In vivo deep network tracing reveals phosphofructokinase-mediated coordination of biosynthetic pathway activity in the myocardium.

Autor: Fulghum KL; Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, United States of America; Department of Physiology, University of Louisville, Louisville, KY, United States of America., Audam TN; Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, United States of America; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, United States of America., Lorkiewicz PK; Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, United States of America; Department of Chemistry, University of Louisville, Louisville, KY, United States of America., Zheng Y; Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, United States of America., Merchant M; Division of Nephrology, Department of Medicine, University of Louisville, Louisville, KY, United States of America., Cummins TD; Division of Nephrology, Department of Medicine, University of Louisville, Louisville, KY, United States of America., Dean WL; Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, United States of America., Cassel TA; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY, United States of America., Fan TWM; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY, United States of America., Hill BG; Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, United States of America. Electronic address: bradford.hill@louisville.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2022 Jan; Vol. 162, pp. 32-42. Date of Electronic Publication: 2021 Sep 03.
DOI: 10.1016/j.yjmcc.2021.08.013
Abstrakt: Glucose metabolism comprises numerous amphibolic metabolites that provide precursors for not only the synthesis of cellular building blocks but also for ATP production. In this study, we tested how phosphofructokinase-1 (PFK1) activity controls the fate of glucose-derived carbon in murine hearts in vivo. PFK1 activity was regulated by cardiac-specific overexpression of kinase- or phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgenes in mice (termed Glyco Lo or Glyco Hi mice, respectively). Dietary delivery of 13 C 6 -glucose to these mice, followed by deep network metabolic tracing, revealed that low rates of PFK1 activity promote selective routing of glucose-derived carbon to the purine synthesis pathway to form 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Consistent with a mechanism of physical channeling, we found multimeric protein complexes that contained phosphoribosylaminoimidazole carboxylase (PAICS)-an enzyme important for AICAR biosynthesis, as well as chaperone proteins such as Hsp90 and other metabolic enzymes. We also observed that PFK1 influenced glucose-derived carbon deposition in glycogen, but did not affect hexosamine biosynthetic pathway activity. These studies demonstrate the utility of deep network tracing to identify metabolic channeling and changes in biosynthetic pathway activity in the heart in vivo and present new potential mechanisms by which metabolic branchpoint reactions modulate biosynthetic pathways.
(Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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