scholarly journals Potential biomarkers in septic shock besides lactate

2020 ◽  
Vol 245 (12) ◽  
pp. 1066-1072
Author(s):  
Hang Yang ◽  
Linlin Du ◽  
Zhaocai Zhang
Keyword(s):  
Septic Shock ◽  
Malate Dehydrogenase ◽  
Tricarboxylic Acid Cycle ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Point Of View ◽  
Acid Cycle ◽  
Nadh Ratio ◽  
Elevated Lactate ◽  
Potential Biomarkers

Septic shock can be defined as sepsis with persisting hypotension and is required for vasopressors after initial unsuccessful fluid resuscitation. Elevated lactate is a biomarker of tissue perfusion and oxygenation and a useful prognostic tool for resuscitation in septic shock, as it is a byproduct of anaerobic glycolysis due to inadequate oxygen delivery and tissue hypoxia. Early and serial systematic lactate measurement will prompt physician more rapid intervention and lactate normalization, which is associated with better outcome. However, lactate formation during septic shock is neither entirely related to tissue hypoxia, nor reversible by increasing oxygen delivery. Meanwhile, lactate can be oxidized via tricarboxylic acid cycle after being transferred into mitochondria via lactate shuttle, which indicates elevated lactate can be used rather than only accumulation. Glycolysis and elevated lactate can be initiated by hypoxia, but persistent hyperlactatemia may not only represent persistent hypoxia. Some other potential biomarkers have been reviewed in the article including intermediates of tricarboxylic acid cycle, malate-aspartate shuttle, the nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratio, NAD+, NADH, malate, and malate dehydrogenase from the point of view of energy metabolism. Among them, malate dehydrogenase participates in both malate-aspartate shuttle and tricarboxylic acid cycle, and it can also indirectly reflex the NAD+/NADH ratio. It is reasonable to hypothesize that the combination of lactate and malate dehydrogenase will be more comprehensive to reflex hypoxia in septic shock. Impact statement Elevated lactate has been commonly considered as a biomarker and a useful prognostic tool for resuscitation in septic shock, facilitating physician more rapid intervention and treatment. However, it can be initiated by hypoxia, but persistent hyperlactatemia may not represent persistent hypoxia only. In the article, it is the first time to review potential biomarkers in septic shock from the point of view of energy metabolism including intermediates of TCA cycle, MAS, the NAD+/NADH ratio, NAD+, NADH, malate, and MDH. And the combination of lactate and MDH is also proposed in septic shock for the first time, as MDH in cytoplasm and mitochondria participates in both MAS and TCA cycle for ATP generation. Its feasibility in clinic has been analyzed at the end, although related research is still limited. It is reasonable the combination of lactate and MDH will be more comprehensive to reflex hypoxia in septic shock.

scholarly journals HISTOCHEMICAL INVESTIGATIONS ON THE IN VIVO EFFECTS OF FLUORIDE ON TRICARBOXYLIC ACID CYCLE DEHYDROGENASES FROM PELARGONIUM ZONALE: PART II

1967 ◽  
Vol 15 (4) ◽  
pp. 202-206
Author(s):  
C. JAMES LOVELACE ◽  
GENE W. MILLER
Keyword(s):  
Sodium Fluoride ◽  
Reductase Activity ◽  
Tricarboxylic Acid Cycle ◽  
Leaf Tissue ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Pelargonium Zonale ◽  
Acid Cycle ◽  
In Vivo Effects

In vivo effects of fluoride on tricarboxylic acid (TCA) cycle dehydrogenase enzymes of Pelargonium zonale were studied using p-nitro blue tetrazoleum chloride. Plants were exposed to 17 ppb HF, and enzyme activities in treated plants were compared to those in controls. Leaves of control plants were incubated in 5 x 10–3 M sodium fluoride. Injuries observed in fumigation and solution experiments were similar. Leaf tissue subjected to HF or sodium fluoride evidenced less succinic p-nitro blue tetrazoleum reductase activity than did control tissue. Other TCA cycle dehydrogenase enzymes were not observably affected by the fluoride concentrations used in these experiments. Excised leaves cultured in 5 x 10–3 M sodium fluoride exhibited less succinic p-nitro blue tetrazoleum reductase activity after 24 hr than did leaves cultured in 5 x 10–3 M sodium chloride.

scholarly journals Association of the malate dehydrogenase-citrate synthase metabolon is modulated by intermediates of the Krebs tricarboxylic acid cycle

2021 ◽  
Author(s):  
Joy Omini ◽  
Izabela Wojciechowska ◽  
Aleksandra Skirycz ◽  
Hideaki Moriyama ◽  
Toshihiro Obata
Keyword(s):  
Malate Dehydrogenase ◽  
Metabolic Flux ◽  
Citrate Synthase ◽  
Tricarboxylic Acid Cycle ◽  
Feedback Regulation ◽  
Dynamic Structure ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Enzyme Complex ◽  
Acetyl Coa

Mitochondrial malate dehydrogenase (MDH)-citrate synthase (CS) multi-enzyme complex is a part of the Krebs tricarboxylic acid (TCA) cycle 'metabolon' which is enzyme machinery catalyzing sequential reactions without diffusion of reaction intermediates into a bulk matrix. This complex is assumed to be a dynamic structure involved in the regulation of the cycle by enhancing metabolic flux. Microscale Thermophoresis analysis of the porcine heart MDH-CS complex revealed that substrates of the MDH and CS reactions, NAD+ and acetyl-CoA, enhance complex association while products of the reactions, NADH and citrate, weaken the affinity of the complex. Oxaloacetate enhanced the interaction only when it was presented together with acetyl-CoA. Structural modeling using published CS structures suggested that the binding of these substrates can stabilize the closed format of CS which favors the MDH-CS association. Two other TCA cycle intermediates, ATP, and low pH also enhanced the association of the complex. These results suggest that dynamic formation of the MDH-CS multi-enzyme complex is modulated by metabolic factors responding to respiratory metabolism, and it may function in the feedback regulation of the cycle and adjacent metabolic pathways.

scholarly journals Staphylococcus epidermidis Polysaccharide Intercellular Adhesin Production Significantly Increases during Tricarboxylic Acid Cycle Stress

2005 ◽  
Vol 187 (9) ◽  
pp. 2967-2973 ◽  
Author(s):  
Cuong Vuong ◽  
Joshua B. Kidder ◽  
Erik R. Jacobson ◽  
Michael Otto ◽  
Richard A. Proctor ◽  
...  
Keyword(s):  
Staphylococcus Epidermidis ◽  
Tricarboxylic Acid Cycle ◽  
Tca Cycle ◽  
Redox Status ◽  
Tricarboxylic Acid ◽  
Polysaccharide Intercellular Adhesin ◽  
Low Oxygen ◽  
Acid Cycle ◽  
The Tca Cycle ◽  
High Concentrations

ABSTRACT Staphylococcal polysaccharide intercellular adhesin (PIA) is important for the development of a mature biofilm. PIA production is increased during growth in a nutrient-replete or iron-limited medium and under conditions of low oxygen availability. Additionally, stress-inducing stimuli such as heat, ethanol, and high concentrations of salt increase the production of PIA. These same environmental conditions are known to repress tricarboxylic acid (TCA) cycle activity, leading us to hypothesize that altering TCA cycle activity would affect PIA production. Culturing Staphylococcus epidermidis with a low concentration of the TCA cycle inhibitor fluorocitrate dramatically increased PIA production without impairing glucose catabolism, the growth rate, or the growth yields. These data lead us to speculate that one mechanism by which staphylococci perceive external environmental change is through alterations in TCA cycle activity leading to changes in the intracellular levels of biosynthetic intermediates, ATP, or the redox status of the cell. These changes in the metabolic status of the bacteria result in the attenuation or augmentation of PIA production.

scholarly journals Blocks in Tricarboxylic Acid Cycle of Salmonella enterica Cause Global Perturbation of Carbon Storage, Motility, and Host-Pathogen Interaction

mSphere ◽  
2019 ◽  
Vol 4 (6) ◽  
Author(s):  
Janina Noster ◽  
Nicole Hansmeier ◽  
Marcus Persicke ◽  
Tzu-Chiao Chao ◽  
Rainer Kurre ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Tricarboxylic Acid Cycle ◽  
Glycogen Synthesis ◽  
Tca Cycle ◽  
Carbon Fluxes ◽  
Tricarboxylic Acid ◽  
Cellular Functions ◽  
Content Type ◽  
Acid Cycle ◽  
Serovar Typhimurium

ABSTRACT The tricarboxylic acid (TCA) cycle is a central metabolic hub in most cells. Virulence functions of bacterial pathogens such as facultative intracellular Salmonella enterica serovar Typhimurium (S. Typhimurium) are closely connected to cellular metabolism. During systematic analyses of mutant strains with defects in the TCA cycle, a strain deficient in all fumarase isoforms (ΔfumABC) elicited a unique metabolic profile. Alongside fumarate, S. Typhimurium ΔfumABC accumulates intermediates of the glycolysis and pentose phosphate pathway. Analyses by metabolomics and proteomics revealed that fumarate accumulation redirects carbon fluxes toward glycogen synthesis due to high (p)ppGpp levels. In addition, we observed reduced abundance of CheY, leading to altered motility and increased phagocytosis of S. Typhimurium by macrophages. Deletion of glycogen synthase restored normal carbon fluxes and phagocytosis and partially restored levels of CheY. We propose that utilization of accumulated fumarate as carbon source induces a status similar to exponential- to stationary-growth-phase transition by switching from preferred carbon sources to fumarate, which increases (p)ppGpp levels and thereby glycogen synthesis. Thus, we observed a new form of interplay between metabolism of S. Typhimurium and cellular functions and virulence. IMPORTANCE We performed perturbation analyses of the tricarboxylic acid cycle of the gastrointestinal pathogen Salmonella enterica serovar Typhimurium. The defect of fumarase activity led to accumulation of fumarate but also resulted in a global alteration of carbon fluxes, leading to increased storage of glycogen. Gross alterations were observed in proteome and metabolome compositions of fumarase-deficient Salmonella. In turn, these changes were linked to aberrant motility patterns of the mutant strain and resulted in highly increased phagocytic uptake by macrophages. Our findings indicate that basic cellular functions and specific virulence functions in Salmonella critically depend on the proper function of the primary metabolism.

scholarly journals A Dysfunctional Tricarboxylic Acid Cycle Enhances Fitness of Staphylococcus epidermidis During β-Lactam Stress

mBio ◽  
2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Vinai Chittezham Thomas ◽  
Lauren C. Kinkead ◽  
Ashley Janssen ◽  
Carolyn R. Schaeffer ◽  
Keith M. Woods ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Citric Acid ◽  
Cell Surface ◽  
Staphylococcus Epidermidis ◽  
Citric Acid Cycle ◽  
Tricarboxylic Acid Cycle ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Content Type ◽  
Acid Cycle

ABSTRACT A recent controversial hypothesis suggested that the bactericidal action of antibiotics is due to the generation of endogenous reactive oxygen species (ROS), a process requiring the citric acid cycle (tricarboxylic acid [TCA] cycle). To test this hypothesis, we assessed the ability of oxacillin to induce ROS production and cell death in Staphylococcus epidermidis strain 1457 and an isogenic citric acid cycle mutant. Our results confirm a contributory role for TCA-dependent ROS in enhancing susceptibility of S. epidermidis toward β-lactam antibiotics and also revealed a propensity for clinical isolates to accumulate TCA cycle dysfunctions presumably as a way to tolerate these antibiotics. The increased protection from β-lactam antibiotics could result from pleiotropic effects of a dysfunctional TCA cycle, including increased resistance to oxidative stress, reduced susceptibility to autolysis, and a more positively charged cell surface. IMPORTANCE Staphylococcus epidermidis, a normal inhabitant of the human skin microflora, is the most common cause of indwelling medical device infections. In the present study, we analyzed 126 clinical S. epidermidis isolates and discovered that tricarboxylic acid (TCA) cycle dysfunctions are relatively common in the clinical environment. We determined that a dysfunctional TCA cycle enables S. epidermidis to resist oxidative stress and alter its cell surface properties, making it less susceptible to β-lactam antibiotics.

scholarly journals New Insights into Heme Utilization Pathways

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-25-SCI-25
Author(s):  
Emanuela Tolosano
Keyword(s):  
Respiratory Chain ◽  
Tricarboxylic Acid Cycle ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Energetic Metabolism ◽  
Acid Cycle ◽  
Heme Synthesis ◽  
Chain Complexes ◽  
The Tca Cycle

Heme, an iron-containing porphyrin, plays pivotal functions in cell energetic metabolism, serving as a cofactor for most of the respiratory chain complexes and interacting with the translocases responsible for the ADP/ATP exchange between mitochondria and cytosol. Moreover, heme biosynthesis is considered a cataplerotic pathway for the tricarboxylic acid cycle (TCA) cycle, as the process consumes succynil-CoA, an intermediate of the TCA cycle. Finally, heme synthesis is one of the major cellular iron-consuming processes, thus competing with mitochondrial biogenesis of iron-sulfur (Fe-S) clusters, the crucial cofactors of electron transport chain complexes and of some TCA cycle enzymes. The process of heme synthesis consists of eight enzymatic reactions starting in mitochondria with the condensation of glycine and succynil-CoA to form δ-aminolevulinic acid (ALA), catalyzed by amino levulinic acid synthase (ALAS), the rate-limiting enzyme in heme biosynthetic pathway. Two isoforms of ALAS exist, ALAS1, ubiquitously expressed and controlled by heme itself through a negative feedback, and ALAS2, specifically expressed in the erythroid cells and mainly controlled by iron availability. ALA is exported from mitochondria to cytosol and converted to coproporphyrinogenIII that is imported back into the mitochondrial intermembrane space and converted to protoporphyrinogen IX. The latter is oxidized to porphyrin IX. Finally, ferrous iron is inserted into porphyrin IX by ferrochelatase, a Fe-S cluster-containing enzyme. Heme is incorporated into mitochondrial heme-containing proteins including complexes of the respiratory chain or exported to cytosol for incorporation into cytosolic apo-hemoproteins. Cytosolic heme level is maintained by the rate of hemoprotein production, the activity of heme transporters, including both heme importers and exporters, and the rate of heme degradation mediated by heme oxygenases. The concerted action of all these mechanisms regulates heme level that in turn controls its own synthesis by regulating the expression and activity of ALAS1. During differentiation of erythroid progenitors, cells bypass the heme-mediated negative regulation of its production by expressing ALAS2 that is responsible for the high rate of heme synthesis required to sustain hemoglobin production. We showed that the process of heme efflux through the plasma membrane heme exporter Feline Leukemia Virus C Receptor (FLVCR)1a is required to sustain ALAS1-catalyzed heme synthesis. In tumor cells, the potentiation of heme synthesis/export axis contributes to the down-modulation of tricarboxylic acid cycle (TCA) cycle favoring a glycolysis- compared to an oxidative-based metabolism. Our data indicate that the heme synthesis/export axis slow down the TCA cycle through two mechanisms, on one hand, by consuming succynil-CoA, an intermediate of the cycle, and, on the other, by consuming mitochondrial iron thus limiting the production of Fe-S clusters, essential co-factors of complexes of the respiratory chain as well as of key enzymes of the cycle. The importance of heme synthesis/export axis in metabolic rewiring occurring during tumorigenesis is highlighted by the impaired proliferation and survival observed in FLVCR1a-silenced cancer cells. We speculate that the heme synthesis/export axis plays a role in metabolic adaptation also in proliferating cells in physiologic conditions, especially when oxygen concentration is limiting, as suggested by the phenotype of murine models of Flvcr1a deficiency. Finally, in post-mitotic cells the heme synthesis/export axis might contribute to modulate mitochondrial activity. This conclusion is supported by the observation that FLVCR1 gene was found mutated in human pathologies characterized by impaired function of neuronal cell populations strongly dependent on mitochondrial oxidative metabolism. In conclusion, our data highlight the crucial role of heme synthesis/export axis in the control of cell energetic metabolism. Future work is required to elucidate the role of exported heme in the extracellular environment. Disclosures No relevant conflicts of interest to declare.

Tricarboxylic acid cycle without malate dehydrogenase in Streptomyces coelicolor M-145

2018 ◽  
Vol 200 (9) ◽  
pp. 1279-1286 ◽  
Author(s):  
Tóshiko Takahashi-Íñiguez ◽  
Joana Barrios-Hernández ◽  
Marion Rodríguez-Maldonado ◽  
María Elena Flores
Keyword(s):  
Malate Dehydrogenase ◽  
Streptomyces Coelicolor ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Acid Cycle

scholarly journals Metabolic Engineering of the Tricarboxylic Acid Cycle for Improved Lysine Production by Corynebacterium glutamicum

2009 ◽  
Vol 75 (24) ◽  
pp. 7866-7869 ◽  
Author(s):  
Judith Becker ◽  
Corinna Klopprogge ◽  
Hartwig Schröder ◽  
Christoph Wittmann
Keyword(s):  
Metabolic Engineering ◽  
Corynebacterium Glutamicum ◽  
Tricarboxylic Acid Cycle ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Start Codon ◽  
Flux Analysis ◽  
Lysine Production ◽  
Acid Cycle ◽  
The Tca Cycle

ABSTRACT In the present work, lysine production by Corynebacterium glutamicum was improved by metabolic engineering of the tricarboxylic acid (TCA) cycle. The 70% decreased activity of isocitrate dehydrogenase, achieved by start codon exchange, resulted in a >40% improved lysine production. By flux analysis, this could be correlated to a flux shift from the TCA cycle toward anaplerotic carboxylation.

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