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

Kevin G. Hicks; Ahmad A. Cluntun; Heidi L. Schubert; Sean R. Hackett; Jordan A. Berg; Paul G. Leonard; Mariana A. Ajalla Aleixo; Youjia Zhou; Alex J. Bott; Sonia R. Salvatore; Fei Chang; Aubrie Blevins; Paige Barta; Samantha Tilley; Aaron Leifer; Andrea Guzman; Ajak Arok; Sarah Fogarty; Jacob M. Winter; Hee Chul Ahn; Karen N. Allen; Samuel Block; Iara A. Cardoso; Jianping Ding; Ingrid Dreveny; William C. Gasper; Quinn Ho; Atsushi Matsuura; Michael J. Palladino; Sabin Prajapati; Pengkai Sun; Kai Tittmann; Dean R. Tolan; Judith Unterlass; Andrew P. VanDemark; Matthew G. Vander Heiden; Bradley A. Webb; Cai Hong Yun; Pengkai Zhao; Bei Wang; Francisco J. Schopfer; Christopher P. Hill; Maria Cristina Nonato; Florian L. Muller; James E. Cox; Jared Rutter

doi:10.1126/science.abm3452

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

Kevin G. Hicks
, Ahmad A. Cluntun
, Heidi L. Schubert
, Sean R. Hackett
, Jordan A. Berg
, Paul G. Leonard
, Mariana A. Ajalla Aleixo
, Youjia Zhou
, Alex J. Bott
, Sonia R. Salvatore
, Fei Chang
, Aubrie Blevins
, Paige Barta
, Samantha Tilley
, Aaron Leifer
, Andrea Guzman
, Ajak Arok
, Sarah Fogarty
, Jacob M. Winter
, Hee Chul Ahn

Karen N. Allen, Samuel Block, Iara A. Cardoso, Jianping Ding, Ingrid Dreveny, William C. Gasper, Quinn Ho, Atsushi Matsuura, Michael J. Palladino, Sabin Prajapati, Pengkai Sun, Kai Tittmann, Dean R. Tolan, Judith Unterlass, Andrew P. VanDemark, Matthew G. Vander Heiden, Bradley A. Webb, Cai Hong Yun, Pengkai Zhao, Bei Wang, Francisco J. Schopfer, Christopher P. Hill, Maria Cristina Nonato, Florian L. Muller, James E. Cox, Jared Rutter

Department of Pharmacy

University of Utah
Alphabet Inc.
University of Texas MD Anderson Cancer Center
Universidade de São Paulo
University of Pittsburgh
Boston University
Massachusetts Institute of Technology
CAS - Center for Excellence in Molecular Cell Science
University of Nottingham
Dongguk University
University of Göttingen
Max Planck Institute for Biophysical Chemistry (Karl Friedrich Bonhoeffer Institute)
Karolinska Institutet
Dana-Farber Cancer Institute
West Virginia University
Peking University
Center for Metabolism and Mitochondrial Medicine (C3M)

Research output: Contribution to journal › Article › peer-review

117 Scopus citations

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.

Original language	English
Article number	eabm3452
Journal	Science
Volume	379
Issue number	6636
DOIs	https://doi.org/10.1126/science.abm3452
State	Published - 10 Mar 2023

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Hicks, K. G., Cluntun, A. A., Schubert, H. L., Hackett, S. R., Berg, J. A., Leonard, P. G., Ajalla Aleixo, M. A., Zhou, Y., Bott, A. J., Salvatore, S. R., Chang, F., Blevins, A., Barta, P., Tilley, S., Leifer, A., Guzman, A., Arok, A., Fogarty, S., Winter, J. M., ... Rutter, J. (2023). Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase. Science, 379(6636), Article eabm3452. https://doi.org/10.1126/science.abm3452

@article{1b9c4adf408f44808ec2a3ee6fe9e2b8,

title = "Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase",

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.",

author = "Hicks, \{Kevin G.\} and Cluntun, \{Ahmad A.\} and Schubert, \{Heidi L.\} and Hackett, \{Sean R.\} and Berg, \{Jordan A.\} and Leonard, \{Paul G.\} and \{Ajalla Aleixo\}, \{Mariana A.\} and Youjia Zhou and Bott, \{Alex J.\} and Salvatore, \{Sonia R.\} and Fei Chang and Aubrie Blevins and Paige Barta and Samantha Tilley and Aaron Leifer and Andrea Guzman and Ajak Arok and Sarah Fogarty and Winter, \{Jacob M.\} and Ahn, \{Hee Chul\} and Allen, \{Karen N.\} and Samuel Block and Cardoso, \{Iara A.\} and Jianping Ding and Ingrid Dreveny and Gasper, \{William C.\} and Quinn Ho and Atsushi Matsuura and Palladino, \{Michael J.\} and Sabin Prajapati and Pengkai Sun and Kai Tittmann and Tolan, \{Dean R.\} and Judith Unterlass and VanDemark, \{Andrew P.\} and \{Vander Heiden\}, \{Matthew G.\} and Webb, \{Bradley A.\} and Yun, \{Cai Hong\} and Pengkai Zhao and Bei Wang and Schopfer, \{Francisco J.\} and Hill, \{Christopher P.\} and Nonato, \{Maria Cristina\} and Muller, \{Florian L.\} and Cox, \{James E.\} and Jared Rutter",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.",

year = "2023",

month = mar,

day = "10",

doi = "10.1126/science.abm3452",

language = "English",

volume = "379",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6636",

}

Hicks, KG, Cluntun, AA, Schubert, HL, Hackett, SR, Berg, JA, Leonard, PG, Ajalla Aleixo, MA, Zhou, Y, Bott, AJ, Salvatore, SR, Chang, F, Blevins, A, Barta, P, Tilley, S, Leifer, A, Guzman, A, Arok, A, Fogarty, S, Winter, JM, Ahn, HC, Allen, KN, Block, S, Cardoso, IA, Ding, J, Dreveny, I, Gasper, WC, Ho, Q, Matsuura, A, Palladino, MJ, Prajapati, S, Sun, P, Tittmann, K, Tolan, DR, Unterlass, J, VanDemark, AP, Vander Heiden, MG, Webb, BA, Yun, CH, Zhao, P, Wang, B, Schopfer, FJ, Hill, CP, Nonato, MC, Muller, FL, Cox, JE & Rutter, J 2023, 'Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase', Science, vol. 379, no. 6636, eabm3452. https://doi.org/10.1126/science.abm3452

TY - JOUR

T1 - Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase

AU - Hicks, Kevin G.

AU - Cluntun, Ahmad A.

AU - Schubert, Heidi L.

AU - Hackett, Sean R.

AU - Berg, Jordan A.

AU - Leonard, Paul G.

AU - Ajalla Aleixo, Mariana A.

AU - Zhou, Youjia

AU - Bott, Alex J.

AU - Salvatore, Sonia R.

AU - Chang, Fei

AU - Blevins, Aubrie

AU - Barta, Paige

AU - Tilley, Samantha

AU - Leifer, Aaron

AU - Guzman, Andrea

AU - Arok, Ajak

AU - Fogarty, Sarah

AU - Winter, Jacob M.

AU - Ahn, Hee Chul

AU - Allen, Karen N.

AU - Block, Samuel

AU - Cardoso, Iara A.

AU - Ding, Jianping

AU - Dreveny, Ingrid

AU - Gasper, William C.

AU - Ho, Quinn

AU - Matsuura, Atsushi

AU - Palladino, Michael J.

AU - Prajapati, Sabin

AU - Sun, Pengkai

AU - Tittmann, Kai

AU - Tolan, Dean R.

AU - Unterlass, Judith

AU - VanDemark, Andrew P.

AU - Vander Heiden, Matthew G.

AU - Webb, Bradley A.

AU - Yun, Cai Hong

AU - Zhao, Pengkai

AU - Wang, Bei

AU - Schopfer, Francisco J.

AU - Hill, Christopher P.

AU - Nonato, Maria Cristina

AU - Muller, Florian L.

AU - Cox, James E.

AU - Rutter, Jared

PY - 2023/3/10

Y1 - 2023/3/10

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85149678415

U2 - 10.1126/science.abm3452

DO - 10.1126/science.abm3452

M3 - Article

C2 - 36893255

AN - SCOPUS:85149678415

SN - 0036-8075

VL - 379

JO - Science

JF - Science

IS - 6636

M1 - eabm3452

ER -

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

Abstract

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