Metabolite control of enzyme activity links stress to biosynthetic regulation

• 成果类型: Article
• 署名作者: Van De Ven, Wilhelmina; Hur, Manhoi; Gomez-Mendez, Maria Fernanda; Guo, Jingzhe; Ke, Haiyan; Mahmood, Raisul Awal; Kim, Sunghwan; Sharkey, Thomas D.; Dehesh, Katayoon
• 署名单位: University of California System; University of California Riverside; Kyungpook National University (KNU); Michigan State University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2529243123
• 发表日期: 2026-02-10
• 页码: e2529243123
• 关键词: MEP pathway; MEcPP; isoprenoid biosynthesis; metabolic feedback regulation; plastidial stress response; PLASTIDIC ISOPRENOID BIOSYNTHESIS; PHOSPHATE MEP PATHWAY; METHYLERYTHRITOL PHOSPHATE; CAROTENOID BIOSYNTHESIS; antimalarial; bacteria; synthase; target; DIPHOSPHATE; DISCOVERY

摘要

Cells must continuously adjust metabolic output to maintain homeostasis under changing environmental conditions, yet the mechanisms that enable rapid and reversible control of pathway activity remain largely unknown. The methylerythritol phosphate (MEP) pathway, of bacterial origin and conserved in plastid-bearing eukaryotes, including plants and apicomplexan parasites, produces isoprenoid precursors essential for growth and stress adaptation. Here, we identify methylerythritol cyclodiphosphate (MEcPP) as a dual-function metabolite that serves both as a biosynthetic intermediate and a direct modulator of enzyme activity. Genetic perturbations and high light stress Biochemical and protease-protection assays showed that MEcPP destabilizes and inhibits thylbutenyl diphosphate synthase (HDS). Molecular docking analyses indicate that and thereby attenuating enzyme activity, suggesting a competitive, feedback-like mechthat translates stress-induced changes into targeted enzymatic control. This mechanism illustrates how pathway intermediates dynamically coordinate biosynthetic activity with environmental cues, representing a broadly conserved strategy for metabolite-driven control of cellular metabolism.