M-LDH Serves as a Regulatory Subunit of the Cytosolic sSbstrate-channelling Complex in Vivo

S Jovanovic, A Jovanovic, Russell Mckenzie Crawford

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Nucleoside diphosphate kinase A (NDPK-A) regulates the (XI isoform of the AMP-activated protein kinase (AMPK alpha 1) selectively, independent of [AMP] and surrounding [ATP], by a process termed substrate channelling. Here, we show, using a range of empirically validated biochemical techniques, that the muscle form (M-LDH or LDH-A) and the heart form (H-LDH or LDH-B) of lactate dehydrogenase are physically associated with the liver cytosolic substrate-channelling complex such that M-LDH associates with NDPK-A, AMPK alpha 1 and casein kinase 2 (CK2), whereas H-LDH associates with local NDPK-B. We find that the species of LDH bound to the substrate-channelling complex regulates the in vivo enzymatic activities of both AMPK and CK2, and has a downstream effect on the phospho-status of acetyl CoA carboxylase, a key regulator of cellular fat metabolism known to be a part of the cytosolic substrate-channelling complex in vivo. We hypothesise that the regulatory presence of LDH in the complex couples the sub strate-channelling mechanism to both the glycolytic and redox states of the cell, allowing for efficient sensing of cell metabolic status, interfacing with the substrate-channelling complex and regulating the enzymatic activities of AMPK and CK2, two critical protein kinases. (C) 2007 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)349-361
Number of pages13
JournalJournal of Molecular Biology
Volume371
Issue number2
DOIs
Publication statusPublished - 10 Aug 2007

Keywords

  • NDPK
  • AMPK
  • lactate dehydrogenase
  • substrate channelling
  • redox status
  • NUCLEOSIDE-DIPHOSPHATE KINASE
  • ACTIVATED PROTEIN-KINASE
  • LACTATE-DEHYDROGENASE
  • CELLS
  • ATP
  • CK2
  • PHOSPHORYLATION
  • INHIBITION
  • METABOLISM
  • EXPRESSION

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