Plasmodium, metabolism

Detection by LDMS and structural elucidation of other secondary metabolite products, generated in the host during the onset of the parasite disease, is discussed. These molecules may serve as additional biomarkers for rapid malaria diagnosis by LDMS. For instance, choline phosphate (CP) is identified as the source of several low-mass ions observed in parasite-infected blood samples in addition to heme biomarker ions. The CP levels track the sample parasitemia levels. This biomarker can provide additional specificity and sensitivity when compared to malaria detection based on heme ion signals alone. Furthermore the observed elevated CP levels are discussed in the context of Plasmodium metabolism during its intra-erythrocytic life cycle. These data can... 

Francis, S. Sullivan, D. J. Goldberg, D. E. Hemoglobin metabolism in the malaria parasite Plasmodium falciparum. Annu. Rev. Microbiol. 1997, 51, 97-123. 

Chloroquine is a rapidly acting blood schizonti-cide with some gametocytocidal activity. It is used with primaquine for Plasmodium vivax and Plasmodium ovale infections. It has been widely used prophylactically by traveler s to endemic areas. Its mechanism of action is unclear. It is believed to hinder the metabolism of hemoglobin in the parasite. Presumably chloroquine prevents the formation in the plasmodia of polymers out of free heme which then builds up and becomes toxic. Resistance occurs as a consequence of the expression of a membrane phospho-glycoprotein pump in the plasmodia which is able to expel chloroquine from the parasite. Plasmodium falciparum is the most likely to become resistant. 

Artemisinin is a natural endoperoxide-containing sesquiterpene, isolated from a plant used in traditional Chinese medicine. Acetalic artemisinin derivatives (arte-mether, artesunate) are very active against chemo-resistant forms of Plasmodium falciparum, and are clinically used for the treatment. However, they suffer from an unfavourable pharmacological profile. They are quickly metabolised by fast oxidative metabolism, hydrolytic cleavage and glucuronidation. 

Mecfianism of Action A quinolone-methanol compound structurally similar to quinine that destroys the asexual blood forms of malarial pafhogens, Plasmodium falciparum, P. vivax, P. malariae, P. ovale. Therapeutic Effect Inhibifs parasite growth. Pharmacokinetics Well absorbed from fhe gasfroinfesfinal (GI) tract. Protein binding 98%. Widely distributed, including cerebrospinal fluid (CSF). Metabolized in liver. Primarily excreted in urine. Half-life 21-22 days. 

Luke, T.C. and Hoffman, S.L. (2003) Rationale and plans for developing a non-replicating, metabolically active, radiation-attenuated Plasmodium falciparum sporozoite vaccine, journal of Experimental Biology 206, 3803-3808. 

DC Kaslow, S Hill. Cloning metabolic pathway genes by complementation in Escherichia coli. Isolation and expression of Plasmodium falciparum glucose phosphate isomerase. J Biol Chem 265 12337-12341, 1990. 

Yeh I, Hanekamp T, Tsoka S et al (2004) Computational analysis of Plasmodium falciparum metabolism organizing genomic information to facilitate drug discovery. Genome Res 14 917-924... 

Plata G, Hsiao TL, Olszewski KL et al (2010) Reconstruction and flux-balance analysis of the Plasmodium falciparum metabolic network. Mol Syst Biol 6 408... 

Fatumo S, Plaimas K, Adebiyi E et al (2011) Comparing metabolic network models based on genomic and automatically inferred enzyme information from Plasmodium and its human host to define drug targets in silico. Infect Genet Evol 11 708-715... 

Fatumo S, Plaimas K, Mallm JP et al (2009) Estimating novel potential drug targets of Plasmodium falciparum by analysing the metabolic network of knock-out strains in silico. Infect Genet Evol 9(3) 351-358... 

P. falciparum Pyruvate Kinase (PfPyrK). Glycolysis is the major energy utilization pathway for Plasmodium parasites and PfPyrK is one enzyme that contributes to this process and the breakdown of carbohydrates during intraerythrocytic development (79). Glycolytic processes have been shown to increase 50-fold in infected erythrocytes compared with uninfected erythrocytes, and this enzyme may be a crucial component of metabolic pathways for... 

Roth E Jr (1990) Plasmodium falciparum carbohydrate metabolism a connection between host cell and parasite. Blood Cells 16(2-3) 453-460, discussion 461-466... 

Kanaani J, Ginsburg H (1989) Metabolic interconnection between the human malarial parasite Plasmodium falciparum and its host erythrocyte. Regulation of ATP levels by means of an adenylate translocator and adenylate kinase. J Biol Chem 264(6) 3194-3199... 

Ulschmid JK, Rahlfs S, Schirmer RH, Becker K (2004) Adenylate kinase and GTP AMP phosphotransferase of the malarial parasite Plasmodium falciparum. Central players in cellular energy metabolism. Mol Biochem Parasitol 136(2 ) 211-220... 

Queen SA, Jagt DL, Reyes P (1990) In vitro susceptibilities of Plasmodium falciparum to compounds which inhibit nucleotide metabolism. Antimicrob Agents Chemother. 34 1393—1398... 

DuttaP (1991) Enhanced uptake and metabolism of riboflavin in erythrocytes infected with Plasmodium falciparum. Journal of Protozoology 38,479-83. 

Saliba KJ, Horner HA, and Kirk K (1998) Transport and metabolism of the essential vitamin pantothenic acid in human erythrocytes infected with the malaria parasite Plasmodium falciparum. Journal of Biological Chemistry 273,10190-5. 

Ralph SA, van Dooren GG, Waller RF, Crawford MJ, Fraunholz, MJ, Foth, BJ, Tonkin, CJ, Roos, DS and McFadden, GI. Tropical infectious diseases metabolic maps and functions of the Plasmodium falciparum apicoplast. Nat. Rev. Microbiol. 2004 2 203-216. 

Mefloquine (t) 21 d) is similar in several respects to quinine although it does not intercalate with plasmodial DNA. It is used for malaria chemoprophylaxis, to treat uncomplicated Plasmodium falciparum (both chloroquine-sensitive and chloroquine resistant) and chloroquine-resistant Plasmodium vivax malaria. Mefloquine is rapidly absorbed from the gastrointestinal tract and its action is terminated by metabolism. When used for prophylaxis, 250 mg (base)/week should be taken, commencing 1-3 weeks before entering and continued for 4 weeks after leaving a malarious area. It should not be given to patients with hepatic or renal impairment. 

Pyrimethamine acts synergistically with suifadoxine (as Fansidar) to inhibit folic acid metabolism (see antifols, above) suifadoxine is excreted in the urine. The combination is chiefly used with quinine to treat acute attacks of malaria caused by susceptible strains of Plasmodium falciparum a single dose of pyrimethamine 75 mg plus suifadoxine 1.5 g (3 tablets) usually suffices. 

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