Lipoic acid metabolism

Lipoic acid is an essential cofactor of dehydrogenase enzymes, mainly the E2 subunit of pyruvate dehydrogenase, branched-chain keto-acid dehydrogenase and 2-oxoglutarate dehydrogenase complexes. Lipoic acid is an organic sulphur compound derived from the 8-carbon fatty acid, octanoic acid. In most eukaryotes, lipoic acid is synthesised in mitochondrion and it is consistent with the localisation of above mentioned three complexes in mitochondria. In apicomplexan parasites, pyruvate dehydrogenase complex is localised in the plastid organelle, apicoplast. As the de novo fatty acid biosynthesis via FAS II pathway (fatty acid biosynthesis in the apicoplast) occurs in apicoplast, it is possible to suggest that Toxoplasma gondii can de novo synthesise lipoic acid in the apicoplast. Although other dehydrogenases are located in mitochondria, de novo fatty acid biosynthesis does not take place in apicomplexan mitochondrion. The work by Crawford et al in T. gondii demonstrated that lipoylation of mitochondrial proteins is reduced when the parasites are grown in lipoic acid-deficient medium and no effect was seen with lipoylation of apicoplast proteins. This effect in mitochondrion has also shown to be reversed with exogenous lipoic acid supply [1]. This clearly shows that apicoplast synthesises lipoic acid de novo, whereas mitochondrion salvages it from host. The plasma membrane and mitochondrial transporter which are involved in lipoic acid salvage and mitochondrial localisation are not yet identified in T. gondii genome. The lipoic acid metabolism pathway for Plasmodium falciparum in MPMP is identical to pathway here and Plasmodium also follows the biosynthesis and salvage mechanisms as in T. gondii.

 

Enzyme EC Number Gene id Protein localisation Localisation data source
E2-subunit KADH 1.2.4.2 TGME49_244200 Mitochondrion Previous publication
E2-subunit PDH 2.3.1.12 TGME49_206610 Apicoplast Apiloc; Previous publication; Orthology transformation from P. falciparum
Lipoyl (octanoyl)-ACP:protein N-lipoyl (octanoyl) transferase 2.3.1.181 TGME49_315640    
Lipoate-protein ligase 2.7.7.63 TGME49_271820 Mitochondrion Previous publication
Lipoic acid synthase 2.8.1.8 TGME49_226400 Apicoplast Previous publication; Orthology transformation from P. falciparum

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Octanoyl-ACP Fatty acid biosynthesis in the apicoplast ACP Fatty acid biosynthesis in the apicoplast
Sulfur Host 5'-deoxyadenosine Purine metabolism
S-adenosylmethionine Methionine metabolism L-methionine Methionine metabolism
Lipoic acid Host