scholarly journals Terminal Respiratory Oxidases: A Targetables Vulnerability of Mycobacterial Bioenergetics?

2020 ◽  
Vol 10 ◽  
Author(s):  
Sapna Bajeli ◽  
Navin Baid ◽  
Manjot Kaur ◽  
Ganesh P. Pawar ◽  
Vinod D. Chaudhari ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Electron Transport ◽  
Molecular Oxygen ◽  
Electron Transport Chain ◽  
Drug Targets ◽  
Atp Synthesis ◽  
Terminal Oxidase ◽  
Terminal Oxidases ◽  
Transport Chain ◽  
Synthase Inhibitor

Recently, ATP synthase inhibitor Bedaquiline was approved for the treatment of multi-drug resistant tuberculosis emphasizing the importance of oxidative phosphorylation for the survival of mycobacteria. ATP synthesis is primarily dependent on the generation of proton motive force through the electron transport chain in mycobacteria. The mycobacterial electron transport chain utilizes two terminal oxidases for the reduction of oxygen, namely the bc1-aa3 supercomplex and the cytochrome bd oxidase. The bc1-aa3 supercomplex is an energy-efficient terminal oxidase that pumps out four vectoral protons, besides consuming four scalar protons during the transfer of electrons from menaquinone to molecular oxygen. In the past few years, several inhibitors of bc1-aa3 supercomplex have been developed, out of which, Q203 belonging to the class of imidazopyridine, has moved to clinical trials. Recently, the crystal structure of the mycobacterial cytochrome bc1-aa3 supercomplex was solved, providing details of the route of transfer of electrons from menaquinone to molecular oxygen. Besides providing insights into the molecular functioning, crystal structure is aiding in the targeted drug development. On the other hand, the second respiratory terminal oxidase of the mycobacterial respiratory chain, cytochrome bd oxidase, does not pump out the vectoral protons and is energetically less efficient. However, it can detoxify the reactive oxygen species and facilitate mycobacterial survival during a multitude of stresses. Quinolone derivatives (CK-2-63) and quinone derivative (Aurachin D) inhibit cytochrome bd oxidase. Notably, ablation of both the two terminal oxidases simultaneously through genetic methods or pharmacological inhibition leads to the rapid death of the mycobacterial cells. Thus, terminal oxidases have emerged as important drug targets. In this review, we have described the current understanding of the functioning of these two oxidases, their physiological relevance to mycobacteria, and their inhibitors. Besides these, we also describe the alternative terminal complexes that are used by mycobacteria to maintain energized membrane during hypoxia and anaerobic conditions.

scholarly journals The oxidation of nicotinic acid by Pseudomonas ovalis Chester. The terminal oxidase

1972 ◽  
Vol 129 (3) ◽  
pp. 755-761 ◽  
Author(s):  
M. V. Jones ◽  
D. E. Hughes
Keyword(s):  
Electron Transport ◽  
Nicotinic Acid ◽  
Electron Transport Chain ◽  
Acid Oxidase ◽  
Terminal Oxidase ◽  
Difference Spectra ◽  
Terminal Oxidases ◽  
Cytochrome O ◽  
Transport Chain ◽  
Terminal Oxidation

In cell-free extracts of Pseudomonas ovalis nicotinic acid oxidase is confined to the wallmembrane fraction. It is associated with an electron-transport chain comprising b- and c-type cytochromes only, differing proportions of which are reduced by nicotinate and NADH. CO difference-spectra show two CO-binding pigments, cytochrome o (absorption maximum at 417nm) and another component absorbing maximally at 425nm. Cytochrome o is not reduced by NADH or by succinate but is by nicotinate, which can also reduce the ‘425’ CO-binding pigment. The effects of inhibitors of terminal oxidation support the idea of two terminal oxidases and a scheme involving the ‘425’ CO-binding pigment and the other components of the electron-transport chain is proposed.

scholarly journals Exploration of Nitrate Reductase Metabolic Pathway inCorynebacterium pseudotuberculosis

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Sintia Almeida ◽  
Cassiana Sousa ◽  
Vinícius Abreu ◽  
Carlos Diniz ◽  
Elaine M. S. Dorneles ◽  
...  
Keyword(s):  
Electron Transport ◽  
Nitrate Reductase ◽  
Virulence Factors ◽  
Electron Transport Chain ◽  
Drug Targets ◽  
Carbon Sources ◽  
The Other ◽  
Ecological Niches ◽  
Transport Chain ◽  
In Silico Methods

Based on the ability of nitrate reductase synthesis,Corynebacterium pseudotuberculosisis classified into two biovars: Ovis and Equi. Due to the presence of nitrate reductase, the Equi biovar can survive in absence of oxygen. On the other hand, Ovis biovar that does not have nitrate reductase is able to adapt to various ecological niches and can grow on certain carbon sources. Apart from these two biovars, some other strains are also able to carry out the reduction of nitrate. The enzymes that are involved in electron transport chain are also identified by in silico methods. Findings about pathogen metabolism can contribute to the identification of relationship between nitrate reductase and theC. pseudotuberculosispathogenicity, virulence factors, and discovery of drug targets.

scholarly journals Reduced efficiency, but increased fat oxidation, in mitochondria from human skeletal muscle after 24-h ultraendurance exercise

2007 ◽  
Vol 102 (5) ◽  
pp. 1844-1849 ◽  
Author(s):  
Maria Fernström ◽  
Linda Bakkman ◽  
Michail Tonkonogi ◽  
Irina G. Shabalina ◽  
Zinaida Rozhdestvenskaya ◽  
...  
Keyword(s):  
Electron Transport ◽  
Electron Transport Chain ◽  
Uncoupling Protein ◽  
Mitochondrial Protein ◽  
Oxygen Demand ◽  
Atp Synthesis ◽  
Whole Body ◽  
Palmitoyl Carnitine ◽  
Transport Chain ◽  
Mitochondrial Efficiency

The hypothesis that ultraendurance exercise influences muscle mitochondrial function has been investigated. Athletes in ultraendurance performance performed running, kayaking, and cycling at 60% of their peak O2 consumption for 24 h. Muscle biopsies were taken preexercise (Pre-Ex), postexercise (Post-Ex), and after 28 h of recovery (Rec). Respiration was analyzed in isolated mitochondria during state 3 (coupled to ATP synthesis) and state 4 (noncoupled respiration), with fatty acids alone [palmitoyl carnitine (PC)] or together with pyruvate (Pyr). Electron transport chain activity was measured with NADH in permeabilized mitochondria. State 3 respiration with PC increased Post-Ex by 39 and 41% ( P < 0.05) when related to mitochondrial protein and to electron transport chain activity, respectively. State 3 respiration with Pyr was not changed ( P > 0.05). State 4 respiration with PC increased Post-Ex but was lower than Pre-Ex at Rec ( P < 0.05 vs. Pre-Ex). Mitochondrial efficiency [amount of added ADP divided by oxygen consumed during state 3 (P/O ratio)] decreased Post-Ex by 9 and 6% ( P < 0.05) with PC and PC + Pyr, respectively. P/O ratio remained reduced at Rec. Muscle uncoupling protein 3, measured with Western blotting, was not changed Post-Ex but tended to decrease at Rec ( P = 0.07 vs. Pre-Ex). In conclusion, extreme endurance exercise decreases mitochondrial efficiency. This will increase oxygen demand and may partly explain the observed elevation in whole body oxygen consumption during standardized exercise (+13%). The increased mitochondrial capacity for PC oxidation indicates plasticity in substrate oxidation at the mitochondrial level, which may be of advantage during prolonged exercise.

Localized energy coupling during photophosphorylation by chromatophores of Rhodopseudomonas capsulata N22

1982 ◽  
Vol 2 (10) ◽  
pp. 743-749 ◽  
Author(s):  
G. Duncan Hitchens ◽  
Douglas B. Kell
Keyword(s):  
Free Energy ◽  
Electron Transport ◽  
Atp Synthase ◽  
Electron Transport Chain ◽  
Energy Coupling ◽  
Rhodopseudomonas Capsulata ◽  
Titration Method ◽  
Dual Inhibitor ◽  
Transport Chain ◽  
Synthase Inhibitor

The principle of the dual inhibitor titration method for testing models of electron-transport phosphorylation is outlined, and the method is applied to the study of photophosphorylation in bacterial chromatophores. It is concluded that energy coupling is strictly localized in nature in this system, in the sense that free energy released by a particular electron-transport chain may be used only by a particular H+-ATP synthase. Dual inhibitor titrations using the uncoupler SF 6847 and the H+-ATP synthase inhibitor oligomycin indicate that uncouplers act by shuttling rapidly between the localized energy-coupling sites.

scholarly journals Induction of Terminal Oxidases of Electron Transport Chain in Broccoli Heads under Controlled Atmosphere Storage

Foods ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 380 ◽  
Author(s):  
Yoshio Makino ◽  
Jun Inoue ◽  
Hsiao-Wen Wang ◽  
Masatoshi Yoshimura ◽  
Kensaku Maejima ◽  
...  
Keyword(s):  
Electron Transport ◽  
Mass Loss ◽  
Electron Transport Chain ◽  
Biological Properties ◽  
Controlled Atmosphere ◽  
High Co2 ◽  
Terminal Oxidases ◽  
Transport Chain ◽  
Atmosphere Storage ◽  
Oxygen Isotope Discrimination

Controlled atmosphere (CA) storage, that is, at low O2 and high CO2 concentrations, effectively extends the shelf life of horticultural products. The influence of CA storage (O2/CO2: 2.5%/6.0% or 2.5%/0.0%) and in normal air (both at 1 °C for 21 d) on the physicochemical (O2 uptake, mass loss and L-ascorbate) and biological properties of broccoli (Brassica oleracea var. italica, Plenck, 1794) via amounts and activities of terminal oxidases of the electron transport chain was investigated. Mass loss, a sensitive index of freshness for broccoli heads under CA, was significantly lower under CA than under normoxia (p < 0.05). Mass loss was depressed 7 d earlier under CA, including 6.0% CO2 than under CA without CO2. High CO2 effectively depressed the degradation of L-ascorbate. During storage, the activity of the alternative oxidase (AOX) was lower under CA than in normal air (p < 0.05), while the amount of cytochrome c oxidase (COX), and the AOX/COX activity ratio (based on oxygen isotope discrimination), were not affected during storage. Our results indicate that CA storage effectively retained the freshness of broccoli heads by depressing the induction of AOX. However, depression of AOX amount was not associated with CO2 around broccoli heads.

scholarly journals CtaM Is Required for Menaquinol Oxidaseaa3Function inStaphylococcus aureus

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
Neal D. Hammer ◽  
Lici A. Schurig-Briccio ◽  
Svetlana Y. Gerdes ◽  
Robert B. Gennis ◽  
Eric P. Skaar
Keyword(s):  
Staphylococcus Aureus ◽  
Electron Transport ◽  
Electron Transport Chain ◽  
Molecular Mechanisms ◽  
Carbon Sources ◽  
Spectroscopic Studies ◽  
Uncharacterized Protein ◽  
Terminal Oxidases ◽  
Transport Chain ◽  
Genes Encoding

ABSTRACTStaphylococcus aureusis the leading cause of skin and soft tissue infections, bacteremia, osteomyelitis, and endocarditis in the developed world. The ability ofS. aureusto cause substantial disease in distinct host environments is supported by a flexible metabolism that allows this pathogen to overcome challenges unique to each host organ. One feature of staphylococcal metabolic flexibility is a branched aerobic respiratory chain composed of multiple terminal oxidases. Whereas previous biochemical and spectroscopic studies reported the presence of three different respiratory oxygen reductases (otype,bdtype, andaa3type), the genome contains genes encoding only two respiratory oxygen reductases,cydABandqoxABCD. Previous investigation showed thatcydABandqoxABCDare required to colonize specific host organs, the murine heart and liver, respectively. This work seeks to clarify the relationship between the genetic studies showing the unique roles of thecydABandqoxABCDin virulence and the respiratory reductases reported in the literature. We establish that QoxABCD is anaa3-type menaquinol oxidase but that this enzyme is promiscuous in that it can assemble as abo3-type menaquinol oxidase. However, thebo3form of QoxABCD restricts the carbon sources that can support the growth ofS. aureus. In addition, QoxABCD function is supported by a previously uncharacterized protein, which we have named CtaM, that is conserved in aerobically respiringFirmicutes. In total, these studies establish the heme A biosynthesis pathway inS. aureus, determine that QoxABCD is a typeaa3menaquinol oxidase, and reveal CtaM as a new protein required for typeaa3menaquinol oxidase function in multiple bacterial genera.IMPORTANCEStaphylococcus aureusrelies upon the function of two terminal oxidases, CydAB and QoxABCD, to aerobically respire and colonize distinct host tissues. Previous biochemical studies support the conclusion that a third terminal oxidase is also present. We establish the components of theS. aureuselectron transport chain by determining the heme cofactors that interact with QoxABCD. This insight explains previous observations by revealing that QoxABCD can utilize different heme cofactors and confirms that the electron transport chain ofS. aureusis comprised of two terminal menaquinol oxidases. In addition, a newly identified protein, CtaM, is found to be required for the function of QoxABCD. These results provide a more complete assessment of the molecular mechanisms that support staphylococcal respiration.

scholarly journals The microbial metabolism of C1 compounds. The electron-transport chain of Pseudomonas AM1

1975 ◽  
Vol 152 (2) ◽  
pp. 349-356 ◽  
Author(s):  
David Widdowson ◽  
Christopher Anthony
Keyword(s):  
Electron Transport ◽  
Cytochrome C ◽  
Redox Potential ◽  
Molecular Oxygen ◽  
Cytochrome B ◽  
Electron Transport Chain ◽  
Difference Spectrum ◽  
Reduced Form ◽  
Transport Chain ◽  
Oxidation By Molecular Oxygen

Pseudomonas AM1, Hyphomicrobium X and Pseudomonas MS all contain cytochrome a/a3 and a b-type cytochrome able to react with CO. Pseudomonas AM1 and Hyphomicrobium X also have a CO-binding cytochrome c. The purified cytochrome c (redox potential 0.26V) of Pseudomonas AM1 was not susceptible to oxidation by molecular oxygen. CO reacted slowly with the reduced form giving a CO difference spectrum with a peak at 412nm and troughs at 420nm and 550nm. Similar results were obtained with the cytochrome c of Hyphomicrobium (aerobically grown or anaerobically grown with nitrate) and with that of Pseudomonas extorquens. The results given in the present paper are incompatible with an oxygenase or oxidase function for the soluble cytochrome c of methylotrophs. Studies with whole cells of Pseudomonas AM1 and a cytochrome c-deficient mutant have demonstrated that cytochrome b (redox potential 0.009V) is the first cytochrome in the electron-transport chain for oxidation of all substrates except methanol (and ethanol) whose oxidation does not involve this cytochrome. All substrates are usually oxidized by way of cytochrome c and cytochrome oxidase (cytochrome a/a3), but there is an alternative route for the reduction of cytochrome a/a3 in the mutant lacking cytochrome c. Results of experiments on cyanide inhibition of respiration and cytochrome oxidation support the suggestion that the susceptibility of cytochrome b to oxidation by molecular oxygen (reflected in its ability to react with CO) is probably irrelevant to the normal physiology of Pseudomonas AM1.

scholarly journals Novel MenA Inhibitors Are Bactericidal againstMycobacterium tuberculosisand Synergize with Electron Transport Chain Inhibitors

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Bryan J. Berube ◽  
Dara Russell ◽  
Lina Castro ◽  
Seoung-ryoung Choi ◽  
Prabagaran Narayanasamy ◽  
...  
Keyword(s):  
Electron Transport ◽  
Drug Treatment ◽  
Electron Transport Chain ◽  
Drug Targets ◽  
Content Type ◽  
Atp Production ◽  
Highly Active ◽  
Enhanced Activity ◽  
Transport Chain ◽  
Long Course

ABSTRACTMycobacterium tuberculosisis the leading cause of morbidity and death resulting from infectious disease worldwide. The incredible disease burden, combined with the long course of drug treatment and an increasing incidence of antimicrobial resistance amongM. tuberculosisisolates, necessitates novel drugs and drug targets for treatment of this deadly pathogen. Recent work has produced several promising clinical candidates targeting components of the electron transport chain (ETC) ofM. tuberculosis, highlighting this pathway’s potential as a drug target. Menaquinone is an essential component of theM. tuberculosisETC, as it functions to shuttle electrons through the ETC to produce the electrochemical gradient required for ATP production for the cell. We show that inhibitors of MenA, a component of the menaquinone biosynthetic pathway, are highly active againstM. tuberculosis. MenA inhibitors are bactericidal againstM. tuberculosisunder both replicating and nonreplicating conditions, with 10-fold higher bactericidal activity against nutrient-starved bacteria than against replicating cultures. MenA inhibitors have enhanced activity in combination with bedaquiline, clofazimine, and inhibitors of QcrB, a component of the cytochromebc1oxidase. Together, these data support MenA as a viable target for drug treatment againstM. tuberculosis. MenA inhibitors not only killM. tuberculosisin a variety of physiological states but also show enhanced activity in combination with ETC inhibitors in various stages of clinical trial testing.

Induction and Activity of Terminal Oxidases of Electron Transport Chain in Broccoli Heads under Controlled Atmosphere Storage

2019 ◽  
Author(s):  
Yoshio Makino ◽  
Jun Inoue ◽  
Hsiao-Wen Wang ◽  
Masatoshi Yoshimura ◽  
Kensaku Maejima ◽  
...  
Keyword(s):  
Electron Transport ◽  
Mass Loss ◽  
Electron Transport Chain ◽  
Biological Properties ◽  
Controlled Atmosphere ◽  
Terminal Oxidases ◽  
Transport Chain ◽  
Horticultural Products ◽  
Atmosphere Storage ◽  
Oxygen Isotope Discrimination

Controlled atmosphere (CA) storage, under atmospheres with low O2 and high CO2 concentrations, is effective for extending the shelflife of horticultural products. We investigated the influence of CA storage (O2/CO2: 2.5%/6.0% or 2.5%/0.0%) at 1C for 21 d versus normoxia (normal air) on the physicochemical and biological properties of broccoli (Brassica oleracea var. italica, Plenck, 1794) via amounts and activities of terminal oxidases of electron transport chain. Mass loss, a sensitive index of freshness for broccoli heads under CA, was significantly lower under CA than under normoxia. The effect for depressing mass loss was observed 7 d earlier under CA including 6.0% CO2 than under CA without CO2. Environmental CO2 was also effective for depressing loss of L-ascorbate. The alternative oxidase (AOX) level under CA was lower than under normoxia during storage, while the level of cytochrome c oxidase (COX), and the AOX/COX activity ratio (based on oxygen isotope discrimination), were stable during storage. Our results indicate that CA storage is effective for retaining freshness of broccoli heads during storage by depressing the induction of AOX. However, depression of AOX level was found to be independent of environmental CO2.

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