RGD Reference Report - Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid. - Rat Genome Database

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Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid.

Authors: Haramaki, N  Han, D  Handelman, GJ  Tritschler, HJ  Packer, L 
Citation: Haramaki N, etal., Free Radic Biol Med. 1997;22(3):535-42.
RGD ID: 2289895
Pubmed: PMID:8981046   (View Abstract at PubMed)

In cellular, tissue, and organismal systems, exogenously supplied alpha-lipoic acid (thioctic acid) has a variety of significant effects, including direct radical scavenging, redox modulation of cell metabolism, and potential to inhibit oxidatively-induced injury. Because reduction of lipoate to dihydrolipoate is a crucial step in many of these processes, we investigated mechanisms of its reduction. The mitochondrial NADH-dependent dihydrolipoamide dehydrogenase exhibits a marked preference for R(+)-lipoate, whereas NADPH-dependent glutathione reductase shows slightly greater activity toward the S(-)-lipoate stereoisomer. Rat liver mitochondria also reduced exogenous lipoic acid. The rate of reduction was stimulated by substrates which increased the NADH content of the mitochondria, and was inhibited by methoxyindole-2-carboxylic acid, a dihydrolipoamide dehydrogenase inhibitor. In rat liver cytosol, NADPH-dependent reduction was greater than NADH, and lipoate reduction was inhibited by glutathione disulfide. In rat heart, kidney, and brain whole cell-soluble fractions, NADH contributed more to reduction (70-90%) than NADPH, whereas with liver, NADH and NADPH were about equally active. An intact organ, the isolated perfused rat heart, reduced R-lipoate six to eight times more rapidly than S-lipoate, consistent with high mitochondrial dihydrolipoamide dehydrogenase activity and results with isolated cardiac mitochondria. On the other hand, erythrocytes, which lack mitochondria, somewhat more actively reduced S- than R-lipoate. These results demonstrate differing stereospecific reduction by intact cells and tissues. Thus, mechanisms of reduction of alpha-lipoate are highly tissue-specific and effects of exogenously supplied alpha-lipoate are determined by tissue glutathione reductase and dihydrolipoamide dehydrogenase activity.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
dihydrolipoamide metabolic process  IDA 2289895 RGD 
lipoate metabolic process  IDA 2289895 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
dihydrolipoyl dehydrogenase activity  IDA 2289895 RGD 
lipoamide binding  IDA 2289895 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dld  (dihydrolipoamide dehydrogenase)


Additional Information