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Article

Activation of Anopheles stephensi Pantothenate Kinase and Coenzyme A Biosynthesis Reduces Infection with Diverse Plasmodium Species in the Mosquito Host

1
Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, ID 83843, USA
2
Department of Entomology, University of Arizona, Tucson, AZ 85721, USA
3
Department of Biological Sciences, University of Idaho, Moscow, ID 83843, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this manuscript.
Academic Editor: Moriya Tsuji
Biomolecules 2021, 11(6), 807; https://doi.org/10.3390/biom11060807
Received: 20 April 2021 / Revised: 23 May 2021 / Accepted: 25 May 2021 / Published: 29 May 2021
(This article belongs to the Special Issue Feature Papers in Section Molecular Medicine)
Malaria parasites require pantothenate from both human and mosquito hosts to synthesize coenzyme A (CoA). Specifically, mosquito-stage parasites cannot synthesize pantothenate de novo or take up preformed CoA from the mosquito host, making it essential for the parasite to obtain pantothenate from mosquito stores. This makes pantothenate utilization an attractive target for controlling sexual stage malaria parasites in the mosquito. CoA is synthesized from pantothenate in a multi-step pathway initiated by the enzyme pantothenate kinase (PanK). In this work, we manipulated A. stephensi PanK activity and assessed the impact of mosquito PanK activity on the development of two malaria parasite species with distinct genetics and life cycles: the human parasite Plasmodium falciparum and the mouse parasite Plasmodium yoelii yoelii 17XNL. We identified two putative A. stephensi PanK isoforms encoded by a single gene and expressed in the mosquito midgut. Using both RNAi and small molecules with reported activity against human PanK, we confirmed that A. stephensi PanK manipulation was associated with corresponding changes in midgut CoA levels. Based on these findings, we used two small molecule modulators of human PanK activity (PZ-2891, compound 7) at reported and ten-fold EC50 doses to examine the effects of manipulating A. stephensi PanK on malaria parasite infection success. Our data showed that oral provisioning of 1.3 nM and 13 nM PZ-2891 increased midgut CoA levels and significantly decreased infection success for both Plasmodium species. In contrast, oral provisioning of 62 nM and 620 nM compound 7 decreased CoA levels and significantly increased infection success for both Plasmodium species. This work establishes the A. stephensi CoA biosynthesis pathway as a potential target for broadly blocking malaria parasite development in anopheline hosts. We envision this strategy, with small molecule PanK modulators delivered to mosquitoes via attractive bait stations, working in concert with deployment of parasite-directed novel pantothenamide drugs to block parasite infection in the human host. In mosquitoes, depletion of pantothenate through manipulation to increase CoA biosynthesis is expected to negatively impact Plasmodium survival by starving the parasite of this essential nutrient. This has the potential to kill both wild type parasites and pantothenamide-resistant parasites that could develop under pantothenamide drug pressure if these compounds are used as future therapeutics for human malaria. View Full-Text
Keywords: coenzyme A; CoA; pantothenate kinase; PanK; Anopheles stephensi; midgut; Plasmodium falciparum; Plasmodium yoelii; malaria; small molecules; PZ-2891; compound 7 coenzyme A; CoA; pantothenate kinase; PanK; Anopheles stephensi; midgut; Plasmodium falciparum; Plasmodium yoelii; malaria; small molecules; PZ-2891; compound 7
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    Description: Supplemental Figure 1. Conserved features in eukaryotic pantothenate kinases. Sequence alignment of the A. stephensi PanK (AsPanK) catalytic core with human PanK1, PanK2, and PanK3 illustrates six conserved signature sequences: xDIGGTLxKLxY, TGGGAxKF, VNxGSGVS, LGGGTFxGLCxLLT, DKLVxDIYGG, and GLxGxxVASSFG. Conserved catalytic residues Glu-128 and Arg-193 are essential for PanK function and present in A. stephensi PanK denoted by blue arrows. Sequence numbering is assigned to A. stephensi PanK. Supplemental Figure 2. Oral provisioning of PZ-2891 and compound 7 had no effects on P. y. yoelii 17XNL sporozoite infection of A. stephensi. Sporozoite infections were analyzed in two of the three separate cohorts of P. y. yoelii 17XNL-infected A. stephensi from Fig. 6. For these analyses, salivary glands were dissected at 12-15 d PI, with sporozoite infections scored on a scale of 1-4 per pair of glands, with 1 for 100-1,000 sporozoites, 2 for 1,000-10,000 sporozoites, 3 for 10,000-100,000 sporozoites and 4 for 100,000+ sporozoites. Prevalence data or proportions of mosquitoes with sporozoite-positive salivary glands (A) were analyzed by Chi-square and Fisher’s exact tests and infection intensity data (B) were analyzed by one-way ANOVA.
MDPI and ACS Style

Simão-Gurge, R.M.; Thakre, N.; Strickland, J.; Isoe, J.; Delacruz, L.R.; Torrevillas, B.K.; Rodriguez, A.M.; Riehle, M.A.; Luckhart, S. Activation of Anopheles stephensi Pantothenate Kinase and Coenzyme A Biosynthesis Reduces Infection with Diverse Plasmodium Species in the Mosquito Host. Biomolecules 2021, 11, 807. https://doi.org/10.3390/biom11060807

AMA Style

Simão-Gurge RM, Thakre N, Strickland J, Isoe J, Delacruz LR, Torrevillas BK, Rodriguez AM, Riehle MA, Luckhart S. Activation of Anopheles stephensi Pantothenate Kinase and Coenzyme A Biosynthesis Reduces Infection with Diverse Plasmodium Species in the Mosquito Host. Biomolecules. 2021; 11(6):807. https://doi.org/10.3390/biom11060807

Chicago/Turabian Style

Simão-Gurge, Raquel M., Neha Thakre, Jessica Strickland, Jun Isoe, Lillian R. Delacruz, Brandi K. Torrevillas, Anna M. Rodriguez, Michael A. Riehle, and Shirley Luckhart. 2021. "Activation of Anopheles stephensi Pantothenate Kinase and Coenzyme A Biosynthesis Reduces Infection with Diverse Plasmodium Species in the Mosquito Host" Biomolecules 11, no. 6: 807. https://doi.org/10.3390/biom11060807

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