scholarly journals Passing the Baton: Substrate Channelling in Respiratory Metabolism

Research ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-16 ◽  
Author(s):  
Alisdair R. Fernie ◽  
Youjun Zhang ◽  
Lee J. Sweetlove
Keyword(s):  
Tricarboxylic Acid Cycle ◽  
Interesting Case ◽  
Respiratory Metabolism ◽  
Ample Evidence ◽  
Protein Protein Interaction ◽  
Transport Chain ◽  
Life Itself ◽  
Substrate Channelling ◽  
Species Specific ◽  
Over 40 Years

Despite species-specific differences in the pathways of respiratory metabolism are remarkably conserved across the kingdoms of life with glycolysis, the tricarboxylic acid cycle, and mitochondrial electron transport chain representing the major components of the process in the vast majority of organisms. In addition to being of critical importance in fueling life itself these pathways serve as interesting case studies for substrate channelling with research on this theme having been carried out for over 40 years. Here we provide a cross-kingdom review of the ample evidence for protein-protein interaction and enzyme assemblies within the three component pathways as well as describing the scarcer available evidence for substrate channelling itself.

The respiratory metabolism of Mycobacterium lepraemurium

1976 ◽  
Vol 22 (9) ◽  
pp. 1293-1299
Author(s):  
Laszlo Kato ◽  
Catherine Adapoe ◽  
M. Ishaque
Keyword(s):  
Tricarboxylic Acid Cycle ◽  
Oxidative Enzymes ◽  
Respiratory Metabolism ◽  
Sprague Dawley ◽  
Succinate Oxidation ◽  
Terminal Electron Acceptor ◽  
Sprague Dawley Rats ◽  
Transport Chain ◽  
Mycobacterium Lepraemurium ◽  
Thiol Binding

The respiratory metabolism of Mycobacterium lepraemurium isolated from Sprague-Dawley rats lepromata using several substrates was investigated. None of the intermediates of the glycolysis cycle as well as of the tricarboxylic acid cycle except succinate was oxidized by purified whole suspensions of M. lepraemurium. Likewise, many sulfur compounds such as cystine, thiourea, thioacetate, thiodiglycol, mercaptosuccinate, and mercaptoethanol were inactive. However, yeast extract and some sulfhydryl compounds, e.g., cysteine, dithioerythritol, dithiothritol, and penicillamine were readily oxidized by murine bacillary suspensions, whereas thioglycolate, thioglucose, and reduced glutathione were oxidized at a slow rate. Succinate was not or was very poorly oxidized by normal cells probably because of impermeability of the cell wall but the addition of succinate to the cell suspensions frozen for 1 min at −40 °C considerably enhanced oxygen uptake over the endogenous value. The oxidation of succinate was unaffected by inhibitors rotenone, atabrine, and amytal but was markedly inhibited by thenoyltrifluoroacetone, antimycin A, 2-N-heptyl-4-hydroxyquinoline-N-oxide, and cyanide. The thiol-binding agents, p-hydroxymercuribenzoate and N-ethylmaleimide were also effective inhibitors of succinate oxidation but the process was not affected by uncouplers dinitrophenol, dibromophenol, pentachlorophenol, and carbonyl-cyanide-m-chlorophenylhydrazone. The results indicated that succinate oxidation by M. lepraemurium was mediated by oxidative enzymes involving an electron transport chain with oxygen as the terminal electron acceptor.

scholarly journals Effects of L-Malate on Mitochondrial Oxidoreductases in Liver of Aged Rats

2011 ◽  
pp. 329-336 ◽  
Author(s):  
J.-L. WU ◽  
Q.-P. WU ◽  
Y.-P. PENG ◽  
J.-M. ZHANG
Keyword(s):  
Electron Transport ◽  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Electron Transport Chain ◽  
Nadh Dehydrogenase ◽  
Tricarboxylic Acid Cycle ◽  
Radical Scavenger ◽  
Aged Rats ◽  
Transport Chain ◽  
Nadh Cytochrome

Accumulation of oxidative damage has been implicated to be a major causative factor in the decline in physiological functions that occur during the aging process. The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), considered as the pathogenic agent of many diseases and aging. L-malate, a tricarboxylic acid cycle intermediate, plays an important role in transporting NADH from cytosol to mitochondria for energy production. Previous studies in our laboratory reported L-malate as a free radical scavenger in aged rats. In the present study we focused on the effect of L-malate on the activities of electron transport chain in young and aged rats. We found that mitochondrial membrane potential (MMP) and the activities of succinate dehydrogenase, NADH-cytochrome c oxidoreductase and cytochrome c oxidase in liver of aged rats were significantly decreased when compared to young control rats. Supplementation of L-malate to aged rats for 30 days slightly increased MMP and improved the activities of NADH-dehydrogenase, NADH-cytochrome c oxidoreductase and cytochrome c oxidase in liver of aged rats when compared with aged control rats. In young rats, L-malate administration increased only the activity of NADH-dehydrogenase. Our result suggested that L-malate could improve the activities of electron transport chain enzymes in aged rats

scholarly journals Genome of Methylobacillus flagellatus, Molecular Basis for Obligate Methylotrophy, and Polyphyletic Origin of Methylotrophy

2007 ◽  
Vol 189 (11) ◽  
pp. 4020-4027 ◽  
Author(s):  
Ludmila Chistoserdova ◽  
Alla Lapidus ◽  
Cliff Han ◽  
Lynne Goodwin ◽  
Liz Saunders ◽  
...  
Keyword(s):  
Formate Dehydrogenase ◽  
Tricarboxylic Acid Cycle ◽  
Methylococcus Capsulatus ◽  
Methylobacterium Extorquens ◽  
Circular Chromosome ◽  
Transport Chain ◽  
Carbon Compounds ◽  
Formaldehyde Oxidation ◽  
Global Carbon ◽  
Single Circular Chromosome

ABSTRACT Along with methane, methanol and methylated amines represent important biogenic atmospheric constituents; thus, not only methanotrophs but also nonmethanotrophic methylotrophs play a significant role in global carbon cycling. The complete genome of a model obligate methanol and methylamine utilizer, Methylobacillus flagellatus (strain KT) was sequenced. The genome is represented by a single circular chromosome of approximately 3 Mbp, potentially encoding a total of 2,766 proteins. Based on genome analysis as well as the results from previous genetic and mutational analyses, methylotrophy is enabled by methanol and methylamine dehydrogenases and their specific electron transport chain components, the tetrahydromethanopterin-linked formaldehyde oxidation pathway and the assimilatory and dissimilatory ribulose monophosphate cycles, and by a formate dehydrogenase. Some of the methylotrophy genes are present in more than one (identical or nonidentical) copy. The obligate dependence on single-carbon compounds appears to be due to the incomplete tricarboxylic acid cycle, as no genes potentially encoding alpha-ketoglutarate, malate, or succinate dehydrogenases are identifiable. The genome of M. flagellatus was compared in terms of methylotrophy functions to the previously sequenced genomes of three methylotrophs, Methylobacterium extorquens (an alphaproteobacterium, 7 Mbp), Methylibium petroleiphilum (a betaproteobacterium, 4 Mbp), and Methylococcus capsulatus (a gammaproteobacterium, 3.3 Mbp). Strikingly, metabolically and/or phylogenetically, the methylotrophy functions in M. flagellatus were more similar to those in M. capsulatus and M. extorquens than to the ones in the more closely related M. petroleiphilum species, providing the first genomic evidence for the polyphyletic origin of methylotrophy in Betaproteobacteria.

scholarly journals Antibacterial Activity and Mode of Action of Dihydromyricetin from Ampelopsis grossedentata Leaves against Food-Borne Bacteria

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2831 ◽  
Author(s):  
Xiao-Nian Xiao ◽  
Fan Wang ◽  
Yi-Ting Yuan ◽  
Jing Liu ◽  
Yue-Zhen Liu ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Metal Ions ◽  
Thermal Processing ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Respiratory Metabolism ◽  
Food Borne ◽  
Effects Of Ph ◽  
Health Promoting ◽  
Ampelopsis Grossedentata

Dihydromyricetin (DMY) has recently attracted increased interest due to its considerable health-promoting activities but there are few reports on its antibacterial activity and mechanism. In this paper, the activity and mechanisms of DMY from Ampelopsis grossedentata leaves against food-borne bacteria are investigated. Moreover, the effects of pH, thermal-processing, and metal ions on the antibacterial activity of DMY are also evaluated. The results show that DMY exhibits ideal antibacterial activity on five types of food-borne bacteria (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella paratyphi, and Pseudomonas aeruginosa). The activities of DMY against bacteria are extremely sensitive to pH, thermal-processing, and metal ions. The morphology of the tested bacteria is changed and damaged more seriously with the exposure time of DMY. Furthermore, the results of the oxidative respiratory metabolism assay and the integrity of the cell membrane and wall tests revealed that the death of bacteria caused by DMY might be due to lysis of the cell wall, leakage of intracellular ingredients, and inhibition of the tricarboxylic acid cycle (TCA) pathway.

scholarly journals Mitocans Revisited: Mitochondrial Targeting as Efficient Anti-Cancer Therapy

2020 ◽  
Vol 21 (21) ◽  
pp. 7941 ◽  
Author(s):  
Lanfeng Dong ◽  
Vinod Gopalan ◽  
Olivia Holland ◽  
Jiri Neuzil
Keyword(s):  
Cancer Progression ◽  
Tricarboxylic Acid Cycle ◽  
Cancer Therapeutics ◽  
Mitochondrial Metabolism ◽  
Signalling Pathways ◽  
Transport Chain ◽  
Ros Homeostasis ◽  
Mitochondrial Functions ◽  
Anti Cancer ◽  
Selective Targeting

Mitochondria are essential cellular organelles, controlling multiple signalling pathways critical for cell survival and cell death. Increasing evidence suggests that mitochondrial metabolism and functions are indispensable in tumorigenesis and cancer progression, rendering mitochondria and mitochondrial functions as plausible targets for anti-cancer therapeutics. In this review, we summarised the major strategies of selective targeting of mitochondria and their functions to combat cancer, including targeting mitochondrial metabolism, the electron transport chain and tricarboxylic acid cycle, mitochondrial redox signalling pathways, and ROS homeostasis. We highlight that delivering anti-cancer drugs into mitochondria exhibits enormous potential for future cancer therapeutic strategies, with a great advantage of potentially overcoming drug resistance. Mitocans, exemplified by mitochondrially targeted vitamin E succinate and tamoxifen (MitoTam), selectively target cancer cell mitochondria and efficiently kill multiple types of cancer cells by disrupting mitochondrial function, with MitoTam currently undergoing a clinical trial.

Control of lipid oxidation at the mitochondrial levelThis paper article is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 382-388 ◽  
Author(s):  
Kent Sahlin
Keyword(s):  
Lipid Oxidation ◽  
Feedback Inhibition ◽  
Peer Review Process ◽  
Energy State ◽  
Tricarboxylic Acid Cycle ◽  
Low Energy ◽  
Acetyl Coa ◽  
Intensive Exercise ◽  
Transport Chain ◽  
Electron Carriers

The rate of lipid oxidation during exercise is controlled at several sites, and there is a reciprocal dependency between oxidation of lipids and carbohydrates (CHO). It is well known that the proportion of the 2 fuels oxidized is influenced by substrate availability and exercise intensity, but the mechanisms regulating fuel preferences remain unclear. During intense exercise, oxidation of long-chain fatty acids (LCFAs) decreases, and the major control is likely to be at the mitochondrial level. Potential mitochondrial sites for control of lipid oxidation include transport of LCFAs into mitochondrial matrix, β-oxidation, the tricarboxylic acid cycle, and the electron transport chain (ETC). CHO catabolism may impair lipid oxidation by interfering with the transfer of LCFAs into mitochondria and by competing for mutual cofactors (i.e., nicotinamide adenine dinucleotide and (or) coenzyme A (CoA)). The different effect of energy state on the catabolism of CHO and lipids is likely to be of major importance in explaining the shift in fuel utilization during intensive exercise. Formation of acetyl-CoA from CHO is activated by a low energy state, and will lead to accumulation of products that are inhibitory to lipid oxidation. In contrast, β-oxidation of LCFAs to acetyl-CoA is not stimulated by a low energy state. Further interaction between CHO and LCFAs may occur by substrate competition for electron carriers at ETC, due to provisions of electrons through different complexes. Feedback inhibition of β-oxidation by redox state is thought to be an important mechanism for the slowing of lipid oxidation during intensive exercise.

Mitochondrial stress causes increased succination of proteins in adipocytes in response to glucotoxicity

2012 ◽  
Vol 445 (2) ◽  
pp. 247-254 ◽  
Author(s):  
Norma Frizzell ◽  
Sonia A. Thomas ◽  
James A. Carson ◽  
John W. Baynes
Keyword(s):  
High Glucose ◽  
Addition Reaction ◽  
Tricarboxylic Acid Cycle ◽  
Michael Addition Reaction ◽  
3T3 Cells ◽  
Mitochondrial Stress ◽  
High Glucose Medium ◽  
Transport Chain ◽  
Type 2 Diabetic

2SC [S-(2-succino)-cysteine] is a chemical modification formed by a Michael addition reaction of fumarate with cysteine residues in proteins. Formation of 2SC, termed ‘succination’ of proteins, increases in adipocytes grown in high-glucose medium and in adipose tissues of Type 2 diabetic mice. However, the metabolic mechanisms leading to increased fumarate and succination of protein in the adipocyte are unknown. Treatment of 3T3 cells with high glucose (30 mM compared with 5 mM) caused a significant increase in cellular ATP/ADP, NADH/NAD+ and Δψm (mitochondrial membrane potential). There was also a significant increase in the cellular fumarate concentration and succination of proteins, which may be attributed to the increase in NADH/NAD+ and subsequent inhibition of tricarboxylic acid cycle NAD+-dependent dehydrogenases. Chemical uncouplers, which dissipated Δψm and reduced the NADH/NAD+ ratio, also decreased the fumarate concentration and protein succination. High glucose plus metformin, an inhibitor of complex I in the electron transport chain, caused an increase in fumarate and succination of protein. Thus excess fuel supply (glucotoxicity) appears to create a pseudohypoxic environment (high NADH/NAD+ without hypoxia), which drives the increase in succination of protein. We propose that increased succination of proteins is an early marker of glucotoxicity and mitochondrial stress in adipose tissue in diabetes.

scholarly journals Oxygen Dependency of Cerebral Oxidative Phosphorylation in Newborn Piglets

2000 ◽  
Vol 20 (2) ◽  
pp. 280-289 ◽  
Author(s):  
Roger Springett ◽  
Marzena Wylezinska ◽  
Ernest B. Cady ◽  
Mark Cope ◽  
David T. Delpy
Keyword(s):  
Oxidative Phosphorylation ◽  
Cytochrome Oxidase ◽  
Oxidation State ◽  
Near Infrared ◽  
Cerebral Oxygenation ◽  
Tricarboxylic Acid Cycle ◽  
High Time Resolution ◽  
Transport Chain ◽  
Hemoglobin Oxygenation ◽  
Phosphorus Metabolites

Changes in hemoglobin oxygenation and oxidation state of the CuA centre of cytochrome oxidase were measured with full spectral near infrared spectroscopy simultaneously with phosphorus metabolites using nuclear magnetic resonance 31P spectroscopy at high time resolution (10 seconds) during transient anoxia (FiO2 = 0.0 for 105 seconds) in the newborn piglet brain. During the onset of anoxia, there was no change in either phosphocreatine (PCr) concentration or the oxidation state of the CuA centre of cytochrome oxidase until there was a substantial fall in cerebral hemoglobin oxygenation, at which point the CuA centre reduced simultaneously with the decline in PCr. At a later time during the anoxia, intracellular pH decreased rapidly, consistent with a fall in cerebral metabolic rate for O2 and reduced flux through the tricarboxylic acid cycle. The simultaneous reduction of CuA and decline in PCr can be explained in terms of the effects of the falling mitochondrial electrochemical potential. From these observations, it is concluded that, at normoxia, oxidative phosphorylation and the oxidation state of the components of the electron transport chain are independent of cerebral oxygenation and that the reduction in the CuA signal occurs when oxygen tension limits the capacity of oxidative phosphorylation to maintain the phosphorylation potential.

scholarly journals Proteomic, Microarray, and Signature-Tagged Mutagenesis Analyses of Anaerobic Pseudomonas aeruginosa at pH 6.5, Likely Representing Chronic, Late-Stage Cystic Fibrosis Airway Conditions

2008 ◽  
Vol 190 (8) ◽  
pp. 2739-2758 ◽  
Author(s):  
Mark D. Platt ◽  
Michael J. Schurr ◽  
Karin Sauer ◽  
Gustavo Vazquez ◽  
Irena Kukavica-Ibrulj ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Late Stage ◽  
Tricarboxylic Acid Cycle ◽  
Major Step ◽  
Transport Chain ◽  
Cystic Fibrosis Airway ◽  
Molecular Machinery ◽  
Microarray Studies ◽  
Pf1 Bacteriophage

ABSTRACT Patients suffering from cystic fibrosis (CF) commonly harbor the important pathogen Pseudomonas aeruginosa in their airways. During chronic late-stage CF, P. aeruginosa is known to grow under reduced oxygen tension and is even capable of respiring anaerobically within the thickened airway mucus, at a pH of ∼6.5. Therefore, proteins involved in anaerobic metabolism represent potentially important targets for therapeutic intervention. In this study, the clinically relevant “anaerobiome” or “proteogenome” of P. aeruginosa was assessed. First, two different proteomic approaches were used to identify proteins differentially expressed under anaerobic versus aerobic conditions. Microarray studies were also performed, and in general, the anaerobic transcriptome was in agreement with the proteomic results. However, we found that a major portion of the most upregulated genes in the presence of NO3 − and NO2 − are those encoding Pf1 bacteriophage. With anaerobic NO2 −, the most downregulated genes are those involved postglycolytically and include many tricarboxylic acid cycle genes and those involved in the electron transport chain, especially those encoding the NADH dehydrogenase I complex. Finally, a signature-tagged mutagenesis library of P. aeruginosa was constructed to further screen genes required for both NO3 − and NO2 − respiration. In addition to genes anticipated to play important roles in the anaerobiome (anr, dnr, nar, nir, and nuo), the cysG and dksA genes were found to be required for both anaerobic NO3 − and NO2 − respiration. This study represents a major step in unraveling the molecular machinery involved in anaerobic NO3 − and NO2 − respiration and offers clues as to how we might disrupt such pathways in P. aeruginosa to limit the growth of this important CF pathogen when it is either limited or completely restricted in its oxygen supply.

scholarly journals Biochemical Studies of Mitochondrial Malate: Quinone Oxidoreductase from Toxoplasma gondii

2021 ◽  
Vol 22 (15) ◽  
pp. 7830
Author(s):  
Rajib Acharjee ◽  
Keith K. Talaam ◽  
Endah D. Hartuti ◽  
Yuichi Matsuo ◽  
Takaya Sakura ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Drug Target ◽  
Tricarboxylic Acid Cycle ◽  
Expression System ◽  
Protozoan Parasite ◽  
New Drugs ◽  
Quinone Oxidoreductase ◽  
Steady State Kinetics ◽  
Transport Chain ◽  
Effective Drugs

Toxoplasma gondii is a protozoan parasite that causes toxoplasmosis and infects almost one-third of the global human population. A lack of effective drugs and vaccines and the emergence of drug resistant parasites highlight the need for the development of new drugs. The mitochondrial electron transport chain (ETC) is an essential pathway for energy metabolism and the survival of T. gondii. In apicomplexan parasites, malate:quinone oxidoreductase (MQO) is a monotopic membrane protein belonging to the ETC and a key member of the tricarboxylic acid cycle, and has recently been suggested to play a role in the fumarate cycle, which is required for the cytosolic purine salvage pathway. In T. gondii, a putative MQO (TgMQO) is expressed in tachyzoite and bradyzoite stages and is considered to be a potential drug target since its orthologue is not conserved in mammalian hosts. As a first step towards the evaluation of TgMQO as a drug target candidate, in this study, we developed a new expression system for TgMQO in FN102(DE3)TAO, a strain deficient in respiratory cytochromes and dependent on an alternative oxidase. This system allowed, for the first time, the expression and purification of a mitochondrial MQO family enzyme, which was used for steady-state kinetics and substrate specificity analyses. Ferulenol, the only known MQO inhibitor, also inhibited TgMQO at IC50 of 0.822 μM, and displayed different inhibition kinetics compared to Plasmodium falciparum MQO. Furthermore, our analysis indicated the presence of a third binding site for ferulenol that is distinct from the ubiquinone and malate sites.

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