Effect of tamoxifen on the sphingolipid biosynthetic pathway in the different intraerythrocytic stages of the apicomplexa Plasmodium falciparum

Abstract Plasmodium falciparum-infected red blood cells (RBCs) are characterized by increases in the activity of glycolytic enzymes. Because nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP) are cofactors in the reactions of glycolysis and pentose phosphate shunt, we have examined NAD and NADP content in P. falciparum-infected RBCs. Although NADP content was not significantly altered, NAD content was increased approximately 10-fold in infected RBCs (66% parasitemia) compared with uninfected control RBCs. To determine the mechanism for the increase in NAD content, we examined the activity of several NAD biosynthetic enzymes. It is known that normal human RBCs make NAD exclusively from nicotinic acid and lack the capacity to make NAD from nicotinamide. We demonstrate that infected RBCs have readily detectable nicotinamide phosphoribosyltransferase (NPRT), the first enzyme in the NAD biosynthetic pathway that uses nicotinamide, and abundant nicotinamide deamidase, the enzyme that converts nicotinamide to nicotinic acid, thereby indicating that infected RBCs can make NAD from nicotinamide. In addition, infected RBCs have a threefold increase in nicotinic acid phosphoribosyltransferase (NAPRT), the first enzyme in the NAD biosynthetic pathway that uses nicotinic acid. Thus, the increase in NAD content in P falciparum-infected RBCs appears to be mediated by increases in NAD synthesis from both nicotinic acid and nicotinamide.

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Insights into the pyrimidine biosynthetic pathway of human malaria parasite Plasmodium falciparum as chemotherapeutic target

Asian Pacific Journal of Tropical Medicine ◽

10.1016/j.apjtm.2016.04.012 ◽

2016 ◽

Vol 9 (6) ◽

pp. 525-534 ◽

Cited By ~ 11

Author(s):

Sudaratana R. Krungkrai ◽

Jerapan Krungkrai

Keyword(s):

Plasmodium Falciparum ◽

Malaria Parasite ◽

Biosynthetic Pathway ◽

Human Malaria Parasite ◽

Human Malaria ◽

Parasite Plasmodium ◽

Parasite Plasmodium Falciparum

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Localisation of Plasmodium falciparum uroporphyrinogen III decarboxylase of the heme-biosynthetic pathway in the apicoplast and characterisation of its catalytic properties

International Journal for Parasitology ◽

10.1016/j.ijpara.2008.10.011 ◽

2009 ◽

Vol 39 (5) ◽

pp. 559-568 ◽

Cited By ~ 32

Author(s):

Viswanathan Arun Nagaraj ◽

Rajavel Arumugam ◽

Nagasuma R. Chandra ◽

Dasari Prasad ◽

Pundi N. Rangarajan ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Biosynthetic Pathway ◽

Catalytic Properties

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Plasmodium falciparum hydroxymethylbilane synthase does not house any cosynthase activity within the haem biosynthetic pathway

10.1101/2021.02.09.429727 ◽

2021 ◽

Author(s):

Alan F. Scott ◽

Evelyne Deery ◽

Andrew D. Lawrence ◽

Martin J. Warren

Keyword(s):

Plasmodium Falciparum ◽

Hplc Analysis ◽

Biosynthetic Pathway ◽

Gene Encoding ◽

E Coli ◽

Aminolaevulinic Acid ◽

Porphobilinogen Synthase

AbstractThe production of uroporphyrinogen III, the universal progenitor of macrocyclic, modified tetrapyrroles, is produced from aminolaevulinic acid (ALA) by a conserved pathway involving three enzymes: porphobilinogen synthase (PBGS), hydroxymethylbilane synthase (HmbS) and uroporphyrinogen III synthase (UroS). The gene encoding uroporphyrinogen III synthase has not yet been identified in Plasmodium falciparum but it has been suggested that this activity is housed inside a bifunctional hybroxymethylbilane synthase (HmbS). In this present study it is demonstrated that P. falciparum HmbS does not have uroporphyrinogen III synthase activity. This was demonstrated by the failure of a codon optimised P. falciparum hemC gene, encoding HmbS, to compliment a defined E. coli hemD- mutant (SASZ31) deficient in uroporphyrinogen III synthase activity. Furthermore, HPLC analysis of the oxidsed reaction product from recombinant, purified HmbS showed that only uroporphyrin I could be detected (corresponding to hydroxymethylbilane production). No uroporphyrin III was detected, thus showing that P. falciparum HmbS does not have UroS activity and can only catalyse the formation of hydroxymethylbilane from porphobilinogen.

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Plasmodium falciparum hydroxymethylbilane synthase does not house any cosynthase activity within the haem biosynthetic pathway

Microbiology ◽

10.1099/mic.0.001095 ◽

2021 ◽

Vol 167 (10) ◽

Author(s):

Alan F. Scott ◽

Evelyne Deery ◽

Andrew D. Lawrence ◽

Martin J. Warren

Keyword(s):

Escherichia Coli ◽

Plasmodium Falciparum ◽

Hplc Analysis ◽

Biosynthetic Pathway ◽

Gene Encoding ◽

The Real ◽

Aminolaevulinic Acid ◽

Unknown Protein ◽

Porphobilinogen Synthase

Uroporphyrinogen III, the universal progenitor of macrocyclic, modified tetrapyrroles, is produced from aminolaevulinic acid (ALA) by a conserved pathway involving three enzymes: porphobilinogen synthase (PBGS), hydroxymethylbilane synthase (HmbS) and uroporphyrinogen III synthase (UroS). The gene encoding uroporphyrinogen III synthase has not yet been identified in Plasmodium falciparum, but it has been suggested that this activity is housed inside a bifunctional hybroxymethylbilane synthase (HmbS). Additionally, an unknown protein encoded by PF3D7_1247600 has also been predicted to possess UroS activity. In this study it is demonstrated that neither of these proteins possess UroS activity and the real UroS remains to be identified. This was demonstrated by the failure of codon-optimized genes to complement a defined Escherichia coli hemD − mutant (SASZ31) deficient in UroS activity. Furthermore, HPLC analysis of the oxidized reaction product from recombinant, purified P. falciparum HmbS showed that only uroporphyrin I could be detected (corresponding to hydroxymethylbilane production). No uroporphyrin III was detected, showing that P. falciparum HmbS does not have UroS activity and can only catalyze the formation of hydroxymethylbilane from porphobilinogen.

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Isoprenoid biosynthetic pathways as anti-infective drug targets

Biochemical Society Transactions ◽

10.1042/bst0330785 ◽

2005 ◽

Vol 33 (4) ◽

pp. 785-791 ◽

Cited By ~ 79

Author(s):

F. Rohdich ◽

A. Bacher ◽

W. Eisenreich

Keyword(s):

Helicobacter Pylori ◽

Plasmodium Falciparum ◽

Mycobacterium Tuberculosis ◽

Drug Targets ◽

Biosynthetic Pathway ◽

Mevalonate Pathway ◽

Biosynthetic Pathways ◽

Isopentenyl Diphosphate ◽

Human Pathogens ◽

Dimethylallyl Diphosphate

IPP (isopentenyl diphosphate) and DMAPP (dimethylallyl diphosphate) serve as the universal precursors for the biosynthesis of isoprenoids. Besides the well-known mevalonate pathway, the existence of a second biosynthetic pathway conducive to IPP and DMAPP formation through 1-deoxy-D-xylulose 5-phosphate and 2C-methyl-D-erythritol 4-phosphate was discovered approx. 10 years ago in plants and certain eubacteria. It is now known that this pathway is widely distributed in the bacterial kingdom including major human pathogens, such as Mycobacterium tuberculosis and Helicobacter pylori. The pathway is also essential in the malaria vector Plasmodium falciparum. During the last few years, the genes, enzymes, intermediates and mechanisms of the biosynthetic route have been elucidated by a combination of comparative genomics, enzymology, advanced NMR technology and crystallography. The results provide the basis for the development of novel anti-infective drugs.

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Genes for Glycosylphosphatidylinositol Toxin Biosynthesis in Plasmodium falciparum

Infection and Immunity ◽

10.1128/iai.70.8.4510-4522.2002 ◽

2002 ◽

Vol 70 (8) ◽

pp. 4510-4522 ◽

Cited By ~ 44

Author(s):

Mauro Delorenzi ◽

Adrienne Sexton ◽

Hosam Shams-Eldin ◽

Ralph T. Schwarz ◽

Terry Speed ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Posttranslational Modification ◽

Cell Biology ◽

Biosynthetic Pathway ◽

Preliminary Evidence ◽

Amino Acid Sequences ◽

Gene Products ◽

New Genes ◽

Organ Specific

ABSTRACT About 2.5 million people die of Plasmodium falciparum malaria every year. Fatalities are associated with systemic and organ-specific inflammation initiated by a parasite toxin. Recent studies show that glycosylphosphatidylinositol (GPI) functions as the dominant parasite toxin in the context of infection. GPIs also serve as membrane anchors for several of the most important surface antigens of parasite invasive stages. GPI anchoring is a complex posttranslational modification produced through the coordinated action of a multicomponent biosynthetic pathway. Here we present eight new genes of P. falciparum selected for encoding homologs of proteins essential for GPI synthesis: PIG-A, PIG-B, PIG-M, PIG-O, GPI1, GPI8, GAA-1, and DPM1. We describe the experimentally verified mRNA and predicted amino acid sequences and in situ localization of the gene products to the parasite endoplasmic reticulum. Moreover, we show preliminary evidence for the PIG-L and PIG-C genes. The biosynthetic pathway of the malaria parasite GPI offers potential targets for drug development and may be useful for studying parasite cell biology and the molecular basis for the pathophysiology of parasitic diseases.

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Biosynthesis of glycosylphosphatidylinositols of Plasmodium falciparum in a cell-free incubation system: inositol acylation is needed for mannosylation of glycosylphosphatidylinositols

Biochemical Journal ◽

10.1042/bj3440731 ◽

1999 ◽

Vol 344 (3) ◽

pp. 731-738 ◽

Cited By ~ 10

Author(s):

Peter GEROLD ◽

Nicole JUNG ◽

Nahid AZZOUZ ◽

Nicole FREIBERG ◽

Sabine KOBE ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Mammalian Cells ◽

Biosynthetic Pathway ◽

Unique Feature ◽

Host Cells ◽

Free System ◽

Incubation System ◽

A Cell ◽

Inositol Ring ◽

Myristoyl Coa

The structures of glycosylphosphatidylinositols (GPIs) in Plasmodium have been described [Gerold, Schuppert and Schwarz (1994) J. Biol. Chem. 269, 2597-2606]. A detailed understanding of GPI synthesis in Plasmodium is a prerequisite for identifying differences present in biosynthetic pathways of parasites and host cells. A comparison of the biosynthetic pathway of GPIs has revealed differences between mammalian cells and parasitic protozoans. A cell-free incubation system prepared from asexual erythrocytic stages of Plasmodium falciparum, the causative agent of malaria in humans, is capable of synthesizing the same spectrum of GPIs as that found in metabolically labelled parasites. The formation of mannosylated GPIs in the cell-free system is shown to be inhibited by GTP and, unexpectedly, micromolar concentrations of GDP-Man. Lower concentrations of GDP-Man affect the spectrum of GPIs synthesized. The inositol ring of GPIs of P. falciparum is modified by an acyl group. The preferred donor of this fatty acid at the inositol ring is myristoyl-CoA. Inositol acylation has to precede the mannosylation of GPIs because, in the absence of acyl-CoA or CoA, mannosylated GPIs were not detected. Inositol myristoylation is a unique feature of plasmodial GPIs and thus might provide a potential target for drug therapy.

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A Sesquiterpene Isonitrile with a New Tricyclic Skeleton from the Indo-Pacific Nudibranch Phyllidiella pustulosa: Spectroscopic and Computational Studies

Australian Journal of Chemistry ◽

10.1071/ch19227 ◽

2020 ◽

Vol 73 (3) ◽

pp. 129

Author(s):

Desmond C.-M. Sim ◽

Natasha L. Hungerford ◽

Elizabeth H. Krenske ◽

Gregory K. Pierens ◽

Katherine T. Andrews ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Molecular Modelling ◽

Density Functional ◽

Biosynthetic Pathway ◽

Antimalarial Activity ◽

Computational Study ◽

Ring System ◽

Computational Studies ◽

Molecular Modelling Studies ◽

Modelling Studies

The sesquiterpene isonitrile, 9-isocyanoneoallopupukeanane 1, has been obtained from the Indo-Pacific nudibranch Phyllidiella pustulosa. The structure of 1, which was investigated by extensive NMR experiments, molecular modelling studies, and density functional calculations, has a different arrangement of the tricyclic ring system compared with other isonitrile metabolites isolated from nudibranchs or sponges. The viability of a biosynthetic pathway leading to 1, proposed to involve a series of carbocation rearrangements, is explored in a computational study. Isonitrile 1 exhibited micromolar antimalarial activity when screened against Plasmodium falciparum infected erythrocytes.

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