Characterization of the Product-inhibited Complex in Catalysis by Human Manganese Superoxide Dismutase

Hearn, Amy S.; Tu, Cong; Nick, Harry S.; Silverman, David N.

doi:10.1074/jbc.274.35.24457

Cited by 69 publications

(122 citation statements)

References 18 publications

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“…Cardiomyocytes paced at 1 Hz were then exposed to 1 m m H 2 O 2 , which would increase the mitochondrial [O 2 · − ] by inducing product inhibition of the superoxide dismutase in the mitochondrial matrix (SOD2) and thereby inhibit conversion of O 2 · − to H 2 O 2 (McAdam et al . 1977; Hearn et al . 1999; Aydin et al .…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial production of reactive oxygen species contributes to the β‐adrenergic stimulation of mouse cardiomycytes

Andersson

Fauconnier

Yamada

et al. 2011

The Journal of Physiology

121

125

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Non-technical summary When under stress, the heart beat becomes stronger, in part due to enhanced fluxes of Ca 2+ at the level of the cardiac cell. It is known that this effect is mediated by activation of β-receptors on the cardiac cell surface. This leads to modifications of intracellular proteins that in turn increase the flux of Ca 2+ within the cell. In this study we show that activation of β-receptors increases the production of reactive oxygen species (ROS) in the heart cell. These ROS generate enhanced Ca 2+ fluxes and more vigorous contraction. This finding shows a new cellular signalling route for regulating the power of the heart beat and might contribute to our understanding of diseases with defective cardiac contraction, such as heart failure.Abstract The sympathetic adrenergic system plays a central role in stress signalling and stress is often associated with increased production of reactive oxygen species (ROS). Furthermore, the sympathetic adrenergic system is intimately involved in the regulation of cardiomyocyte Ca 2+ handling and contractility. In this study we hypothesize that endogenously produced ROS contribute to the inotropic mechanism of β-adrenergic stimulation in mouse cardiomyocytes. Cytoplasmic Ca 2+ transients, cell shortening and ROS production were measured in freshly isolated cardiomyocytes using confocal microscopy and fluorescent indicators. As a marker of oxidative stress, malondialdehyde (MDA) modification of proteins was detected with Western blotting. Isoproterenol (ISO), a β-adrenergic agonist, increased mitochondrial ROS production in cardiomyocytes in a concentration-and cAMP-protein kinase A-dependent but Ca 2+ -independent manner. Hearts perfused with ISO showed a twofold increase in MDA protein adducts relative to control. ISO increased Ca 2+ transient amplitude, contraction and L-type Ca 2+ current densities (measured with whole-cell patch-clamp) in cardiomyocytes and these increases were diminished by application of the general antioxidant N -acetylcysteine (NAC) or the mitochondria-targeted antioxidant SS31. In conclusion, increased mitochondrial ROS production plays an integral role in the acute inotropic response of cardiomyocytes to β-adrenergic stimulation. On the other hand, chronically sustained adrenergic stress is associated with the development of heart failure and cardiac arrhythmias and prolonged increases in ROS may contribute to these defects.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial production of reactive oxygen species contributes to the β‐adrenergic stimulation of mouse cardiomycytes

Andersson

Fauconnier

Yamada

et al. 2011

The Journal of Physiology

121

125

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“…20 With these structural differences, it is noteworthy that MnSOD exhibits product inhibition whereas Cu/ZnSOD does not (excluding Fenton effects). [11][12][13][14] MnSOD is strongly product inhibited, and earlier kinetic studies on MnSOD assigned the inactive form of the enzyme to characteristic bands near 650 and 410 nm. 11 This inactivation was speculated to occur by oxidative addition of superoxide to Mn(II), within a Michaelis complex, forming a cyclic peroxo complex of Mn(III).…”

mentioning

confidence: 97%

“…Adding peroxide to MnSOD gives a visible absorption spectrum identical with the product-inhibited complex. 13 Therefore, the sideon peroxide structure determined here most likely represents this inhibited state of the enzyme.…”

mentioning

confidence: 98%

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Structural Analysis of Peroxide-Soaked MnSOD Crystals Reveals Side-On Binding of Peroxide to Active-Site Manganese

Porta

Vahedi-Faridi

Borgstahl³

2010

Journal of Molecular Biology

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“…Υπάρχει σε τρεις ισόμορφες και όλες απαιτούν την ύπαρξη ενός οξειδοαναγωγικά ενεργού μετάλλου, έτσι ώστε να επιτευχθεί η καταλυτική διάσπαση του O 2 •- (Powers & Jackson, 2008). Από αυτές τις ισόμορφες της υπεροξειδικής δισμουτάσης, οι 2 βρίσκονται ενδοκυττάρια ενώ η τρίτη βρίσκεται εξωκυττάρια (Hearn, Tu, Nick, & Silverman, 1999). Η SOD1 βρίσκεται στο κυτοσόλιο και στο χώρο μεταξύ των μιτοχονδριακών μεμβρανών.…”

Section: σχηµατισµός περοξυνιτρίτηunclassified

Η Επίδραση Της Έκκεντρης Προπόνησης Σε Δείκτες Μυϊκής Βλάβης Και Οξειδωτικού Στρες

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Anastasios A. Theodorou : The effect of eccentric training on muscle damage and redox status indices (Under the supervision of Athanasios Jamurtas, Assistand Professor)Antioxidant supplementation is quite often among athletes in an attempt to counteract the increased production of free radicals during exercise and especially after exerciseinduced muscle damage (eccentric). Recently an increasing number of studies reported negative effects of antioxidant supplementation on the training and cellular adaptations to chronic exercise. The aim of the present study was to investigate the effects of vitamin C and E supplementation on muscle performance, blood and muscle redox status, hemolysis and blood lipid profile in both trained and untrained individuals after acute and chronic exercise. After previous investigations of our group, a specific type of exercise was applied (eccentric) in order to produce long lasting and extensive changes in all biomarkers and examine more easily any effects of antioxidant supplementation. In a double-blinded fashion, participants received either a daily oral supplementation of vitamin C and vitamin E (n=14) or placebo (n=14) for eleven weeks. Following baseline tests, volunteers performed an eccentric exercise session two times per week for four weeks. Before and after the chronic eccentric exercise volunteers were subjected to one session of acute eccentric exercise, and physiological measurements were performed as well as blood samples and muscle biopsies (from 8 participants) were collected. The present results failed to support any effect of antioxidant supplementation; eccentric exercise similarly modified muscle damage and performance, blood redox status, hemolysis and lipid profile in both supplemented and non-supplemented groups. This is despite the fact that eccentric exercise induced marked changes in muscle damage and performance as well as redox status and lipid profile for several days after exercise. The complete lack of any effect on the physiological and biochemical outcome measures employed questions the validity of using orally antioxidant supplementation as redox modulators of muscle and redox status in healthy humans. Moreover, the lack of any effect of antioxidant supplementation on training and cellural adaptation to exercise observed in this study, opposed previous studies suggesting that antioxidant may block training adaptations.

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Characterization of the Product-inhibited Complex in Catalysis by Human Manganese Superoxide Dismutase

Cited by 69 publications

References 18 publications

Mitochondrial production of reactive oxygen species contributes to the β‐adrenergic stimulation of mouse cardiomycytes

Mitochondrial production of reactive oxygen species contributes to the β‐adrenergic stimulation of mouse cardiomycytes

Structural Analysis of Peroxide-Soaked MnSOD Crystals Reveals Side-On Binding of Peroxide to Active-Site Manganese

Η Επίδραση Της Έκκεντρης Προπόνησης Σε Δείκτες Μυϊκής Βλάβης Και Οξειδωτικού Στρες

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