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

Hicks, Kevin G.; Cluntun, Ahmad A.; Schubert, Heidi L.; Hackett, Sean R.; Berg, Jordan A.; Leonard, Paul G.; Ajalla Aleixo, Mariana A.; 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; Schopfer, Francisco J.; Hill, Christopher P.; Nonato, Maria Cristina; Muller, Florian L.; Cox, James E.; Rutter, Jared

Abstract

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.

• Journal Article Type: Article
• Acceptance Date: Feb 7, 2023
• Online Publication Date: Mar 9, 2023
• Publication Date: Mar 9, 2023
• Deposit Date: May 14, 2023
• Publicly Available Date: May 19, 2023
• Journal: Science
• Print ISSN: 0036-8075
• Electronic ISSN: 1095-9203
• Publisher: American Association for the Advancement of Science (AAAS)
• Peer Reviewed: Peer Reviewed
• Volume: 379
• Issue: 6636
• Pages: 996-1003
• DOI: https://doi.org/10.1126/science.abm3452
• Keywords: Humans, Fatty Acids - metabolism, Carbohydrate Metabolism, L-Lactate Dehydrogenase - metabolism
• Public URL: https://nottingham-repository.worktribe.com/output/18993587
• Publisher URL: https://www.science.org/doi/10.1126/science.abm3452
• Additional Information: Received: 2021-09-10; Accepted: 2023-02-07; Published: 2023-03-09