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Energy Provision, Fuel Use and Regulation of Skeletal Muscle Metabolism During The Exercise Intensity/Duration Continuum
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
It should also be pointed out that the production of aerobic ATP is turning on during very intense exercise and 70–100% of the VO2 max can be reached in an all-out 30 s sprint (Figure 2.5) (52, 65). However, the time for aerobic ATP contribution is short, and while little is provided in the first 5–10 s, ∼50% of the energy contribution in the last 5 s of the 30 s sprint is aerobic (65). If the exercise task lasts beyond about 1 min, oxidative phosphorylation becomes the major ATP-generating pathway (59). During the transition from rest to intense exercise, the substrate for the increasing aerobic ATP production is from muscle glycogen as a small amount of the produced pyruvate is transported into the mitochondria to produce acetyl-CoA and the reducing equivalent NADH in the pyruvate dehydrogenase (PDH) reaction (Figure 2.6). This enzyme is also under covalent control, existing in an inactive form at rest and moved to a fully active form by Ca2+ during exercise. The power of Ca2+, with help from pyruvate, keeps the enzyme in the active form despite increases in acetyl-CoA that would normally inactivate the enzyme at rest (47).
Protein Phosphorylation of Prolactin Target Tissue: Mammary Gland
Published in James A. Rillema, Actions of Prolactin on Molecular Processes, 1987
The structure and control of pyruvate dehydrogenase has been well studied in liver, muscle, and adipose tissue.71 An associated protein kinase can be isolated from the enzyme complex, which phosphorylates the α subunit of the pyruvate decarboxylase components.72 The activity of this kinase is controlled by insulin73 in vivo and by a yet to be characterized soluble insulin-stimulated second messenger in vitro.74 A phosphatase has also been described.71,75 The enzymatic activity of pyruvate dehydrogenase is inactivated by phosphorylation.
Regulation of Enzymatic Activity
Published in D. B. Keech, J. C. Wallace, Pyruvate Carboxylase, 2018
The regulation of pyruvate carboxylase by the concentrations of substrates and modifiers, and covalent modification and product inhibition of pyruvate dehydrogenase appear to constitute the main mechanism which cause the activities of these enzymes to vary inversely. Thus, high ratios of acetyl-CoA:CoA-SH and ATP:ADP stimulate pyruvate carboxylation (Sections I.C.3 and I.C.2), but inhibit pyruvate dehydrogenase (reviewed by Denton and Halestrap223). Ca2+ may also play a role in preferentially directing carbon flow through one of these pathways.223
Hyperglycaemia and the risk of post-surgical adhesion
Published in Archives of Physiology and Biochemistry, 2022
Gordon A. Ferns, Seyed Mahdi Hassanian, Mohammad-Hassan Arjmand
Hyperglycaemia increases superoxide production (Nishikawa et al.2000). Under hyperglycaemic conditions, there is increased glucose entering the glycolytic pathway (important biochemical pathway in the cells for glucose metabolism) that produced two molecules of pyruvate. In aerobic conditions, pyruvates are converted to acetyl-CoA by pyruvate dehydrogenase. Acetyl-CoA produced by pyruvate entered to the Krebs cycle in mitochondria. Three molecules of NADH are produced by each Krebs cycle (Sabri 1984). NADH is an electron carrier to transport electron in complex 1 of the electron transport chain in mitochondria for ATP synthesis. An excessive amount of NADH causes reductive stress by intracellular production of superoxide O2– (Liu et al.2002) (Figure 3). Superoxide is one of the most important ROS factors and can damage biomolecules and increase of inflammation (McCord 1980). Increase of ROS such as superoxide causes excessive production of proinflammatory cytokines and growth factors by immune cells which are associated with adhesion formation post-surgical (Fortin et al.2015).
Targeting glucose metabolism to develop anticancer treatments and therapeutic patents
Published in Expert Opinion on Therapeutic Patents, 2022
Yan Zhou, Yizhen Guo, Kin Yip Tam
Pyruvate dehydrogenase complex (PDC) is a 9.5 million Da multi-enzyme complex located in mitochondrial matrix and consisting of four major enzyme components: pyruvate dehydrogenase (E1), dihydrolipoyl transacetylase (E2), dihydrolipoamide dehydrogenase (E3), and E3-binding protein (E3BP), as well as the two kinds of dedicated regulatory enzymes: PDKs and pyruvate dehydrogenase phosphatase [47]. The detailed structure and function of PDC have been well reviewed [48]. As an important gatekeeper enzyme that links pyruvate to the TCA cycle, PDC catalyzes the conversion of pyruvate to acetyl-CoA coupled with the reduction of NAD+ to NADH. The modulation of PDC activities depends on the reversible phosphorylation and dephosphorylation [49]. Phosphorylation of E1α component, regardless of which one of the three serine residues, is enough to switch off PDC activity. Thus, phosphorylation of PDC by PDKs will downregulate its activity, and subsequently reduce the flux of pyruvate into the TCA cycle. In human, phosphorylation of PDC is catalyzed by any of four isoforms of pyruvate dehydrogenase kinase (PDK1-4) which are expressed differently in specific tissues. In particular, PDK1 is closely associated with cancer malignancy and serves as the only PDK isoform that could phosphorylate all serine sites of PDC [50]. To sum up, inhibiting PDKs has been one of the recognized strategies to fight against cancer by increasing OXPHOS and reversing Warburg effect.
The commensal bacterium Lactiplantibacillus plantarum imprints innate memory-like responses in mononuclear phagocytes
Published in Gut Microbes, 2021
Aize Pellon, Diego Barriales, Ainize Peña-Cearra, Janire Castelo-Careaga, Ainhoa Palacios, Nerea Lopez, Estibaliz Atondo, Miguel Angel Pascual-Itoiz, Itziar Martín-Ruiz, Leticia Sampedro, Monika Gonzalez-Lopez, Laura Bárcena, Teresa Martín-Mateos, Jose María Landete, Rafael Prados-Rosales, Laura Plaza-Vinuesa, Rosario Muñoz, Blanca de las Rivas, Juan Miguel Rodríguez, Edurne Berra, Ana M. Aransay, Leticia Abecia, Jose Luis Lavín, Hector Rodríguez, Juan Anguita
Transcriptomic analyses of primed human monocytes further confirmed the prominent decrease in the expression of pro-inflammatory mediators and effectors, including an array of cytokines, chemokines and antimicrobial peptides. Moreover, we observed a differential regulation of genes and pathways involved in metabolism, especially in the transport and use of carbohydrates, amino acids and fatty acids, which could be linked to the decreased metabolic rates and ROS production observed in primed cells. Cellular metabolism is intimately linked to the regulation of immune responses, with metabolic rewiring being described in both acutely stimulated 44 and innate memory cells 45. Notably, priming with live bacteria increased the expression of pyruvate dehydrogenase kinase genes PDK2, PDK3, PDK4. These proteins are involved in cellular metabolism regulation through the inactivation of components of pyruvate dehydrogenase, the enzyme complex converting pyruvate to acetyl-CoA, leading to decreased glucose and lipid metabolism, and aerobic respiration. 46 In addition, ACO1 and ACOD1, coding for aconitase and aconitate decarboxylase, were found downregulated. Itaconate, a metabolite with anti-microbial and immunomodulatory properties, 47 has been associated with the modulation of β-glucan-induced trained immunity, and ACOD1 expression showed decreased levels in memory monocytes compared to acutely stimulated cells. 48 Thus, the observed differential gene expression suggests a reduction in the integrity of the tricarboxylic acid (TCA) cycle and the itaconate pathway that might be relevant for the L. plantarum-induced long-term memory phenotype in monocytes.