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

Kyle L. Fulghum, Timothy N. Audam, Pawel K. Lorkiewicz, Yuting Zheng, Michael Merchant, Timothy D. Cummins, William L. Dean, Teresa A. Cassel, Teresa W.M. Fan, Bradford G. Hill

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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 GlycoLo or GlycoHi mice, respectively). Dietary delivery of 13C6-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.

Original languageEnglish
Pages (from-to)32-42
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume162
DOIs
StatePublished - Jan 2022

Bibliographical note

Publisher Copyright:
© 2021 The Authors

Keywords

  • Anabolism
  • Channeling
  • Glycolysis
  • Metabolomics
  • Metabolons
  • Stable isotope

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'In vivo deep network tracing reveals phosphofructokinase-mediated coordination of biosynthetic pathway activity in the myocardium'. Together they form a unique fingerprint.

Cite this