opening avenues for future research. These compounds might prove useful as molecular tools to study mevalonate pathway regulation and evaluate mevalonate kinase as a potential therapeutic target. Mevalonate kinase constitutes a key regulatory step in the mevalonate pathway, an established drug target for its role in the synthesis of isoprenoid molecules. Using a structure‐based rational approach, we identified several synthetic compounds that inhibit mevalonate kinase with nanomolar potency. Further analysis revealed their mode of inhibition and the structural features that correlate with their inhibitory potency.
AbstractList Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring compounds originally synthesized as allosteric inhibitors of farnesyl pyrophosphate synthase, we discovered mevalonate kinase inhibitors with nanomolar activity. Kinetic characterization of the two most potent inhibitors demonstrated K values of 3.1 and 22 nm. Structural comparison suggested features of these inhibitors likely responsible for their potency. Our findings introduce the first class of nanomolar inhibitors of human mevalonate kinase, opening avenues for future research. These compounds might prove useful as molecular tools to study mevalonate pathway regulation and evaluate mevalonate kinase as a potential therapeutic target.
Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring compounds originally synthesized as allosteric inhibitors of farnesyl pyrophosphate synthase, we discovered mevalonate kinase inhibitors with nanomolar activity. Kinetic characterization of the two most potent inhibitors demonstrated Ki values of 3.1 and 22 nm. Structural comparison suggested features of these inhibitors likely responsible for their potency. Our findings introduce the first class of nanomolar inhibitors of human mevalonate kinase, opening avenues for future research. These compounds might prove useful as molecular tools to study mevalonate pathway regulation and evaluate mevalonate kinase as a potential therapeutic target. Mevalonate kinase constitutes a key regulatory step in the mevalonate pathway, an established drug target for its role in the synthesis of isoprenoid molecules. Using a structure‐based rational approach, we identified several synthetic compounds that inhibit mevalonate kinase with nanomolar potency. Further analysis revealed their mode of inhibition and the structural features that correlate with their inhibitory potency.
Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring compounds originally synthesized as allosteric inhibitors of farnesyl pyrophosphate synthase, we discovered mevalonate kinase inhibitors with nanomolar activity. Kinetic characterization of the two most potent inhibitors demonstrated Ki values of 3.1 and 22 nm. Structural comparison suggested features of these inhibitors likely responsible for their potency. Our findings introduce the first class of nanomolar inhibitors of human mevalonate kinase, opening avenues for future research. These compounds might prove useful as molecular tools to study mevalonate pathway regulation and evaluate mevalonate kinase as a potential therapeutic target.Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring compounds originally synthesized as allosteric inhibitors of farnesyl pyrophosphate synthase, we discovered mevalonate kinase inhibitors with nanomolar activity. Kinetic characterization of the two most potent inhibitors demonstrated Ki values of 3.1 and 22 nm. Structural comparison suggested features of these inhibitors likely responsible for their potency. Our findings introduce the first class of nanomolar inhibitors of human mevalonate kinase, opening avenues for future research. These compounds might prove useful as molecular tools to study mevalonate pathway regulation and evaluate mevalonate kinase as a potential therapeutic target.
Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring compounds originally synthesized as allosteric inhibitors of farnesyl pyrophosphate synthase, we discovered mevalonate kinase inhibitors with nanomolar activity. Kinetic characterization of the two most potent inhibitors demonstrated K i values of 3.1 and 22 n m . Structural comparison suggested features of these inhibitors likely responsible for their potency. Our findings introduce the first class of nanomolar inhibitors of human mevalonate kinase, opening avenues for future research. These compounds might prove useful as molecular tools to study mevalonate pathway regulation and evaluate mevalonate kinase as a potential therapeutic target. Mevalonate kinase constitutes a key regulatory step in the mevalonate pathway, an established drug target for its role in the synthesis of isoprenoid molecules. Using a structure‐based rational approach, we identified several synthetic compounds that inhibit mevalonate kinase with nanomolar potency. Further analysis revealed their mode of inhibition and the structural features that correlate with their inhibitory potency.
Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring compounds originally synthesized as allosteric inhibitors of farnesyl pyrophosphate synthase, we discovered mevalonate kinase inhibitors with nanomolar activity. Kinetic characterization of the two most potent inhibitors demonstrated Ki values of 3.1 and 22 nm. Structural comparison suggested features of these inhibitors likely responsible for their potency. Our findings introduce the first class of nanomolar inhibitors of human mevalonate kinase, opening avenues for future research. These compounds might prove useful as molecular tools to study mevalonate pathway regulation and evaluate mevalonate kinase as a potential therapeutic target.
Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring compounds originally synthesized as allosteric inhibitors of farnesyl pyrophosphate synthase, we discovered mevalonate kinase inhibitors with nanomolar activity. Kinetic characterization of the two most potent inhibitors demonstrated K i values of 3.1 and 22 n m . Structural comparison suggested features of these inhibitors likely responsible for their potency. Our findings introduce the first class of nanomolar inhibitors of human mevalonate kinase, opening avenues for future research. These compounds might prove useful as molecular tools to study mevalonate pathway regulation and evaluate mevalonate kinase as a potential therapeutic target.
Author Tsantrizos, Youla S.
Park, Jaeok
Salari, Saman
Lee, Hiu‐Fung
AuthorAffiliation 1 Department of Biochemistry Memorial University of Newfoundland St. John's Canada
2 Department of Chemistry McGill University Montreal Canada
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Issue 8
Keywords phosphonate compounds
isoprenoid synthesis
mevalonate pathway
mevalonate kinase
farnesyl pyrophosphate
feedback inhibition
Language English
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Snippet Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this...
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SubjectTerms Allosteric properties
Allosteric Regulation - drug effects
Alzheimer's disease
Cancer therapies
Chromatography
Dehydrogenases
Enzyme inhibitors
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Enzyme Kinetics
Enzymes
farnesyl pyrophosphate
Farnesyl pyrophosphate synthase
Feedback
Feedback inhibition
Geranyltranstransferase - antagonists & inhibitors
Geranyltranstransferase - metabolism
Humans
isoprenoid synthesis
Kinases
Kinetics
Metabolites
Mevalonate kinase
Mevalonate pathway
Pharmacology
phosphonate compounds
Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Polyisoprenyl Phosphates - metabolism
Sesquiterpenes - chemistry
Sesquiterpenes - metabolism
Sesquiterpenes - pharmacology
Signal transduction
Software
Therapeutic targets
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Title Inhibition of human mevalonate kinase by allosteric inhibitors of farnesyl pyrophosphate synthase
URI https://onlinelibrary.wiley.com/doi/abs/10.1002%2F2211-5463.13853
https://www.ncbi.nlm.nih.gov/pubmed/38923323
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https://pubmed.ncbi.nlm.nih.gov/PMC11301271
https://doaj.org/article/f3b39f8cb51148878b197019f34d72a3
Volume 14
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