Myricetin is a novel inhibitor of human inosine 5'-monophosphate dehydrogenase with anti-leukemia activity

Biochem Biophys Res Commun. 2016 Sep 2;477(4):915-922. doi: 10.1016/j.bbrc.2016.06.158. Epub 2016 Jul 1.

Abstract

Human inosine 5'-monophosphate dehydrogenase (hIMPDH) is a rate-limiting enzyme in the de novo biosynthetic pathway of purine nucleotides, playing crucial roles in cellular proliferation, differentiation, and transformation. Dysregulation of hIMPDH expression and activity have been found in a variety of human cancers including leukemia. In this study, we found that myricetin, a naturally occurring phytochemical existed in berries, wine and tea, was a novel inhibitor of human type 1 and type 2 IMPDH (hIMPDH1/2) with IC50 values of 6.98 ± 0.22 μM and 4.10 ± 0.14 μM, respectively. Enzyme kinetic analysis using Lineweaver-Burk plot revealed that myricetin is a mix-type inhibitor for hIMPDH1/2. Differential scanning fluorimetry and molecular docking simulation data demonstrate that myricetin is capable of binding with hIMPDH1/2. Myricetin treatment exerts potent anti-proliferative and pro-apoptotic effects on K562 human leukemia cells in a dose-dependent manner. Importantly, cytotoxicity of myricetin on K562 cells were markedly attenuated by exogenous addition of guanosine, a salvage pathway of maintaining intracellular pool of guanine nucleotides. Taking together, these results indicate that natural product myricetin exhibits potent anti-leukemia activity by interfering with purine nucleotides biosynthetic pathway through the suppression of hIMPDH1/2 catalytic activity.

Keywords: Anti-cancer; Guanine nucleotide; Inosine 5′-monophosphate dehydrogenase; Leukemia; Myricetin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Apoptosis / drug effects
  • Binding Sites
  • Cell Cycle Checkpoints / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Flavonoids / administration & dosage*
  • Flavonoids / chemistry*
  • Humans
  • IMP Dehydrogenase / antagonists & inhibitors*
  • IMP Dehydrogenase / metabolism*
  • K562 Cells
  • Molecular Docking Simulation
  • Molecular Targeted Therapy / methods
  • Protein Binding
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Flavonoids
  • myricetin
  • IMP Dehydrogenase