Plasmodium falciparum:Cyanide-Resistant Oxygen Consumption

Murphy, Anina D.; Doeller, Jeannette E.; Hearn, Brian R.; Lang‐Unnasch, Naomi

doi:10.1006/expr.1997.4194

Cited by 39 publications

(50 citation statements)

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“…cytochrome a 3 ) [10], as well as to the ¢ndings of experiments where the oxygen consumption of Plasmodia was measured in the presence of cyanide. These data lead the authors to suggest the existence of a cyanide resistant, alternative respiratory pathway in P. falciparum, as described for plants and fungi [11]; (ii) parasites can grow in the conditions adopted in our experiment suggesting that they are capable of utilizing carboxy-Hb as well as oxy-Hb. This indirectly con¢rms that Plasmodia are microaerophilic organisms [12]; (iii) most importantly, the presence of oxygen appears to be irrelevant for chloroquine to act.…”

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confidence: 72%

Does chloroquine really act through oxidative stress?

et al. 2002

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To assess whether molecular oxygen and oxidative stress contribute to chloroquine activity, we cultivated strains of Plasmodium falciparum in erythrocytes with carboxyhemoglobin and an atmosphere containing 2% CO, 5% CO 2 and 93% N 2 . Results indicate that, contrary to common belief, oxygen is not involved in the activity of chloroquine. Reactive radicals formation is suggested. ß 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.Key words: Carboxyhemoglobin; Chloroquine; Carbon monoxide ; Oxygen; Malaria; Plasmodium falciparum Malaria continues to be a major health problem in tropical countries. Some 300^500 million clinical cases occur annually and result in 700 000^2.7 million deaths [1]. Chloroquine, a 4-amino 7-chloro quinoline, has been the mainstay of malaria control for decades. Despite years of use, its mode of action and the mechanism by which malaria parasites become resistant are only partly known. We know, however, that they are unrelated and independent [2]. Resistance of Plasmodium falciparum to chloroquine is multigenic and concerns drug accumulation in the parasite. In contrast, chloroquine and other quinoline drugs target a unique, essential metabolic pathway of the parasite, the ingestion and degradation of host cell hemoglobin (Hb) within the parasite's food vacuole. While globin-derived amino acids are used by the parasite, the remaining free heme moiety must be disposed: iron(II)protoporphyrin IX (Fe[II]PPIX) is oxidized to iron(III)protoporphyrin IX (Fe[III]PPIX) and, for the most part, converted into a crystalline pigment called hemozoin [3]. So, although chloroquine resistance is nowadays widely spread, knowing how chloroquine works is important in order to design newer and more e¡ective drugs.It is generally accepted that chloroquine prevents heme disposal through the formation of complexes with Fe[III]PPIX. Nuclear magnetic resonance, UV-visible and Mo « ssbauer spectroscopy data concur to show that Z^Z interaction between the drug and the electronic system of hematin governs the formation of these adducts. The accumulation of free heme and/or of chloroquine^Fe(III)PPIX adducts is thought to generate oxidative stress, leading to peroxidation of parasite membrane lipids and parasitic death [3^5]. However, uncertainties still exist.If the peroxidative damage hypothesis were correct, molecular oxygen would be important and play a key role in the initiation and ampli¢cation of the oxidative reactions. However, our ¢ndings are not supportive of this view. We found no signi¢cant variation in the activity of chloroquine when the oxygen tension in the culture was increased [6]. Also the presence of preformed peroxides was necessary for membranes to react with the drug^Fe[III]PPIX complexes and for lipid peroxidation to occur [7]. To further clarify if molecular oxygen and oxidative stress had a role in the mechanism of action of chloroquine, we compared P. falciparum (chloroquine resistant and susceptible clones) cultured in sta...

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Does chloroquine really act through oxidative stress?

et al. 2002

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“…A pesar de la sensibilidad de la citocromo oxidasa de P. berghei al cianuro (25 mM) (55), en los trofozoítos de P. falciparum se observó que la inhibición es sólo un cuarto de la informada para P. berghei a la concentración de 2 mM (56). Se conoce un sistema de oxidasa alternativo presente en la mitocondria del Plasmodium (33), el cual es insensible al cianuro pero susceptible al ácido salicilhidroxiámico (SHAM) y al propilgalato, dos inhibidores conocidos de la oxidasa alternativa de naturaleza vegetal (56). La importancia para el parásito de esta oxidasa alternativa quedó demostrada por el efecto de los inhibidores SHAM y el propilgalato sobre el crecimiento in vitro del parásito (56).…”

Section: Complejo IVunclassified

“…Se conoce un sistema de oxidasa alternativo presente en la mitocondria del Plasmodium (33), el cual es insensible al cianuro pero susceptible al ácido salicilhidroxiámico (SHAM) y al propilgalato, dos inhibidores conocidos de la oxidasa alternativa de naturaleza vegetal (56). La importancia para el parásito de esta oxidasa alternativa quedó demostrada por el efecto de los inhibidores SHAM y el propilgalato sobre el crecimiento in vitro del parásito (56). Este efecto se expresa diferencialmente de acuerdo con el estadio de desarrollo del los gametocitos, así, los inhibidores de la enzima reducen en 70% a 75% el número de gametocitos tempranos mientras que sólo reducen en 25% los gametocitos tardíos (56,39).…”

Section: Complejo IVunclassified

“…La importancia para el parásito de esta oxidasa alternativa quedó demostrada por el efecto de los inhibidores SHAM y el propilgalato sobre el crecimiento in vitro del parásito (56). Este efecto se expresa diferencialmente de acuerdo con el estadio de desarrollo del los gametocitos, así, los inhibidores de la enzima reducen en 70% a 75% el número de gametocitos tempranos mientras que sólo reducen en 25% los gametocitos tardíos (56,39). Sin embargo, el potencial de membrana mitocondrial en los gametocitos tardíos de P. falciparum es más sensible a SHAM o una combinación de SHAM con cianuro, que al cianuro solo (56).…”

Section: Complejo IVunclassified

“…Este efecto se expresa diferencialmente de acuerdo con el estadio de desarrollo del los gametocitos, así, los inhibidores de la enzima reducen en 70% a 75% el número de gametocitos tempranos mientras que sólo reducen en 25% los gametocitos tardíos (56,39). Sin embargo, el potencial de membrana mitocondrial en los gametocitos tardíos de P. falciparum es más sensible a SHAM o una combinación de SHAM con cianuro, que al cianuro solo (56). En contraste, en los estadios eritrocíticos asexuados de P. falciparum, el potencial de membrana mitocondrial acoplado a la oxidasa alternativa no se afecta por SHAM, lo cual indica que la actividad oxidasa alternativa del complejo IV solamente se ejerce en los gametocitos (56).…”

Section: Complejo IVunclassified

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La mitocondria en el género Plasmodium.

Segura

Blair

2003

biomedica

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La mitocondria en las células eucarióticas juega un papel central en el metabolismo energético. En Plasmodium, la mitocondria se adapta morfológica y fisiológicamente a las condiciones metabólicas de sus hospederos. Así, en el mosquito, los gametocitos tienen un metabolismo aerobio y una mitocondria de apariencia típica, mientras que en vertebrados, los esporozoítos y merozoitos responden a un metabolismo microaerofílico, su mitocondria tiene pocas crestas y matriz menos densa. Como consecuencia de estos cambios metabólicos, la cadena transportadora de electrones y la susceptibilidad a los inhibidores mitocondriales difiere sustancialmente. La dependencia de la síntesis de novo de pirimidinas a inhibidores metabólicos ha sido de particular interés en el desarrollo de drogas antimaláricas. El objeto de esta breve revisión es describir las adaptaciones de la mitocondria de Plasmodium durante su desarrollo y su potencial como blanco terapéutico. Se mencionan los aspectos bioquímicos importantes de la función mitocondrial en Plasmodium.Palabras clave: mitocondria, Plasmodium, malaria, complejos mitocondriales I, II, III y IV, blanco terapéutico. Mitochondria in the malaria genus PlasmodiumIn eukaryotic cells, mitochondria are the ATP-producing and oxygen respiring organelles. In malaria cells, mitochondria adapts morphologically and physiologically to the metabolic conditions of the host. Therefore, in the mosquito, gametocytes have aerobic metabolism and a mitochondria of typical appearance, whereas in the vertebrate, sporozoites and merozoites respond to a microaerophilic metabolism and the mitochondria have cristae inner membranes and a low density matrix. Consequently, its electron transport chain and susceptibility to mitochondrial-inhibitors differ substantially. The influence of metabolic inhibitors on pyrimidine de novo synthesis has been of particular interest in malaria drug development. The current review briefly describes adaptations of Plasmodium mitochondria during development, biochemical aspects of mitochondrial function and the potential of mitochondria as antimalarial drug targets.Key words: mitochondria, Plasmodium, malaria, mitochondrial complexes I, II, III y IV, therapeutic target.La mitocondria se especializa en la síntesis de ATP en la célula mediante procesos como la fosforilación oxidativa y el transporte de electrones (1). Está conformada por dos membranas, una interna, otra externa y una matriz: la membrana externa es permeable para metabolitos pequeños debido a la presencia del canal aniónico dependiente de voltaje (VIDAC), el cual tiene preferencia por nucleótidos y compuestos fosforilados, su límite de permeabilidad es de 1.500 Dalton. La membrana externa permite el intercambio de sustancias con el medio citoplasmático. La membrana interna funciona como un aislante eléctrico, es impermeable para iones y metabolitos hidrofílicos; en ella se insertan los diferentes complejos encargados del transporte de electrones y mantiene un gradiente iónico (de protones) negativo, esenciales para la ...

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Alternative oxidase inhibitors: Mitochondrion‐targeting as a strategy for new drugs against pathogenic parasites and fungi

Ebiloma

Balogun

Cueto-Díaz

et al. 2019

Medicinal Research Reviews

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The alternative oxidase (AOX) is a ubiquitous terminal oxidase of plants and many fungi, catalyzing the four‐electron reduction of oxygen to water alongside the cytochrome‐based electron transfer chain. Unlike the classical electron transfer chain, however, the activity of AOX does not generate adenosine triphosphate but has functions such as thermogenesis and stress response. As it lacks a mammalian counterpart, it has been investigated intensely in pathogenic fungi. However, it is in African trypanosomes, which lack cytochrome‐based respiration in their infective stages, that trypanosome alternative oxidase (TAO) plays the central and essential role in their energy metabolism. TAO was validated as a drug target decades ago and among the first inhibitors to be identified was salicylhydroxamic acid (SHAM), which produced the expected trypanocidal effects, especially when potentiated by coadministration with glycerol to inhibit anaerobic energy metabolism as well. However, the efficacy of this combination was too low to be of practical clinical use. The antibiotic ascofuranone (AF) proved a much stronger TAO inhibitor and was able to cure Trypanosoma vivax infections in mice without glycerol and at much lower doses, providing an important proof of concept milestone. Systematic efforts to improve the SHAM and AF scaffolds, aided with the elucidation of the TAO crystal structure, provided detailed structure‐activity relationship information and reinvigorated the drug discovery effort. Recently, the coupling of mitochondrion‐targeting lipophilic cations to TAO inhibitors has dramatically improved drug targeting and trypanocidal activity while retaining target protein potency. These developments appear to have finally signposted the way to preclinical development of TAO inhibitors.

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Plasmodium falciparum:Cyanide-Resistant Oxygen Consumption

Cited by 39 publications

References 29 publications

Does chloroquine really act through oxidative stress?

Does chloroquine really act through oxidative stress?

La mitocondria en el género Plasmodium.

Alternative oxidase inhibitors: Mitochondrion‐targeting as a strategy for new drugs against pathogenic parasites and fungi

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