Year-end Sale % OFF 
Abstract
Oxamate, structural analog of pyruvate, inhibits gluconeogenesis from pyruvate or substrates yielding pyruvate. The inhibitory effect is the result of a decreased mitochondrial pyruvate utilization. Although the inhibition of gluconeogenesis is competitive for pyruvate, in isolated mitochondria oxamate displays a mixed type kinetics inhibitory pattern of pyruvate utilization. Evidence is presented indicating that this mixed type pattern of inhibition is the result of the action of oxamate on two different sites: noncompetitive inhibition of pyruvate carboxylation, and competitive inhibition of pyruvate entry into the mitochondria. At concentrations of pyruvate above 0.4 mM, although pyruvate carboxylation is decreased by 40% by oxamate, no detectable effects on the gluconeogenic flux were observed. This finding strongly indicates that pyruvate carboxylase is not an important rate-limiting step for hepatic gluconeogenesis. Thus, the inhibition of gluconeogenesis at low pyruvate concentrations (less than 0.4 mM) seems to be the result of an interaction of oxamate with the mitochondrial pyruvate translocator, indicating that pyruvate transport across the mitochondrial membrane is the first nonequilibrium step in the gluconeogenic pathway when low physiological concentrations of this substrate are utilized.
Highlights
From the Instituto de Endocrinologia y Metabolism0 “G. Mararion,” Centro de Investigaciones Bioldgicas, ConsejoSuperior de Investigaciones Cientificas, Velazquez 144, 28006 Madrid, Spain
The inhibitory effect is the result of a decreased mitochondrial pyruvate utilization
The inhibition of gluconeogenesis is competitive for pyruvate,in isolated mitochondria oxamate displays a mixed type kineticsinhibitory pattern of pyruvate utilization
Summary
From the Instituto de Endocrinologia y Metabolism0 “G. Mararion,” Centro de Investigaciones Bioldgicas, ConsejoSuperior de Investigaciones Cientificas, Velazquez 144, 28006 Madrid, Spain. Evidence is presented indicating that this mixed type pattern of inhibition is the result of the action of oxamate on two different sites: 1) noncompetitive inhibition of pyruvate carboxylation, and 2) competitive inhibition of pyruvate entry into the mitochondria. At concentrations of pyruvate above 0.4 mM, pyruvate carboxylation is decreased by 40%by oxamate, no detectable effects on the gluconeogenic flux were observed This finding strongly indicates that pyruvate carboxylase is not an important rate-limiting step for hepatic gluconeogenesis. We have recently described [1] that oxamate (-OOC-CONH,), structural analog of pyruvate, known by its specific inhibitory effect on lactate dehydrogenase ( 2 , 3 ) was a potent inhibitor of hepatic gluconeogenesis This effect was observed from substrates yielding pyruvate other than lactate, ruling out lactate dehydrogenase as the primary site of action of oxamate. Since gluconeogenesis is not inhibited by oxamate at these pyruvate concentrations, this observation addsdirectly conclusive support to previous evidence suggesting that pyruvate carboxylation is not rate-limiting for gluconeogenesis [1]
Sign-in/Register to view highlights & summary 
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
