Document Detail


Interaction of oxamate with the gluconeogenic pathway in rat liver.
MedLine Citation:
PMID:  3963816     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Oxamate, a structural analog of pyruvate, known as a potent inhibitor of lactic dehydrogenase, lactic dehydrogenase, produces an inhibition of gluconeogenic flux in isolated perfused rat liver or hepatocyte suspensions from low concentrations of pyruvate (less than 0.5 mM) or substrates yielding pyruvate. The following observations indicate that oxamate inhibits flux through pyruvate carboxylase: accumulation of substrates and decreased concentration of all metabolic intermediates beyond pyruvate; decreased levels of aspartate, glutamate, and alanine; and enhanced ketone body production, which is a sensitive indicator of decreased mitochondrial free oxaloacetate levels. The decreased pyruvate carboxylase flux does not seem to be the result of a direct inhibitory action of oxamate on this enzyme but is secondary to a decreased rate of pyruvate entry into the mitochondria. This assumption is based on the following observations: Above 0.4 mM pyruvate, no significant inhibitory effect of oxamate on gluconeogenesis was observed. The competitive nature of oxamate inhibition is in conflict with its effect on isolated pyruvate carboxylase which is noncompetitive for pyruvate. Fatty acid oxidation was effective in stimulating gluconeogenesis in the presence of oxamate only at concentrations of pyruvate above 0.4 mM. Since only at low pyruvate concentrations its entry into the mitochondria occurs via the monocarboxylate translocator, from these observations it follows that pyruvate transport across the mitochondrial membrane, and not its carboxylation, is the first nonequilibrium step in the gluconeogenic pathway. In the presence of oxamate, fatty acid oxidation inhibited gluconeogenesis from lactate, alanine, and low pyruvate concentrations (less than 0.5 mM), and the rate of transfer of reducing equivalents to the cytosol was significantly decreased. Whether fatty acids stimulate or inhibit gluconeogenesis appears to correlate with the rate of flux through pyruvate carboxylase which ultimately seems to rely on pyruvate availability. Unless adequate rates of oxaloacetate formation are maintained, the shift of the mitochondrial NAD couple to a more reduced state during fatty acid oxidation seems to decrease mitochondrial oxaloacetate resulting in a decreased rate of transfer of carbon and reducing power to the cytosol.
Authors:
A Martin-Requero; M S Ayuso; R Parrilla
Related Documents :
22254076 - Folate status of reproductive age women and neural tube defect risk: the effect of long...
2407766 - Magnesium bioavailability from magnesium citrate and magnesium oxide.
6408986 - The stimulus-secretion coupling of glucose-induced insulin release: fuel metabolism in ...
15094106 - Effects of amino acid supplementation on left ventricular remodeling in patients with c...
3731106 - Influence of lipids on gap-junction-mediated intercellular communication between chines...
20875396 - Diaryl dimers of estradiol and of estrone may be formed as major metabolites by mouse m...
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Archives of biochemistry and biophysics     Volume:  246     ISSN:  0003-9861     ISO Abbreviation:  Arch. Biochem. Biophys.     Publication Date:  1986 Apr 
Date Detail:
Created Date:  1986-05-12     Completed Date:  1986-05-12     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0372430     Medline TA:  Arch Biochem Biophys     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  114-27     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Alanine / metabolism
Amino Acids / pharmacology*
Animals
Cytosol / metabolism
Fatty Acids / metabolism
Gluconeogenesis / drug effects*
L-Lactate Dehydrogenase / antagonists & inhibitors
Lactates / metabolism
Liver / enzymology,  metabolism*
Male
NAD / metabolism
Oxamic Acid / pharmacology*
Oxidation-Reduction
Pyruvates / biosynthesis
Rats
Rats, Inbred Strains
Chemical
Reg. No./Substance:
0/Amino Acids; 0/Fatty Acids; 0/Lactates; 0/Pyruvates; 471-47-6/Oxamic Acid; 53-84-9/NAD; 56-41-7/Alanine; EC 1.1.1.27/L-Lactate Dehydrogenase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Activation of spinach chloroplast NADP-linked glyceraldehyde-3-phosphate dehydrogenase by concerted ...
Next Document:  The effect of substrate on the expression of activity catalyzed by cytochrome P-450: metabolism medi...