Cytochrome bc1-aa3 oxidase supercomplex as emerging and potential drug target against tuberculosis

2021 ◽  
Vol 14 ◽  
Author(s):  
Thangaraj Sindhu ◽  
Pal Debnath
Keyword(s):  
Drug Target ◽  
Therapeutic Potential ◽  
Complex Iii ◽  
Cytochrome Bc1 ◽  
Cytochrome Bc1 Complex ◽  
Complex Iv ◽  
Transport Chain ◽  
And Function ◽  
Potential Inhibitors ◽  
Role And Function

: The cytochrome bc1-aa3 supercomplex plays an essential role in the cellular respiratory system of Mycobacterium Tuberculosis. It transfers electrons from menaquinol to cytochrome aa3 (Complex IV) via cytochrome bc1 (Complex III), which reduces the oxygen. The electron transfer from a variety of donors into oxygen through the respiratory electron transport chain is essential to pump protons across the membrane creating an electrochemical transmembrane gradient (proton motive force, PMF) that regulates the synthesis of ATP via the oxidative phosphorylation process. Cytochrome bc1-aa3 supercomplex in M. tuberculosis is, therefore, a major drug target for antibiotic action. In recent years, several respiratory chain components have been targeted for developing new candidate drugs, illustrating the therapeutic potential of obstructing energy conversion of M. tuberculosis. The recently available cryo-EM structure of mycobacterial cytochrome bc1-aa3 supercomplex with open and closed conformations has opened new avenues for understanding its structure and function for developing more effective, new therapeutics against pulmonary tuberculosis. In this review, we discuss the role and function of several components, subunits, and drug targeting elements of the supercomplex cytochrome bc1-aa3, and its potential inhibitors in detail.

scholarly journals Respiratory chain supercomplexes associate with the cysteine desulfurase complex of the iron–sulfur cluster assembly machinery

2018 ◽  
Vol 29 (7) ◽  
pp. 776-785 ◽  
Author(s):  
Lena Böttinger ◽  
Christoph U. Mårtensson ◽  
Jiyao Song ◽  
Nicole Zufall ◽  
Nils Wiedemann ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Complex Iii ◽  
Bc1 Complex ◽  
Cytochrome Bc1 Complex ◽  
Respiratory Chain Complexes ◽  
Cysteine Desulfurase ◽  
Complex Iv ◽  
Iron Sulfur Cluster ◽  
Iron Sulfur ◽  
Chain Complexes

Mitochondria are the powerhouses of eukaryotic cells. The activity of the respiratory chain complexes generates a proton gradient across the inner membrane, which is used by the F1FO-ATP synthase to produce ATP for cellular metabolism. In baker’s yeast, Saccharomyces cerevisiae, the cytochrome bc1 complex (complex III) and cytochrome c oxidase (complex IV) associate in respiratory chain supercomplexes. Iron–sulfur clusters (ISC) form reactive centers of respiratory chain complexes. The assembly of ISC occurs in the mitochondrial matrix and is essential for cell viability. The cysteine desulfurase Nfs1 provides sulfur for ISC assembly and forms with partner proteins the ISC-biogenesis desulfurase complex (ISD complex). Here, we report an unexpected interaction of the active ISD complex with the cytochrome bc1 complex and cytochrome c oxidase. The individual deletion of complex III or complex IV blocks the association of the ISD complex with respiratory chain components. We conclude that the ISD complex binds selectively to respiratory chain supercomplexes. We propose that this molecular link contributes to coordination of iron–sulfur cluster formation with respiratory activity.

scholarly journals S15/1 The QO site semiquinone state in isolated cytochrome bc1 (complex iii) from Rhodobacter capsulatus

2008 ◽  
Vol 1777 ◽  
pp. S102
Author(s):  
Haibo Zhang ◽  
Artur Osyczka ◽  
Sarah E. Chobot ◽  
P. Leslie Dutton ◽  
Christopher C. Moser
Keyword(s):  
Rhodobacter Capsulatus ◽  
Complex Iii ◽  
Cytochrome Bc1 ◽  
Bc1 Complex ◽  
Cytochrome Bc1 Complex ◽  
Qo Site

scholarly journals Divergent features of the coenzyme Q:cytochrome c oxidoreductase complex in Toxoplasma gondii parasites

2021 ◽  
Vol 17 (2) ◽  
pp. e1009211
Author(s):  
Jenni A. Hayward ◽  
Esther Rajendran ◽  
Soraya M. Zwahlen ◽  
Pierre Faou ◽  
Giel G. van Dooren
Keyword(s):  
Toxoplasma Gondii ◽  
Drug Target ◽  
Protein Composition ◽  
Complex Iii ◽  
Mitochondrial Electron Transport Chain ◽  
Eukaryotic Evolution ◽  
Mitochondrial Oxygen Consumption ◽  
Apicomplexan Parasites ◽  
Transport Chain ◽  
Important Drug

The mitochondrion is critical for the survival of apicomplexan parasites. Several major anti-parasitic drugs, such as atovaquone and endochin-like quinolones, act through inhibition of the mitochondrial electron transport chain at the coenzyme Q:cytochrome c oxidoreductase complex (Complex III). Despite being an important drug target, the protein composition of Complex III of apicomplexan parasites has not been elucidated. Here, we undertake a mass spectrometry-based proteomic analysis of Complex III in the apicomplexan Toxoplasma gondii. Along with canonical subunits that are conserved across eukaryotic evolution, we identify several novel or highly divergent Complex III components that are conserved within the apicomplexan lineage. We demonstrate that one such subunit, which we term TgQCR11, is critical for parasite proliferation, mitochondrial oxygen consumption and Complex III activity, and establish that loss of this protein leads to defects in Complex III integrity. We conclude that the protein composition of Complex III in apicomplexans differs from that of the mammalian hosts that these parasites infect.

scholarly journals The Effect of Irisin as a Metabolic Regulator and Its Therapeutic Potential for Obesity

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Hui Li ◽  
Fang Wang ◽  
Mu Yang ◽  
Jiao Sun ◽  
Yi Zhao ◽  
...  
Keyword(s):  
Proteolytic Enzyme ◽  
Therapeutic Strategy ◽  
Therapeutic Potential ◽  
Detection Methods ◽  
Inflammatory Conditions ◽  
Fibronectin Type Iii ◽  
Fibronectin Type Iii Domain ◽  
And Function ◽  
Role And Function ◽  
Fibronectin Type

Obesity is a worldwide health problem due to the imbalance of energy intake and energy expenditure. Irisin, a newly identified exercise-responsive myokine, which is produced by the proteolytic cleavage of fibronectin type III domain-containing protein 5 (FNDC5), has emerged as a promising therapeutic strategy to combat obesity and obesity-related complications. Various studies in mice have shown that irisin could respond to systematic exercise training and promote white-to-brown fat transdifferentiation, but the role and function of irisin in humans are controversial. In this review, we systematically introduced and analyzed the factors that may contribute to these inconsistent results. Furthermore, we also described the potential anti-inflammatory properties of irisin under a variety of inflammatory conditions. Finally, the review discussed the existing unresolved issues and controversies about irisin, including the transcription of the irisin precursor FNDC5 gene in humans, the cleavage site of the yet unknown proteolytic enzyme that cleaves irisin from FNDC5, and the reliability of irisin levels measured with available detection methods.

scholarly journals Bridging a Gap Between Cytochrome Bc1 Complex Structure and Function

2014 ◽  
Vol 106 (2) ◽  
pp. 586a-587a
Author(s):  
Pekka A. Postila ◽  
Oana Cramariuc ◽  
Sanja Pöyry ◽  
Karol Kaszuba ◽  
Ilpo Vattulainen ◽  
...  
Keyword(s):  
Complex Structure ◽  
Structure And Function ◽  
Cytochrome Bc1 ◽  
Bc1 Complex ◽  
Cytochrome Bc1 Complex ◽  
And Function

scholarly journals Overcoming drug-resistant malaria through rational drug design in cytochrome bc1

2014 ◽  
Vol 70 (a1) ◽  
pp. C806-C806
Author(s):  
Michael Capper ◽  
Paul O'Neill ◽  
Giancarlo Biagini ◽  
Samar Hasnain ◽  
Svetlana Antonyuk
Keyword(s):  
Single Point ◽  
Rational Drug Design ◽  
Complex Iii ◽  
Cytochrome Bc1 ◽  
Single Point Mutation ◽  
Drug Resistant ◽  
Cytochrome Bc1 Complex ◽  
Phase I Clinical Trials ◽  
Inner Mitochondrial Membrane ◽  
Resistant Strains

Over three billion people live in regions affected by malaria and there are over one million deaths each year [1]. Malaria is caused by the Plasmodium parasite and various drugs are currently used in both treatment and prophylaxis but resistant strains are rapidly emerging. One of the most commonly used anti-malarial drugs is Atovaquone, a hydroxynapthoquinone that is currently used in combination with Proguanil and sold as Malarone™. Atovaquone targets cytochrome bc1 (Complex III, ubiquinol-cytochrome c oxidoreductase), a multi subunit electron transfer protein complex embedded in the inner mitochondrial membrane [2]. Drug resistance rises through a single point mutation in cytochrome b at the Qo site, one of two quinone binding sites. By visualising compounds bound to cytochrome bc1 through x-ray crystallography, it may be possible to modify the compounds to both bind stronger and more specifically. We have worked on compounds that recently failed phase I clinical trials due to cross-reactivity with human cytochrome bc1 [3]. Our structural studies have shown that these compounds appear to bind at the Qi site, which would overcome current drug-resistant strains. Further work here could produce a novel class of anti-malarial drug.

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