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

• Published in: FEBS open bio Vol. 14; no. 8; pp. 1320 - 1339
• Main Authors: Salari, Saman, Lee, Hiu‐Fung, Tsantrizos, Youla S., Park, Jaeok
• Format: Journal Article
• Language: English
• 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

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...