Presence of Phylloquinone in the Intraerythrocytic Stages of Plasmodium falciparum

Abstract

Malaria is one of the most widespread parasitic diseases, especially in Africa, Southeast Asia and South America. One of the greatest problems for control of the disease is the emergence of drug resistance, which leads to a need for the development of new antimalarial compounds. The biosynthesis of isoprenoids has been investigated as part of a strategy to identify new targets to obtain new antimalarial drugs. Several isoprenoid quinones, including menaquinone-4 (MK-4/vitamin K2), α- and γ-tocopherol and ubiquinone (UQ) homologs UQ-8 and UQ-9, were previously detected in in vitro cultures of Plasmodium falciparum in asexual stages. Herein, we described for the first time the presence of phylloquinone (PK/vitamin K1) in P. falciparum and discuss the possible origins of this prenylquinone. While our results in metabolic labeling experiments suggest a biosynthesis of PK prenylation via phytyl pyrophosphate (phytyl-PP) with phytol being phosphorylated, on the other hand, exogenous PK attenuated atovaquone effects on parasitic growth and respiration, showing that this metabolite can be transported from extracellular environment and that the mitochondrial electron transport system (ETS) of P. falciparum is capable to interact with PK. Although the natural role and origin of PK remains elusive, this work highlights the PK importance in plasmodial metabolism and future studies will be important to elucidate in seeking new targets for antimalarial drugs.

Isoprenoid alcohols utilization by malaria parasites

“…Isoprenoid alcohols phosphorylation and parasite utilization indicate the presence of, at least, one still unknown polyprenol kinase that would convert FOH and GGOH into their active pyrophosphorylated forms (Crick et al, 1997) and a novel salvage pathway utilizing FOH and GGOH for protein prenylation. This kinase reaction was previously suggested in parasitic extracts by employing POH as a substrate (Sussmann et al, 2022). Biochemical evidence for a metabolic pathway for 15-20 carbon isoprenoid alcohol phosphorylation had been found in several organisms including Archaebacteria (Ohnuma et al, 1996), animal tissues (Bentinger et al, 1998), and plants (Ischebeck et al, 2006;Fitzpatrick et al, 2011;Vom Dorp et al, 2015).…”

“…This finding confirmed previous results ( Yeh and DeRisi, 2011 ; Guggisberg et al, 2016 ; Kennedy et al, 2019 ) and indicates that P. falciparum possesses an enzymatic system to phosphorylate FOH/GGOH into their pyrophosphate forms. This phosphorylation process was also suggested in P. falciparum by employing POH as a substrate ( Sussmann et al, 2022 ). Besides it, other radiolabelled apolar substances were detected.…”

“…Here, we demonstrated that not only GGOH and FOH can be used for protein prenylation but also exogenous dolichols and POH, an acyclic diterpene produced through the hydrogenation of GGPP ( Hansen, 1980 ). Some authors suggest the parasite uses POH for the biosynthesis of some vitamins in the parasite ( Sussmann et al, 2011 ; Sussmann et al, 2022 ). In nature, POH can be obtained through two pathways.…”

“…In the parasite, Sussmann et al observed the incorporation of exogenous [1-(n)- 3 H]-POH ( Sussmann et al, 2011 ; Sussmann et al, 2022 ). However, the ability of the parasite to produce POH or even obtain it from the exogenous environment is not understood.…”

“…Finally, some authors previously suggested that the parasite can use phytol (POH) to synthesize vitamin E ( Sussmann et al, 2011 ). POH ((2E,7R,11R)-3,7,11,15-Tetramethylhexadec-2-en-1-ol) is an acyclic diterpene produced through the hydrogenation of GGPP ( Hansen, 1980 ; Proteau, 1998 ; Sussmann et al, 2022 ). In the parasite, Sussmann et al ( Sussmann et al, 2011 ) observed the incorporation of exogenous [1-(n)- 3 H]-POH into prenylquinones.…”