Effect of geranylated dihydrochalcone from Artocarpus altilis leaves extract on Plasmodium falciparum ultrastructural changes and mitochondrial malate: Quinone oxidoreductase.

Nearly half of the world's population is at risk of being infected by Plasmodium falciparum, the pathogen of malaria. Increasing resistance to common antimalarial drugs has encouraged investigations to find compounds with different scaffolds. Extracts of Artocarpus altilis leaves have previously been reported to exhibit in vitro antimalarial activity against P. falciparum and in vivo activity against P. berghei. Despite these initial promising results, the active compound from A. altilis is yet to be identified. Here, we have identified 2-geranyl-2', 4', 3, 4-tetrahydroxy-dihydrochalcone (1) from A. altilis leaves as the active constituent of its antimalarial activity. Since natural chalcones have been reported to inhibit food vacuole and mitochondrial electron transport chain (ETC), the morphological changes in food vacuole and biochemical inhibition of ETC enzymes of (1) were investigated. In the presence of (1), intraerythrocytic asexual development was impaired, and according to the TEM analysis, this clearly affected the ultrastructure of food vacuoles. Amongst the ETC enzymes, (1) inhibited the mitochondrial malate: quinone oxidoreductase (PfMQO), and no inhibition could be observed on dihydroorotate dehydrogenase (DHODH) as well as bc1 complex activities. Our study suggests that (1) has a dual mechanism of action affecting the food vacuole and inhibition of PfMQO-related pathways in mitochondria.

Novel TK2 mutations as a cause of delayed muscle maturation in mtDNA depletion syndrome.

Recessive mutations in TK2 cause a severe mitochondrial DNA depletion syndrome (MDS),(1) characterized by severe myopathy from early infancy. Recent reports have suggested a wider clinical spectrum including encephalomyopathic form.(1,2) We report a patient with infantile-onset fatal encephalomyopathy presenting with extreme muscle fiber immaturity.

Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria.

Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 µM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 µM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs.

Design, synthesis, and biological evaluation of air-stable nafuredin-γ analogs as complex I inhibitors.

Nafuredin-γ (2), converted from nafuredin (1) under mild basic conditions, demonstrates potent and selective inhibitory activity against helminth complex I. However, 2 is unstable in air because the conjugated dienes are oxygen-labile. To address this, we designed and synthesized air-stable nafuredin-γ analogs. Although the complex I inhibitory activities of all the new nafuredin-γ analogs were lower than that of 2, all were in the high nM range (IC50: 300-820nM).

Diversity of parasite complex II.

Parasites have developed a variety of physiological functions necessary for completing at least part of their life cycles in the specialized environments of surrounding the parasites in the host. Regarding energy metabolism, which is essential for survival, parasites adapt to the low oxygen environment in mammalian hosts by using metabolic systems that are very different from those of the hosts. In many cases, the parasite employs aerobic metabolism during the free-living stage outside the host but undergoes major changes in developmental control and environmental adaptation to switch to anaerobic energy metabolism. Parasite mitochondria play diverse roles in their energy metabolism, and in recent studies of the parasitic nematode, Ascaris suum, the mitochondrial complex II plays an important role in anaerobic energy metabolism of parasites inhabiting hosts by acting as a quinol-fumarate reductase. In Trypanosomes, parasite complex II has been found to have a novel function and structure. Complex II of Trypanosoma cruzi is an unusual supramolecular complex with a heterodimeric iron-sulfur subunit and seven additional non-catalytic subunits. The enzyme shows reduced binding affinities for both substrates and inhibitors. Interestingly, this structural organization is conserved in all trypanosomatids. Since the properties of complex II differ across a wide range of parasites, this complex is a potential target for the development of new chemotherapeutic agents. In this regard, structural information on the target enzyme is essential for the molecular design of drugs. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.