Exploring the Untapped Biosynthetic Potential of Apicomplexan Parasites

Abstract

Apicomplexan parasites encompass a diverse group of eukaryotic intracellular pathogens that infect various animal hosts to cause disease. Intriguingly, apicomplexans possess a unique organelle of algal origin, the apicoplast, which phylogenetically links these parasites to dinoflagellates and photosynthetic, coral-associated organisms. While production of secondary metabolites in closely related organisms has been thoroughly examined, it remains widely unexplored in apicomplexans. In this Perspective, we discuss previous work toward understanding secondary metabolite building block biosynthesis in apicomplexans and highlight the unexplored enzymology and biosynthetic potential of these parasites in the context of evolution.

A single amino acid residue controls acyltransferase activity in a polyketide synthase from Toxoplasma gondii

“…A recent bioinformatic survey found that at least 95% of assembly-line PKSs identified are from bacteria, while only 1% are from eukaryotes ( Nivina et al., 2019 ). Despite this small percentage, modular PKSs are found across eukaryotic lineages, including unicellular protists ( Bushkin et al., 2013 ; Ganley et al., 2017 ; John et al., 2008 ; Sasso et al., 2012 ; Zhu et al., 2002 ), nematodes ( Feng et al., 2021 ; Shou et al., 2016 ), arthropods ( Brückner et al., 2020 ; Pankewitz and Hilker, 2008 ), and even chordates ( Cooke et al., 2017 ), indicating that eukaryotic PKSs may be more phylogenetically widespread than previously assumed. One such example is PKSs from protistan lineages, including dinoflagellates, green algae, and apicomplexan parasites.…”

Linking Genes to Molecules in Eukaryotic Sources: An Endeavor to Expand Our Biosynthetic Repertoire

“…Of particular note are parasites from the Plasmodium, Toxoplasma, and Cryptosporidium genera that cause malaria, toxoplasmosis, and cryptosporidiosis, respectively. These organisms are phylogenetically related to red algae and dinoflagellates [126,127] and their potential as untapped sources of novel metabolites has been previously reviewed by our group [128]. Some secondary metabolites from these organisms have been associated with altering specific life cycle stages, including facilitating egress from the host cell [129] and potentially increasing transmission rates [130].…”

“…Some secondary metabolites from these organisms have been associated with altering specific life cycle stages, including facilitating egress from the host cell [129] and potentially increasing transmission rates [130]. Remarkably, many of these organisms contain multi-modular type I PKS and FAS genes with unknown metabolites [128,131,132]. While there is not a definitively known function for the polyketide metabolites within these organisms, we [131] and others [133,134] have hypothesized structural roles in oocyst wall formation, analogous to polyketide-derived mycolic acids in Mycobacterium spp.…”

Investigating the Role of Class I Adenylate-Forming Enzymes in Natural Product Biosynthesis

“…123−126 Although members of the closely related phylum dinoflagellates are known producers of complex natural products, apicomplexan parasites remain an unexplored area in natural product discovery. 127 This is due in large part to poor genome annotations and difficulties associated with culturing these parasites in vitro. Using the biosynthetic gene cluster prediction software fungiSMASH, several interesting PKS genes with unique domain architectures are shown to exist in apicomplexan parasites (Figure 5A).…”

“…Apicomplexan parasites encompass some of the most widespread eukaryotic pathogens on earth, including the human-infective Plasmodium sp., Cryptosporidium parvum , and Toxoplasma gondii , the causative agents of malaria, cryptosporidiosis, and toxoplasmosis, respectively . Fatty acid biosynthesis in these parasites has been described, with most species utilizing type I and/or type II fatty acid synthases (FAS), as well as scavenging lipids from the host. − Although members of the closely related phylum dinoflagellates are known producers of complex natural products, apicomplexan parasites remain an unexplored area in natural product discovery . This is due in large part to poor genome annotations and difficulties associated with culturing these parasites in vitro .…”