Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 275, Issue 52, Pages 41424-41429Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M007903200
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- NHLBI NIH HHS [HL64822, HL07111] Funding Source: Medline
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Rapid exchange of high energy carrying molecules between intracellular compartments is essential in sustaining cellular energetic homeostasis, Adenylate kinase (AK)-catalyzed transfer of adenine nucleotide beta- and gamma -phosphoryls has been implicated in intracellular energy communication and nucleotide metabolism. To demonstrate the significance of this reaction in cardiac energetics, phosphotransfer dynamics were determined by [O-18]phosphoryl oxygen analysis using P-31 NMR and mass spectrometry. In hearts with a null mutation of the AK1 gene, which encodes the major AK isoform, total AX activity and beta -phosphoryl transfer was reduced by 94% and 36%, respectively. This was associated with up-regulation of phosphoryl flux through remaining minor AK isoforms and the glycolytic phosphotransfer enzyme, S-phosphoglycerate kinase, In the absence of metabolic stress, deletion of AK1 did not translate into gross abnormalities in nucleotide levels, gamma -ATP turnover rate or creatine kinase-catalyzed phosphotransfer. However, under hypoxia AK1-deficient hearts, compared with the wild type, had a blunted AK-catalyzed phosphotransfer response, lowered intracellular ATP levels, increased P-i/ATP ratio, and suppressed generation of adenosine, Thus, although lack of AK1 phosphotransfer can be compensated in the absence of metabolic challenge, under hypoxia AK1-knockout hearts display compromised energetics and impaired cardioprotective signaling, This study, therefore, provides first direct evidence that AK1 is essential in maintaining myocardial energetic homeostasis, in particular under metabolic stress.
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