Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets

PLoS Pathog. 2021 Dec 30;17(12):e1010124. doi: 10.1371/journal.ppat.1010124. eCollection 2021 Dec.

Abstract

The Apicomplexa phylum comprises thousands of distinct intracellular parasite species, including coccidians, haemosporidians, piroplasms, and cryptosporidia. These parasites are characterized by complex and divergent life cycles occupying a variety of host niches. Consequently, they exhibit distinct adaptations to the differences in nutritional availabilities, either relying on biosynthetic pathways or by salvaging metabolites from their host. Pantothenate (Pan, vitamin B5) is the precursor for the synthesis of an essential cofactor, coenzyme A (CoA), but among the apicomplexans, only the coccidian subgroup has the ability to synthesize Pan. While the pathway to synthesize CoA from Pan is largely conserved across all branches of life, there are differences in the redundancy of enzymes and possible alternative pathways to generate CoA from Pan. Impeding the scavenge of Pan and synthesis of Pan and CoA have been long recognized as potential targets for antimicrobial drug development, but in order to fully exploit these critical pathways, it is important to understand such differences. Recently, a potent class of pantothenamides (PanAms), Pan analogs, which target CoA-utilizing enzymes, has entered antimalarial preclinical development. The potential of PanAms to target multiple downstream pathways make them a promising compound class as broad antiparasitic drugs against other apicomplexans. In this review, we summarize the recent advances in understanding the Pan and CoA biosynthesis pathways, and the suitability of these pathways as drug targets in Apicomplexa, with a particular focus on the cyst-forming coccidian, Toxoplasma gondii, and the haemosporidian, Plasmodium falciparum.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antiparasitic Agents / pharmacology*
  • Apicomplexa / metabolism*
  • Apicomplexa / parasitology*
  • Coenzyme A / biosynthesis*
  • Humans
  • Pantothenic Acid / biosynthesis*
  • Protozoan Infections*

Substances

  • Antiparasitic Agents
  • Pantothenic Acid
  • Coenzyme A

Grants and funding

LEdV was supported by a PhD fellowship from the Radboud Institute for Molecular Life Sciences, Radboudumc (RIMLS015-010) and TWAK by the Netherlands Organization for Scientific Research (NWO-VIDI 864.13.009). ML is supported by a PhD salary award granted by the Institute of Genetics and Genomics of Geneva (IGE3), AK and DSF are supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program under grant agreement no. 695596. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.