Plasmodium falciparum dolichol phosphate mannose synthase represents a novel clade

Shams‐Eldin, Hosam; Macedo, Cristiana Santos de; Niehus, Sebastian; Dorn, Caroline; Kimmel, Jürgen; Azzouz, Nahid; Schwarz, Ralph Τ.

doi:10.1016/j.bbrc.2008.03.033

Cited by 15 publications

(10 citation statements)

References 36 publications

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“…Once IPP and DMAPP are synthesized and transported out of the apicoplast, a myriad of isoprenoid products with different cellular localization and functions are synthesized in the malaria parasite. Many isoprenoid products have been identified as being present in the intraerythrocytic asexual stages of P. falciparum, such as ubiquinones and menaquinone (32,33,56), carotenoids and vitamin E (57-59), dolichols (50,60,61), and prenylated proteins (60,(62)(63)(64)(65). The presence and function of these isoprenoids in gametocytes remain to be confirmed and are under investigation.…”

Section: Discussionmentioning

confidence: 99%

Isoprenoid Precursor Biosynthesis Is the Essential Metabolic Role of the Apicoplast during Gametocytogenesis in Plasmodium falciparum

et al. 2015

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The malaria parasite harbors a relict plastid called the apicoplast and its discovery opened a new avenue for drug discovery and development due to its unusual, nonmammalian metabolism. The apicoplast is essential during the asexual intraerythrocytic and hepatic stages of the parasite, and there is strong evidence supporting its essential metabolic role during the mosquito stages of the parasite. Supply of the isoprenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) is the essential metabolic function of the apicoplast during the asexual intraerythrocytic stages. However, the metabolic role of the apicoplast during gametocyte development, the malaria stages transmitted to the mosquito, remains unknown. In this study, we showed that production of IPP for isoprenoid biosynthesis is the essential metabolic function of the apicoplast during gametocytogenesis, by obtaining normal gametocytes lacking the apicoplast when supplemented with IPP. When IPP supplementation was removed early in gametocytogenesis, developmental defects were observed, supporting the essential role of isoprenoids for normal gametocytogenesis. Furthermore, mosquitoes infected with gametocytes lacking the apicoplast developed fewer and smaller oocysts that failed to produce sporozoites. This finding further supports the essential role of the apicoplast in establishing a successful infection in the mosquito vector. Our study supports isoprenoid biosynthesis as a valid drug target for development of malaria transmission-blocking inhibitors.

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Section: Discussionmentioning

confidence: 99%

Isoprenoid Precursor Biosynthesis Is the Essential Metabolic Role of the Apicoplast during Gametocytogenesis in Plasmodium falciparum

et al. 2015

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“…Dolichol phosphate mannose synthase (EC 2.4.1.83, PlasmoDB ID PF3D7_1141600) catalyzes the addition of sugar moieties in both GPI anchor glycosylations and N-linked glycosylations. The P. falciparum enzyme has been shown to be of a novel clade distinct from animal or yeast synthases of the same type (132).…”

Section: Dolicholsmentioning

confidence: 99%

Isoprenoid Biosynthesis in Plasmodium falciparum

2014

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bMalaria kills nearly 1 million people each year, and the protozoan parasite Plasmodium falciparum has become increasingly resistant to current therapies. Isoprenoid synthesis via the methylerythritol phosphate (MEP) pathway represents an attractive target for the development of new antimalarials. The phosphonic acid antibiotic fosmidomycin is a specific inhibitor of isoprenoid synthesis and has been a helpful tool to outline the essential functions of isoprenoid biosynthesis in P. falciparum. Isoprenoids are a large, diverse class of hydrocarbons that function in a variety of essential cellular processes in eukaryotes. In P. falciparum, isoprenoids are used for tRNA isopentenylation and protein prenylation, as well as the synthesis of vitamin E, carotenoids, ubiquinone, and dolichols. Recently, isoprenoid synthesis in P. falciparum has been shown to be regulated by a sugar phosphatase. We outline what is known about isoprenoid function and the regulation of isoprenoid synthesis in P. falciparum, in order to identify valuable directions for future research.

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“…Kimura et al (1996) demonstrated the effect of N - linked glycoproteins on differentiation of intraerythrocytic stages of P. falciparum [18]. The reaction between dolichol phosphate (Dol-P) and guanosine diphosphate mannose (GDP-Man) to form dolichol-phosphate-mannose (Dol-P-Man) is catalyzed by dolichol phosphate mannose synthase (DPM) enzyme [19]. This molecule acts as mannose donor for N- glycosylation and glycosylphosphatidylinositol (GPI) biosynthesis.…”

Section: Isoprenoid Biosynthesismentioning

confidence: 99%

Exploring Drug Targets in Isoprenoid Biosynthetic Pathway forPlasmodium falciparum

Qidwai¹,

Jamal

Khan

et al. 2014

Biochemistry Research International

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Emergence of rapid drug resistance to existing antimalarial drugs in Plasmodium falciparum has created the need for prediction of novel targets as well as leads derived from original molecules with improved activity against a validated drug target. The malaria parasite has a plant plastid-like apicoplast. To overcome the problem of falciparum malaria, the metabolic pathways in parasite apicoplast have been used as antimalarial drug targets. Among several pathways in apicoplast, isoprenoid biosynthesis is one of the important pathways for parasite as its multiplication in human erythrocytes requires isoprenoids. Therefore targeting this pathway and exploring leads with improved activity is a highly attractive approach. This report has explored progress towards the study of proteins and inhibitors of isoprenoid biosynthesis pathway. For more comprehensive analysis, antimalarial drug-protein interaction has been covered.

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Plasmodium falciparum dolichol phosphate mannose synthase represents a novel clade

Cited by 15 publications

References 36 publications

Isoprenoid Precursor Biosynthesis Is the Essential Metabolic Role of the Apicoplast during Gametocytogenesis in Plasmodium falciparum

Isoprenoid Precursor Biosynthesis Is the Essential Metabolic Role of the Apicoplast during Gametocytogenesis in Plasmodium falciparum

Isoprenoid Biosynthesis in Plasmodium falciparum

Exploring Drug Targets in Isoprenoid Biosynthetic Pathway forPlasmodium falciparum

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