New insights on myocardial pyridine nucleotides and thiol redox state in ischemia and reperfusion damage

Ceconi, Claudio; Bernocchi, Palmira; Boraso, Antonella; Cargnoni, Anna; Pepi, Patrizia; Curello, Salvatore; Ferrari, Roberto

doi:10.1016/s0008-6363(00)00104-8

Cited by 54 publications

(41 citation statements)

References 46 publications

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“…Although putative binding motifs for pyridine dinucleotide phosphates could be proposed using the primary structure of GCL, clearly further work is required to unequivocally map the binding site(s), as has been achieved for enzymes such as glutathione reductase [61]. Consistent with the regulatory effects of NADPH/NADP on GCL activity, this redox couple is primarily represented in the cytosol [62], i.e., it is colocalized with GCL, whereas the NADH/NAD redox couple is mainly represented within the mitochondrial compartment, where GCL has not been detected [62].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of γ-glutamylcysteine ligase regulation

Toroser

Yarian

Orr

et al. 2006

Biochimica et Biophysica Acta (BBA) - General Subjects

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The principal objective of this study was to investigate the mechanisms regulating the activity of γ-glutamylcysteine ligase (GCL; EC 6.3.2.2), the rate limiting enzyme in glutathione biosynthesis. Two phylogenetically divergent species, mouse and the fruitfly, Drosophila melanogaster were used to test the hypothesis that reversible protein phosphorylation and pyridine dinucleotide phosphate dependent allostery regulate GCL activity. GCL was almost completely inhibited under phosphorylating conditions, involving preincubations with MgATP and endogenous protein kinases. Maximal GCL inhibitions of 94%, 77%, 85%, 87%, 83%, 95% and 89% occurred, respectively, in mouse cerebellum, hippocampus, brainstem, striatum, cortex and heart, and Drosophila. These changes in GCL activity were detected using saturating levels of substrates, suggesting that V max was dramatically affected, whereas K m values showed no differences. In vitro activation of GCL, presumably due to dephosphorylation, was blocked by inhibitors of protein phosphatases, suggesting that GCL exists in vivo as a mixture of phosphorylated and dephosphorylated forms. The reversibility of the dephosphorylation-dependent activation was indicated by the time-dependent inactivation of the in vitro activated Drosophila GCL, by preincubation with MgATP. NADPH increased maximal GCL activity by up to 93%, whereas several other nucleotide analogues did not, thereby demonstrating specificity. Kinetic analysis using Hanes-Woolf replots of initial velocity data suggested that the NADPH-dependent stimulation of GCL activity is brought about by a change in the maximal activity, V max , rather than changes in substrate affinity. Results of this study suggest that mechanisms of modulation of eukaryotic GCL enzymes may include specific binding of ligands such as pyridine dinucleotide phosphates and reversible protein phosphorylation.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of γ-glutamylcysteine ligase regulation

Toroser

Yarian

Orr

et al. 2006

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…NAD þ þ NADPH. (41)(42)(43) Of course, reactions such as reduction of a-lipoate (a wellknown fatty acid antioxidant) to dihydrolipoate, use NADH directly and thus do not require 'transhydrogenase' function to influence redox elsewhere in the cell. (1,44) In the malignant prostate, this FAS contribution to redox status seems to be so effective that, despite the lower pO 2 , redox balance in malignancy may actually be improved (i.e., lower NADH/ NAD þ ratios).…”

Section: How Is the Transformation Achieved?mentioning

confidence: 99%

Going malignant: the hypoxia‐cancer connection in the prostate

et al. 2002

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The metabolic organization of both normal and malignant prostate cellular phenotypes involves some unusual and surprising features. In particular, both conditions exhibit ratios of NADH/NAD+ and NADPH/NADP+ characteristic of high oxidative states despite a chronic shortage of O2 in both conditions. In this paper, we observe that, in prostate cancer cells, the oxidizing power of the fatty acid synthesis (FAS) pathway is so large that redox is stabilized more favorably (more oxidized) than in normal prostate cells. This FAS-facilitated redox improvement occurs despite the fact that malignant cells are more O2 limited and therefore express more hypoxia inducible factor 1 (HIF1) and express hypoxia-regulated genes more robustly. This unusual metabolic situation clearly separates direct regulatory effects of redox balance from secondary effects of hypoxia per se. The physiological significance of the FAS pathway is thus the harnessing of its oxidizing power for improving redox balance despite conditions of more extreme hypoxia. Similar hypoxia defense strategies are found in animal species that are unusually tolerant to oxygen lack. Our hypothesis is that the metabolic organization in the "low zinc, low citrate" phenotype reflects an hypoxia-defense adaptation geared toward redox balance, with prostate cancer cells being relatively more oxidized, even if more hypoxic, than normal prostate cells. Recognition and understanding of these redox balancing and hypoxia defense functions may lead to new intervention strategies by developing new intracellular targets for prostate cancer therapy.

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“…Recently the role of nucleotides in the cellular antioxidant system has been greatly emphasized [1,2]; intracellular pyridine nucleotides play an important role in energy transduction, signaling pathways, and the antioxidant system [3][4][5], particularly in many cardiovascular diseases in which oxidative stress is involved, such as in heart failure, myocardial ischemia, unstable angina [6][7][8], and ischemia reperfusion injury [9,10]. Nucleotide status provides biochemical and clinical information on cardiovascular diseases [1,[6][7][8][9][10][11][12][13], cellular energetic alterations, and redox metabolism disorders [4,14,15].…”

mentioning

confidence: 99%

“…Nucleotide status provides biochemical and clinical information on cardiovascular diseases [1,[6][7][8][9][10][11][12][13], cellular energetic alterations, and redox metabolism disorders [4,14,15]. Furthermore, alteration of the nucleotide level characterizes diVerent enzymatic deWciencies in human erythrocytes [14].…”

mentioning

confidence: 99%