Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Abstract

The malaria parasite Plasmodium possesses a relict, non-photosynthetic plastid known as the apicoplast. The apicoplast is essential for parasite survival, and harbors several plant-like metabolic pathways including a type II fatty acid synthesis (FASII) pathway. The FASII pathway was discovered in 1998, and much of the early research in the field pursued it as a therapeutic drug target. These studies identified a range of compounds with activity against bloodstage parasites and led to the localization and characterization of most enzymes in the pathway. However, when genetic studies revealed FASII was dispensable in bloodstage parasites, it effectively discounted the pathway as a therapeutic drug target, and suggested these compounds instead interfered with other processes. Interest in FASII then shifted toward its disruption for malaria prophylaxis and vaccine development, with experiments in rodent malaria models identifying a crucial role for the pathway in the parasite's transition from the liver to the blood. Unexpectedly however, the human malaria parasite P. falciparum was recently found to differ from rodent models and require FASII for mosquito stage development. This requirement blocked the production of the FASII-deficient forms that might be used as a genetically attenuated parasite vaccine, suggesting the pathway was also unsuitable as a vaccine target. This review discusses how perception of FASII has changed over time, and presents key findings about each enzyme in the pathway to identify remaining questions and opportunities for malaria control.

The apicoplast: now you see it, now you don’t

“…A flurry of reports described various putative inhibitors of FASII as parasiticidal, but in hindsight we now recognise that all these particular inhibitors are off-target (Shears et al, 2015). The crunch for FASII as a therapeutic drug target came with gene knockout studies showing that malaria parasites can do without vital enzymes of the fatty acid biosynthesis pathway during the red blood cell portion of their life cycle, implying that parasites do not need to synthesise fatty acids at this stage (Yu et al, 2008; Vaughan et al, 2009; Lindner et al, 2014).…”

“…By contrast, apicoplast fatty acid biosynthesis is essential in T. gondii in mice since ablation of the acyl carrier protein in vivo clears the infection (Mazumdar et al, 2006). It remains uncertain why so many bacterial FASII inhibitors kill blood stage malaria parasites even though they have mostly been shown to be off-target (Shears et al, 2015). One suggestion is that these compounds could be targeting cytosolic fatty acid elongases used to modify scavenged fatty acids (Shears et al, 2015).…”

“…It remains uncertain why so many bacterial FASII inhibitors kill blood stage malaria parasites even though they have mostly been shown to be off-target (Shears et al, 2015). One suggestion is that these compounds could be targeting cytosolic fatty acid elongases used to modify scavenged fatty acids (Shears et al, 2015). Another open question is whether FASII can be targeted in liver stages, where it is essential in rodent malarias (and probably human malaria parasites) for prophylaxis.…”

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

“…The precise nature of these putative contributions is currently unknown and is currently under investigation. The TCA cycle may have a similar role in the rapidly-dividing liver stages of Plasmodium where fatty acid biosynthesis is prevalent (reviewed in [105]), although it is important to note that ACL and plastidial Aco and IDH have not been found in these species.…”

Comparative sequence analysis of Cyclospora cayetanensis apicoplast genomes originating from diverse geographical regions

“…Previous studies have shown that the apicoplast is involved in critical metabolic processes such as, heme and isoprenoid biosynthesis, fatty acid synthesis [11, 14–17], and is essential for growth in Plasmodium falciparum [18]. Because apicoplasts are vital to the survival of the parasites, they provide an attractive target for antiparasitic drugs [19, 20]. The sequence, gene content and map of various apicoplast genomes, including C. cayatenensis apicoplast genome, have been reported [21–25].…”