2-Oxo acid dehydrogenase complexes in redox regulation.
A number of cellular systems cooperate in redox regulation, providing metabolic responses according to changes in the oxidation (or reduction) of the redox active components of a cell. Key systems of central metabolism, such as the 2-oxo acid dehydrogenase complexes, are important participants in redox regulation, because their function is controlled by the NADH/NAD+ ratio and the complex-bound dihydrolipoate/lipoate ratio. Redox state of the complex-bound lipoate is an indicator of the availability of the reaction substrates (2-oxo acid, CoA and NAD+) and thiol-disulfide status of the medium. Accumulation of the dihydrolipoate intermediate causes inactivation of the first enzyme of the complexes. With the mammalian pyruvate dehydrogenase, the phosphorylation system is involved in the lipoate-dependent regulation, whereas mammalian 2-oxoglutarate dehydrogenase exhibits a higher sensitivity to direct regulation by the complex-bound dihydrolipoate/lipoate and external SH/S-S, including mitochondrial thioredoxin. Thioredoxin efficiently protects the complexes from self-inactivation during catalysis at low NAD+. As a result, 2-oxoglutarate dehydrogenase complex may provide succinyl-CoA for phosphorylation of GDP and ADP under conditions of restricted NAD+ availability. This may be essential upon accumulation of NADH and exhaustion of the pyridine nucleotide pool. Concomitantly, thioredoxin stimulates the complex-bound dihydrolipoate-dependent production of reactive oxygen species. It is suggested that this side-effect of the 2-oxo acid oxidation at low NAD+in vivo would be overcome by cooperation of mitochondrial thioredoxin and the thioredoxin-dependent peroxidase, SP-22.
Bunik
Victoria I
VI
A.N.Belozersky Institute of Physico-Chemical Biology, Moscow State University, Russia. bunik@genebee.msu.su
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D004220:Disulfides / Q000378:metabolism; D007658:Ketone Oxidoreductases / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D008063:Thioctic Acid / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism*
D004220:Disulfides; D009097:Multienzyme Complexes; D013438:Sulfhydryl Compounds; D009243:NAD; D013481:Superoxides; D013879:Thioredoxins; D008063:Thioctic Acid; D007658:Ketone Oxidoreductases; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)