Document Detail


Compromised energetics in the adenylate kinase AK1 gene knockout heart under metabolic stress.
MedLine Citation:
PMID:  11006295     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 [(18)O]phosphoryl oxygen analysis using( 31)P NMR and mass spectrometry. In hearts with a null mutation of the AK1 gene, which encodes the major AK isoform, total AK 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, 3-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.
Authors:
D Pucar; E Janssen; P P Dzeja; N Juranic; S Macura; B Wieringa; A Terzic
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  275     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2000 Dec 
Date Detail:
Created Date:  2001-01-25     Completed Date:  2001-01-26     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  41424-9     Citation Subset:  IM    
Affiliation:
Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / analysis
Adenylate Kinase / genetics,  physiology*
Animals
Energy Metabolism*
Homeostasis
Mice
Mice, Knockout
Myocardium / metabolism*
Grant Support
ID/Acronym/Agency:
HL07111/HL/NHLBI NIH HHS; HL64822/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
56-65-5/Adenosine Triphosphate; EC 2.7.4.3/Adenylate Kinase

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