Differential effects of polyamine on the cytosolic and mitochondrial NADP‐isocitrate dehydrogenases

Murakami, Keiko; Haneda, Miyako; Iwata, S.; Yoshino, Masataka

doi:10.1002/biof.1026

Cited by 2 publications

(2 citation statements)

References 30 publications

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“…Cardiomyocytes harbor distinct NADP þ -isocitrate dehydrogenase isoenzymes in the cytosol and mitochondrial matrix. 94,95 Because aconitase, the Krebs cycle enzyme that converts citrate to isocitrate, is near-equilibrium, pyruvate-induced citrate accumulation will, in turn, generate isocitrate, the substrate for isocitrate dehydrogenase. Thus, pyruvate carboxylation could support production of NADPH, the source of electrons to maintain GSH in its reduced, antioxidant form.…”

Section: Pyruvate-enhanced Ca 21 Sensitivity Of the Contractile Machinerymentioning

confidence: 99%

Pyruvate enhancement of cardiac performance: Cellular mechanisms and clinical application

Mallet

Olivencia‐Yurvati

Bünger

2017

Exp Biol Med (Maywood)

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Cardiac contractile function is adenosine-5'-triphosphate (ATP)-intensive, and the myocardium's high demand for oxygen and energy substrates leaves it acutely vulnerable to interruptions in its blood supply. The myriad cardioprotective properties of the natural intermediary metabolite pyruvate make it a potentially powerful intervention against the complex injury cascade ignited by myocardial ischemia-reperfusion. A readily oxidized metabolic substrate, pyruvate augments myocardial free energy of ATP hydrolysis to a greater extent than the physiological fuels glucose, lactate and fatty acids, particularly when it is provided at supra-physiological plasma concentrations. Pyruvate also exerts antioxidant effects by detoxifying reactive oxygen and nitrogen intermediates, and by increasing nicotinamide adenine dinucleotide phosphate reduced form (NADPH) production to maintain glutathione redox state. These enhancements of free energy and antioxidant defenses combine to augment sarcoplasmic reticular Ca release and re-uptake central to cardiac mechanical performance and to restore β-adrenergic signaling of ischemically stunned myocardium. By minimizing Ca mismanagement and oxidative stress, pyruvate suppresses inflammation in post-ischemic myocardium. Thus, pyruvate administration stabilized cardiac performance, augmented free energy of ATP hydrolysis and glutathione redox systems, and/or quelled inflammation in a porcine model of cardiopulmonary bypass, a canine model of cardiac arrest-resuscitation, and a caprine model of hypovolemia and hindlimb ischemia-reperfusion. Pyruvate's myriad benefits in preclinical models provide the mechanistic framework for its clinical application as metabolic support for myocardium at risk. Phase one trials have demonstrated pyruvate's safety and efficacy for intravenous resuscitation for septic shock, intracoronary infusion for heart failure and as a component of cardioplegia for cardiopulmonary bypass. The favorable outcomes of these trials, which argue for expanded, phase three investigations of pyruvate therapy, mirror findings in isolated, perfused hearts, underscoring the pivotal role of preclinical research in identifying clinical interventions for cardiovascular diseases. Impact statement This article reviews pyruvate's cardioprotective properties as an energy-yielding metabolic fuel, antioxidant and anti-inflammatory agent in mammalian myocardium. Preclinical research has shown these properties make pyruvate a powerful intervention to curb the complex injury cascade ignited by ischemia and reperfusion. In ischemically stunned isolated hearts and in large mammal models of cardiopulmonary bypass, cardiac arrest-resuscitation and hypovolemia, intracoronary pyruvate supports recovery of myocardial contractile function, intracellular Ca homeostasis and free energy of ATP hydrolysis, and its antioxidant actions restore β-adrenergic signaling and suppress inflammation. The first clinical trials of pyruvate for cardiopulmonary bypass, fluid resuscitation and intracoronary interventio...

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Section: Pyruvate-enhanced Ca 21 Sensitivity Of the Contractile Machinerymentioning

confidence: 99%

Pyruvate enhancement of cardiac performance: Cellular mechanisms and clinical application

Mallet

Olivencia‐Yurvati

Bünger

2017

Exp Biol Med (Maywood)

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“…For example, non-covalent binding of polyamines activates cytosolic NADP-isocitrate dehydrogenase (Murakami et al 2012), attenuates the physical interaction between Src and activated EGFR (Ray et al 2012), enhances tubulins to microtubule assembly (Lefevre et al 2011), accelerates codon recognition by transfer RNAs on the ribosome (Hetrick et al 2010), blocks outward current in the inwardly rectifying potassium channels (Osawa et al 2009), and activates the capsaicin receptor TRPV1 (Ahern et al 2006). On the other hand, covalent conjugation of polyamines catalyzed by transglutaminases hinders the interaction of high-risk human papillomavirus (HPV) E7 with tumor suppressor Rb (Jeon et al 2006), reduces the GTPase activity of RhoA leading to constitutive activation (Masuda et al 2000), and increases stability and activity of glyoxalase 1 (Lee and Chang 2014).…”

Section: Discussionmentioning

confidence: 97%

Uncovering protein polyamination by the spermine-specific antiserum and mass spectrometric analysis

Chou

Lee

et al. 2014

Amino Acids

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The polyamines spermidine and spermine, and their precursor putrescine, have been shown to play an important role in cell migration, proliferation, and differentiation. Because of their polycationic property, polyamines are traditionally thought to be involved in DNA replication, gene expression, and protein translation. However, polyamines can also be covalently conjugated to proteins by transglutaminase 2 (TG2). This modification leads to an increase in positive charge in the polyamine-incorporated region which significantly alters the structure of proteins. It is anticipated that protein polyamine conjugation may affect the protein-protein interaction, protein localization, and protein function of the TG2 substrates. In order to investigate the roles of polyamine modification, we synthesized a spermine-conjugated antigen and generated an antiserum against spermine. In vitro TG2-catalyzed spermine incorporation assays were carried out to show that actin, tubulins, heat shock protein 70 and five types of histone proteins were modified with spermine, and modification sites were also identified by liquid chromatography and linear ion trap-orbitrap hybrid mass spectrometry. Subsequent mass spectrometry-based shotgun proteomic analysis also identified 254 polyaminated sites in 233 proteins from the HeLa cell lysate catalyzed by human TG2 with spermine, thus allowing, for the first time, a global appraisal of site-specific protein polyamination. Global analysis of mouse tissues showed that this modification really exists in vivo. Importantly, we have demonstrated that there is a new histone modification, polyamination, in cells. However, the functional significance of histone polyamination demands further investigations.

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Differential effects of polyamine on the cytosolic and mitochondrial NADP‐isocitrate dehydrogenases

Cited by 2 publications

References 30 publications

Pyruvate enhancement of cardiac performance: Cellular mechanisms and clinical application

Pyruvate enhancement of cardiac performance: Cellular mechanisms and clinical application

Uncovering protein polyamination by the spermine-specific antiserum and mass spectrometric analysis

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