Parasite Mitochondria as a Target for Chemotherapy.

Kita, Kiyoshi; Miyadera, Haruo; Saruta, Fumiko; Miyoshi, Hideto

doi:10.1248/jhs.47.219

Cited by 17 publications

(13 citation statements)

References 101 publications

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“…The anaerobic energy metabolism of the helminthes has been reviewed (63,67). Humans and other mammalian hosts use Q for aerobic energy metabolism but do not produce or require RQ; therefore, selective inhibition of RQ biosynthesis may lead to highly specific antihelminthic drugs that do not have a toxic effect on the host (35,48).…”

Section: Based On the Results Presented We Have Demonstrated That Q mentioning

confidence: 99%

Evidence that Ubiquinone Is a Required Intermediate for Rhodoquinone Biosynthesis in Rhodospirillum rubrum

et al. 2010

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Rhodoquinone (RQ) is an important cofactor used in the anaerobic energy metabolism of Rhodospirillum rubrum. RQ is structurally similar to ubiquinone (coenzyme Q or Q), a polyprenylated benzoquinone used in the aerobic respiratory chain. RQ is also found in several eukaryotic species that utilize a fumarate reductase pathway for anaerobic respiration, an important example being the parasitic helminths. RQ is not found in humans or other mammals, and therefore inhibition of its biosynthesis may provide a parasite-specific drug target. In this report, we describe several in vivo feeding experiments with R. rubrum used for the identification of RQ biosynthetic intermediates. Cultures of R. rubrum were grown in the presence of synthetic analogs of ubiquinone and the known Q biosynthetic precursors demethylubiquinone, demethoxyubiquinone, and demethyldemethoxyubiquinone, and assays were monitored for the formation of RQ 3 . Data from time course experiments and S-adenosyl-L-methionine-dependent O-methyltransferase inhibition studies are discussed. Based on the results presented, we have demonstrated that Q is a required intermediate for the biosynthesis of RQ in R. rubrum.Rhodospirillum rubrum is a well-characterized and metabolically diverse member of the family of purple nonsulfur bacteria (29, 61). R. rubrum is typically found in aquatic environments and can adapt to a variety of growth conditions by using photosynthesis, respiration, or fermentation pathways (28, 70). In the light, R. rubrum exhibits photoheterotrophic growth using organic substrates or photoautotrophic growth using CO 2 and H 2 (15, 70). In the dark, R. rubrum can utilize either aerobic respiration (70,73) or anaerobic respiration with a fumarate reduction pathway or with nonfermentable substrates in the presence of oxidants such as dimethyl sulfoxide (DMSO) or trimethylamine oxide (15,58,73). R. rubrum can also grow anaerobically in the dark by fermentation of sugars in the presence of bicarbonate (58). The focus of this work was the biosynthesis of quinones used by R. rubrum for aerobic and anaerobic respiration.Rhodoquinone (RQ; compound 1 in Fig. 1) is an aminoquinone structurally similar to ubiquinone (coenzyme Q or Q [compound 2]) (44); however, the two differ considerably in redox potential (that of RQ is Ϫ63 mV, and that of Q is ϩ100 mV) (2). Both RQ and Q have a fully substituted benzoquinone ring and a polyisoprenoid side chain that varies in length (depending on the species; see Fig. 1 for examples). The only difference between the structures is that RQ has an amino substituent (NH 2 ) instead of a methoxy substituent (OCH 3 ) on the quinone ring. While Q is a ubiquitous lipid component involved in aerobic respiratory electron transport (9, 36, 60), RQ functions in anaerobic respiration in R. rubrum (19) and in several other phototrophic purple bacteria (21,22,41) and is also present in a few aerobic chemotrophic bacteria, including Brachymonas denitrificans and Zoogloea ramigera (23). In these varied species of bacteria, RQ has been ...

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Section: Based On the Results Presented We Have Demonstrated That Q mentioning

confidence: 99%

Evidence that Ubiquinone Is a Required Intermediate for Rhodoquinone Biosynthesis in Rhodospirillum rubrum

et al. 2010

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“…The anaerobic energy metabolism of the helminths was reviewed previously (43,46). Humans and other mammalian hosts use Q for aerobic energy metabolism but do not produce or require RQ; therefore, the discovery of molecules that selectively inhibit RQ biosynthesis may lead to highly specific antihelminthic therapeutics that do not have a toxic effect on the host (24).…”

mentioning

confidence: 99%

Identification of a New Gene Required for the Biosynthesis of Rhodoquinone in Rhodospirillum rubrum

Lonjers¹,

Dickson²,

Chu³

et al. 2011

Journal of Bacteriology

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Rhodoquinone (RQ) is a required cofactor for anaerobic respiration in Rhodospirillum rubrum, and it is also found in several helminth parasites that utilize a fumarate reductase pathway. RQ is an aminoquinone that is structurally similar to ubiquinone (Q), a polyprenylated benzoquinone used in the aerobic respiratory chain. RQ is not found in humans or other mammals, and therefore, the inhibition of its biosynthesis may provide a novel antiparasitic drug target. To identify a gene specifically required for RQ biosynthesis, we determined the complete genome sequence of a mutant strain of R. rubrum (F11), which cannot grow anaerobically and does not synthesize RQ, and compared it with that of a spontaneous revertant (RF111). RF111 can grow anaerobically and has recovered the ability to synthesize RQ. The two strains differ by a single base pair, which causes a nonsense mutation in the putative methyltransferase gene rquA. To test whether this mutation is important for the F11 phenotype, the wildtype rquA gene was cloned into the pRK404E1 vector and conjugated into F11. Complementation of the anaerobic growth defect in F11 was observed, and liquid chromatography-time of flight mass spectrometry (LC-TOF-MS) analysis of lipid extracts confirmed that plasmid-complemented F11 was able to synthesize RQ. To further validate the requirement of rquA for RQ biosynthesis, we generated a deletion mutant from wild-type R. rubrum by the targeted replacement of rquA with a gentamicin resistance cassette. The ⌬rquA mutant exhibited the same phenotype as that of F11. These results are significant because rquA is the first gene to be discovered that is required for RQ biosynthesis. R hodoquinone (RQ) (Fig. 1, compound 1) is found in the mitochondrial membrane of parasitic helminths (43, 46) and other eukaryotic species capable of fumarate reduction, such as Euglena gracilis (17) and Caenorhabditis elegans (41). These species can adapt their metabolism to both aerobic and anaerobic conditions throughout their life cycle. Adult parasitic species such as Ascaris suum, Fasciola hepatica, and Haemonchus contortus rely heavily on fumarate reduction for their energy generation while inside a host organism, where the oxygen tension is very low (20,45,48). Under these conditions, the biosynthesis of RQ is upregulated; however, during free-living stages of their life cycle, the helminth parasites use primarily aerobic respiration, which requires ubiquinone (Q) (Fig. 1, compound 2) (20,44,48). The anaerobic energy metabolism of the helminths was reviewed previously (43,46). Humans and other mammalian hosts use Q for aerobic energy metabolism but do not produce or require RQ; therefore, the discovery of molecules that selectively inhibit RQ biosynthesis may lead to highly specific antihelminthic therapeutics that do not have a toxic effect on the host (24).The pathway of RQ biosynthesis has not been completely elucidated, and enzymes specifically required for RQ synthesis still must be identified. RQ is structurally similar to Q, an important ...

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“…These dysfunctions are a major problem and a challenge for drug development. There is mounting evidence of the mitotoxicity of certain antidiabetic (e.g., metformin) (11), anticancer (e.g., doxorubicin) (13), antiparasitic (e.g., atovaquone) (14), antiviral (e.g., zidovudine) (15), antiepileptic (valproic acid [VPA]) (10), anesthetic (e.g., propofol) (16), anti-inflammatory (e.g., indomethacin) (17), and antiarrhythmic (e.g., carvedinol) (11) drugs. Therefore, taking such drugs can lead to organ damage, particularly damage to the liver (18), kidneys, heart (19), or skeletal muscles (20).…”

Section: Mitochondrial Drugs Toxicitymentioning

confidence: 99%

“…Ascofuranone in vitro is an effective agent for the treatment of African trypanosomiasis in mice with a high level of parasitemia (43). As noted in many reviews (14,43), ascofuranone, isolated from the phytopathogenic fungus Ascochyta visiae, is a potent inhibitor of trypanosome cyanide-insensitive alternative oxidase (TAO) localized in the mitochondrial inner membrane of the parasite mitochondria. Other excellent examples include nafuredin, isolated from Aspergillus niger, and nafuredin-c (a c-lactone derivative).…”

Section: Figmentioning

confidence: 99%

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Mitochondria as a pharmacological target: Magnum overview

Olszewska

Szewczyk

2013

IUBMB Life

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Mitochondria, responsible for energy metabolism within the cell, act as signaling organelles. Mitochondrial dysfunction may lead to cell death and oxidative stress and may disturb calcium metabolism. Additionally, mitochondria play a pivotal role in cardioprotective phenomena and a variety of neurodegenerative disorders ranging from Parkinson's to Alzheimer's disease. Mitochondrial DNA mutations may lead to impaired respiration. Hence, targeting the mitochondria with drugs offers great potential for new therapeutic approaches. The purpose of this overview is to present the recent state of knowledge concerning the interactions of various substances with mitochondria. V C 2013 IUBMB Life, 65(3): [273][274][275][276][277][278][279][280][281] 2013

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Parasite Mitochondria as a Target for Chemotherapy.

Cited by 17 publications

References 101 publications

Evidence that Ubiquinone Is a Required Intermediate for Rhodoquinone Biosynthesis in Rhodospirillum rubrum

Evidence that Ubiquinone Is a Required Intermediate for Rhodoquinone Biosynthesis in Rhodospirillum rubrum

Identification of a New Gene Required for the Biosynthesis of Rhodoquinone in Rhodospirillum rubrum

Mitochondria as a pharmacological target: Magnum overview

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