RT Journal Article
SR Electronic
T1 Protein-Metabolite Interactomics Reveals Novel Regulation of Carbohydrate Metabolism
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.28.458030
DO 10.1101/2021.08.28.458030
A1 Kevin G. Hicks
A1 Ahmad A. Cluntun
A1 Heidi L. Schubert
A1 Sean R. Hackett
A1 Jordan A. Berg
A1 Paul G. Leonard
A1 Mariana A. Ajalla Aleixo
A1 Aubrie Blevins
A1 Paige Barta
A1 Samantha Tilley
A1 Sarah Fogarty
A1 Jacob M. Winter
A1 Hee-Chul Ahn
A1 Karen N. Allen
A1 Samuel Block
A1 Iara A. Cardoso
A1 Jianping Ding
A1 Ingrid Dreveny
A1 Clarke Gasper
A1 Quinn Ho
A1 Atsushi Matsuura
A1 Michael J. Palladino
A1 Sabin Prajapati
A1 PengKai Sun
A1 Kai Tittmann
A1 Dean R. Tolan
A1 Judith Unterlass
A1 Andrew P. VanDemark
A1 Matthew G. Vander Heiden
A1 Bradley A. Webb
A1 Cai-Hong Yun
A1 PengKai Zhap
A1 Christopher P. Hill
A1 Maria Cristina Nonato
A1 Florian L. Muller
A1 Daniel E. Gottschling
A1 James E. Cox
A1 Jared Rutter
YR 2021
UL http://biorxiv.org/content/early/2021/08/28/2021.08.28.458030.abstract
AB Metabolism is highly interconnected and also has profound effects on other cellular processes. However, the interactions between metabolites and proteins that mediate this connectivity are frequently low affinity and difficult to discover, hampering our understanding of this important area of cellular biochemistry. Therefore, we developed the MIDAS platform, which can identify protein-metabolite interactions with great sensitivity. We analyzed 33 enzymes from central carbon metabolism and identified 830 protein-metabolite interactions that were mostly novel, but also included known regulators, substrates, products and their analogs. We validated previously unknown interactions, including two atomic-resolution structures of novel protein-metabolite complexes. We also found that both ATP and long-chain fatty acyl-CoAs inhibit lactate dehydrogenase A (LDHA), but not LDHB, at physiological concentrations in vitro. Treating cells with long-chain fatty acids caused a loss of pyruvate/lactate interconversion, but only in cells reliant on LDHA. We propose that these regulatory mechanisms are part of the metabolic connectivity that enables survival in an ever-changing nutrient environment, and that MIDAS enables a broader and deeper understanding of that network.Competing Interest StatementThe authors have declared no competing interest.