Abstract
Coenzyme A is synthesised from pantothenate via five enzyme-mediated steps. The first step is catalysed by pantothenate kinase (PanK). All PanKs characterised to date form homodimers. Many organisms express multiple PanKs. In some cases, these PanKs are not functionally redundant, and some appear to be non-functional. Here, we investigate the PanKs in two pathogenic apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii. Each of these organisms express two PanK homologues (PanK1 and PanK2). We demonstrate that PfPanK1 and PfPanK2 associate, forming a single, functional PanK complex that includes the multi-functional protein, Pf14-3-3I. Similarly, we demonstrate that TgPanK1 and TgPanK2 form a single complex that possesses PanK activity. Both TgPanK1 and TgPanK2 are essential for T. gondii proliferation, specifically due to their PanK activity. Our study constitutes the first examples of heteromeric PanK complexes in nature and provides an explanation for the presence of multiple PanKs within certain organisms.
Highlights
Coenzyme A (CoA) is an essential enzyme cofactor in all living organisms [1]
The first reaction in the CoA biosynthesis pathway is catalysed by the enzyme pantothenate kinase (PanK)
We demonstrate that the two PanK homologues encoded in the genomes of the apicomplexans Plasmodium falciparum and Toxoplasma gondii, PanK1 and PanK2, exist as functional heteromeric complexes
Summary
Coenzyme A (CoA) is an essential enzyme cofactor in all living organisms [1]. CoA itself, and the CoA-derived phosphopantetheine prosthetic group required by various carrier proteins, function as acyl group carriers and activators in key cellular processes such as fatty acid biosynthesis, β-oxidation and the citric acid cycle. PanKs from all three types have been shown to exist as homodimers based on their solved protein structures [3,4,5,6,7,8,9,10]. In some organisms harbouring multiple PanKs, it has not been possible to demonstrate functional activity for all enzymes. One of the four human type II PanKs was shown to be catalytically inactive [21,26], as is a type III PanK from Mycobacterium tuberculosis [23], and a type II PanK from B. anthracis [7]. The reason for the presence of multiple PanKs within certain cells, and the apparent inactivity of certain PanKs, is unclear
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