Hart Robert J, Abraham Amanah, Aly Ahmed S I
Department of Tropical Medicine, Tulane UniversityNew Orleans, LA, United States.
Front Cell Infect Microbiol. 2017 Jun 20;7:260. doi: 10.3389/fcimb.2017.00260. eCollection 2017.
Coenzyme A (CoA) is an essential universal cofactor for all prokaryotic and eukaryotic cells. In nearly all non-photosynthetic cells, CoA biosynthesis depends on the uptake and phosphorylation of vitamin B5 (pantothenic acid or pantothenate). Recently, putative pantothenate transporter (PAT) and pantothenate kinases (PanKs) were functionally characterized in . PAT and PanKs were shown to be dispensable for blood stage development, but they were essential for mosquito stages development. Yet, little is known about the cellular functions of the other enzymes of the CoA biosynthesis pathway in malaria parasite life cycle stages. All enzymes of this pathway were targeted for deletion or deletion/complementation analyses by knockout/knock-in plasmid constructs to reveal their essential roles in life cycle stages. The intermediate enzymes PPCS (Phosphopantothenylcysteine Synthase), PPCDC (Phosphopantothenylcysteine Decarboxylase) were shown to be dispensable for asexual and sexual blood stage development, but they were essential for oocyst development and the production of sporozoites. However, the last two enzymes of this pathway, PPAT (Phosphopantetheine Adenylyltransferase) and DPCK (Dephospho-CoA Kinase), were essential for blood stage development. These results indicate alternative first substrate requirement for the malaria parasite, other than the canonical pantothenate, for the synthesis of CoA in the blood but not inside the mosquito midgut. Collectively, our data shows that CoA biosynthesis is essential for both blood and mosquito stages, and thus validates the enzymes of this pathway as potential antimalarial targets.
辅酶A（CoA）是所有原核细胞和真核细胞必不可少的通用辅因子。在几乎所有非光合细胞中，CoA的生物合成依赖于维生素B5（泛酸）的摄取和磷酸化。最近，在……中对假定的泛酸转运蛋白（PAT）和泛酸激酶（PanK）进行了功能表征。结果表明，PAT和PanK对于疟原虫血液阶段的发育并非必需，但对蚊子阶段的发育至关重要。然而，关于CoA生物合成途径中其他酶在疟原虫生命周期各阶段的细胞功能，人们所知甚少。通过敲除/敲入质粒构建体对该途径的所有酶进行靶向缺失或缺失/互补分析，以揭示它们在生命周期各阶段的重要作用。中间酶磷酸泛酰巯基乙胺半胱氨酸合成酶（PPCS）和磷酸泛酰巯基乙胺半胱氨酸脱羧酶（PPCDC）对无性和有性血液阶段的发育并非必需，但对卵囊发育和子孢子的产生至关重要。然而，该途径的最后两种酶，磷酸泛酰巯基乙胺腺苷酰转移酶（PPAT）和脱磷酸辅酶A激酶（DPCK）对血液阶段的发育至关重要。这些结果表明，疟原虫在血液中合成CoA时，除了经典的泛酸外，对第一种底物有其他需求，而在蚊子中肠内则不然。总体而言，我们的数据表明CoA生物合成对血液阶段和蚊子阶段都至关重要，因此验证了该途径的酶作为潜在抗疟靶点的有效性。
