α-Lipoic acid (6,8-thioctic acid; LA) is a vital co-factor of α-ketoacid dehydrogenase complexes and the glycine cleavage system.
In recent years it was shown that biosynthesis and salvage of LA in Plasmodium are necessary for the parasites to complete their
complex life cycle. LA salvage requires two lipoic acid protein ligases (LplA1 and LplA2). LplA1 is confined to the mitochondrion while
LplA2 is located in both the mitochondrion and the apicoplast. LplA1 exclusively uses salvaged LA and lipoylates α-ketoglutarate dehydrogenase,
branched chain α-ketoacid dehydrogenase and the H-protein of the glycine cleavage system. LplA2 cannot compensate for the
loss of LplA1 function during blood stage development suggesting a specific function for LplA2 that has yet to be elucidated. LA salvage
is essential for the intra-erythrocytic and liver stage development of Plasmodium and thus offers great potential for future drug or vaccine
LA biosynthesis, comprising octanoyl-acyl carrier protein (ACP) : protein N-octanoyltransferase (LipB) and lipoate synthase (LipA), is
exclusively found in the apicoplast of Plasmodium where it generates LA de novo from octanoyl-ACP, provided by the type II fatty acid
biosynthesis (FAS II) pathway also present in the organelle. LA is the co-factor of the acetyltransferase subunit of the apicoplast located
pyruvate dehydrogenase (PDH), which generates acetyl-CoA, feeding into FAS II. LA biosynthesis is not vital for intra-erythrocytic development
of Plasmodium, but the deletion of several genes encoding components of FAS II or PDH was detrimental for liver stage development
of the parasites indirectly suggesting that the same applies to LA biosynthesis.
These data provide strong evidence that LA salvage and biosynthesis are vital for different stages of Plasmodium development and offer
potential for drug and vaccine design against malaria.
Keywords: Lipoic acid salvage, lipoic acid biosynthesis, malaria, vaccine development, chemotherapy, Plasmodium, octanoyl-acyl carrier protein (ACP), apicoplast, lipoate synthase (LipA), type II fatty acid biosynthesis (FAS II)
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