Stimulation of rat liver AMP-activated protein kinase by AMP analogues

Biochim Biophys Acta. 1996 Jun 4;1290(2):197-203. doi: 10.1016/0304-4165(96)00021-9.

Abstract

Stimulation of AMP-activated kinase (AMP-PK) by ZMP (5-amino-4-imidazolecarboxamide ribotide, AICAR), formed by adenosine kinase upon addition of AICAriboside to isolated rat hepatocytes, results in inhibition of fatty acid and cholesterol synthesis by inactivation of acetyl-CoA carboxylase and 3-hydroxy-3-methylglutaryl-CoA reductase, respectively (Henin et al. (1995) FASEB J. 9, 541-546). The effects of ZMP and other AMP analogues have now been compared with those of AMP on AMP-PK purified from rat liver. ZMP stimulated AMP-PK to the same maximal extent as AMP (about 10-fold). ZMP had less affinity for AMP-PK than AMP, but this affinity was similarly influenced by ATP: half-maximal effects, requiring 0.4 mM AMP or 5 mM ZMP at 3 mM ATP, were obtained with 9 microM AMP or 0.4 mM ZMP at 0.2 mM ATP. The kinetic parameters of AMP-PK for the SAMS peptide and for ATP were influenced in the same way by ZMP and AMP. Stimulation of AMP-PK by ZMP was additive with AMP, up to when maximal stimulation was obtained. Taken together, these results indicate that ZMP binds to the same site as AMP on AMP-PK. Tubercidin 5'-monophosphate, 2'-deoxy-AMP and Ara-AMP stimulated AMP-PK, but N6-methyl-AMP, 1,N6-etheno-AMP, 6-mercaptopurine riboside 5'-monophosphate, adenylosuccinate and succinyl-AICAR were ineffective, suggesting that a free 6-NH2 group may be important for binding of effectors to AMP-PK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Adenine Nucleotides / pharmacology*
  • Allosteric Regulation
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Binding, Competitive
  • Enzyme Activation / drug effects
  • Kinetics
  • Liver / enzymology
  • Multienzyme Complexes / metabolism*
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases*
  • Rats
  • Ribonucleotides / pharmacology

Substances

  • Adenine Nucleotides
  • Multienzyme Complexes
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide