Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase

• 成果类型: Article
• 署名作者: Hicks, Kevin G.; Cluntun, Ahmad A.; Schubert, Heidi L.; Hackett, Sean R.; Berg, Jordan A.; Leonard, Paul G.; Aleixo, Mariana A. Ajalla; Zhou, Youjia; Bott, Alex J.; Salvatore, Sonia R.; Chang, Fei; Blevins, Aubrie; Barta, Paige; Tilley, Samantha; Leifer, Aaron; Guzman, Andrea; Arok, Ajak; Fogarty, Sarah; Winter, Jacob M.; Ahn, Hee-Chul; Allen, Karen N.; Block, Samuel; Cardoso, Iara A.; Ding, Jianping; Dreveny, Ingrid; Gasper, William C.; Ho, Quinn; Matsuura, Atsushi; Palladino, Michael J.; Prajapati, Sabin; Sun, Pengkai; Tittmann, Kai; Tolan, Dean R.; Unterlass, Judith; VanDemark, Andrew P.; Vander Heiden, Matthew G.; Webb, Bradley A.; Yun, Cai-Hong; Zhao, Pengkai; Wang, Bei; Schopter, Francisco J.; Hill, Christopher P.; Nonato, Maria Cristina; Muller, Florian L.; Cox, James E.; Rutter, Jared
• 署名单位: Utah System of Higher Education; University of Utah; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Universidade de Sao Paulo; Utah System of Higher Education; University of Utah; Utah System of Higher Education; University of Utah; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Howard Hughes Medical Institute; Utah System of Higher Education; University of Utah; Dongguk University; Boston University; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Center for Excellence in Molecular Cell Science, CAS; University of Nottingham; Boston University; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Gottingen; Max Planck Society; Karolinska Institutet; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; West Virginia University; Peking University; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; University of Texas Southwestern Medical Center; Scripps Research Institute; Baylor University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10860
• DOI: 10.1126/science.abm3452
• 发表日期: 2023-03-10
• 页码: 996-1003
• 关键词: hepatic glucose-production; pyruvate-kinase; skeletal-muscle; fatty-acids; coenzyme-a; inhibition; insulin; oxidation; mechanism; identification

摘要

Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) to identify such interactions. Analysis of 33 enzymes from human carbohydrate metabolism identified 830 protein-metabolite interactions, including known regulators, substrates, and products as well as previously unreported interactions. We functionally validated a subset of interactions, including the isoform-specific inhibition of lactate dehydrogenase by long-chain acyl-coenzyme A. Cell treatment with fatty acids caused a loss of pyruvate-lactate interconversion dependent on lactate dehydrogenase isoform expression. These protein-metabolite interactions may contribute to the dynamic, tissue-specific metabolic flexibility that enables growth and survival in an ever-changing nutrient environment.