Antimetabolites of Coenzyme Q. Their Potential Application as Antimalarials

Porter, Thomas H.; Folkers, Karl

doi:10.1002/anie.197405591

Cited by 27 publications

(7 citation statements)

References 46 publications

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“…Investigation into the mode of action of the hydroxynaphthoquinones reported herein has focused on the parasite respiratory systems. Although previous studies have provided circumstantial evidence for these being the biochemical target of the quinones, work was only reported with preparations from mammalian cells (Porter & Folkers, 1974). Our results provide convincing evidence that the toxicity of BW 58C, BW 568C and BW 720C towards Sporozoea stems from selective inhibition of their electron transport systems.…”

Section: Discussionsupporting

confidence: 63%

“…The hydroxynaphthoquinone-sensitive protozoa discussed above are all Sporozoea and hence it is likely that the site of action of the quinones will be similar in all these parasites. In previous studies a correlation was noted between the anti-plasmodial properties of hydroxynaphthoquinones and their ability to inhibit mammalian electron transport processes by acting as ubiquinone antagonists (Porter & Folkers, 1974). We have now examined the effects of BW 58C, 568C, 720C and menoctone on the respiratory systems of E. tenella, P. yoelii, T. parva and T. gondii.…”

Section: Resultsmentioning

confidence: 95%

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Novel anti-malarial hydroxynaphthoquinones with potent broad spectrum anti-protozoal activity

et al. 1985

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Section: Discussionsupporting

confidence: 63%

Section: Resultsmentioning

confidence: 95%

Novel anti-malarial hydroxynaphthoquinones with potent broad spectrum anti-protozoal activity

et al. 1985

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“…The combination of either Antimycin A plus TTFA, or cyanide plus SHAM, did not produce any significant additional inhibition to the amount produced by each individual compound. As malarial parasites have been reported to contain ubiquinones which differ from those found in mammalian systems (Porter and Folkers, 1974), four ubiquinone analogs were tested as DHO-DHase inhibitors on the reticulocyte and P. berghei enzymes and the results are included in Table 3. Menoctone, a naphtboquinone, was a potent inhibitor of DHO-DHase from both the reticulocyte and P. berghei, probably acting as a structural analog of ubiquinone.…”

Section: Linkage To the Respiratory Chainmentioning

confidence: 99%

COMPARATIVE STUDIES ON DIHYDROOROTATE DEHYDROGENASE FROM P. BERGHEI AND THE MOUSE RETICULOCYTE

Gero

Finney

Bennett

et al. 1981

Aust J Exp Biol Med

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Summary. Kinetic parameters on dihydroorotate dehydrogenase (DHO-DHase) from the rodent malarial parasite, Plasmodium berghei, have been determined. This enzyme, the fourth in de novo pyrimidine biosynthesis, is particulate and is absent in the mature mammalian red cell. The K,,, of the substrate, dihydroorotate, was determined to be 23 MM and the Ki values for a number of substrate analogues have been determined. The most potent inhibitor was dihydroazaorotate (Kl, 3 MM). The product orotate was also a good inhibitor (Ki, 5 MM) as were methylorotate (Ki, 10 /"M), 5-azaorotate (Ki, 20 MM) and other pyrimidine analogues. The activity of the enzyme was also affected by a number of respiratory chain inhibitors.As the P. berghei infection is accompanied by reticulocytosis, a comparative study of DHO-DHase in mouse reticulocytes was also carried out. The general properties of the enzyme from these sources were similar to those of the parasite enzyme. However, significant differences in the response of the two enzymes to various inhibitors were observed and could provide a rational basis for the development of chemotherapeutic agents active against the parasite.

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“…Next to each arrow, the corresponding enzyme is cited. For biosynthesis of tocopherol, plastochromanol and PQ, different enzymes can perform the same enzymatic step depending on the organism [141]. Enzymes: MqnA (chorismate dehydratase, EC:4.2.1.151).…”

Section: Figurementioning

confidence: 99%

Prenylquinones in Human Parasitic Protozoa: Biosynthesis, Physiological Functions, and Potential as Chemotherapeutic Targets

et al. 2019

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Human parasitic protozoa cause a large number of diseases worldwide and, for some of these diseases, there are no effective treatments to date, and drug resistance has been observed. For these reasons, the discovery of new etiological treatments is necessary. In this sense, parasitic metabolic pathways that are absent in vertebrate hosts would be interesting research candidates for the identification of new drug targets. Most likely due to the protozoa variability, uncertain phylogenetic origin, endosymbiotic events, and evolutionary pressure for adaptation to adverse environments, a surprising variety of prenylquinones can be found within these organisms. These compounds are involved in essential metabolic reactions in organisms, for example, prevention of lipoperoxidation, participation in the mitochondrial respiratory chain or as enzymatic cofactors. This review will describe several prenylquinones that have been previously characterized in human pathogenic protozoa. Among all existing prenylquinones, this review is focused on ubiquinone, menaquinone, tocopherols, chlorobiumquinone, and thermoplasmaquinone. This review will also discuss the biosynthesis of prenylquinones, starting from the isoprenic side chains to the aromatic head group precursors. The isoprenic side chain biosynthesis maybe come from mevalonate or non-mevalonate pathways as well as leucine dependent pathways for isoprenoid biosynthesis. Finally, the isoprenic chains elongation and prenylquinone aromatic precursors origins from amino acid degradation or the shikimate pathway is reviewed. The phylogenetic distribution and what is known about the biological functions of these compounds among species will be described, as will the therapeutic strategies associated with prenylquinone metabolism in protozoan parasites.

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Antimetabolites of Coenzyme Q. Their Potential Application as Antimalarials

Cited by 27 publications

References 46 publications

Novel anti-malarial hydroxynaphthoquinones with potent broad spectrum anti-protozoal activity

Novel anti-malarial hydroxynaphthoquinones with potent broad spectrum anti-protozoal activity

COMPARATIVE STUDIES ON DIHYDROOROTATE DEHYDROGENASE FROM P. BERGHEI AND THE MOUSE RETICULOCYTE

Prenylquinones in Human Parasitic Protozoa: Biosynthesis, Physiological Functions, and Potential as Chemotherapeutic Targets

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