Zinc Is a Potent Inhibitor of Thiol Oxidoreductase Activity and Stimulates Reactive Oxygen Species Production by Lipoamide Dehydrogenase

Gazaryan, I. G.; Krasnikov, Boris F.; Ashby, G. A.; Thorneley, R. N. F.; Kristal, Bruce S.; Brown, Abraham M.

doi:10.1074/jbc.m108264200

Cited by 155 publications

(114 citation statements)

References 33 publications

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“…Furthermore, zinc inhibits alpha-ketoglutarate-dependent mitochondrial respiration suggesting that Zn 2+ can interfere with mitochondrial antioxidant production and may also stimulate production of reactive oxygen [13].…”

Section: Zinc and The Diabetic Patientmentioning

confidence: 99%

Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

152

104

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Zn 2+ ions are essential for the normal processing and storage of insulin and altered pancreatic insulin content is associated with all forms of diabetes mellitus. Work of the past decade has identified variants in the human SLC30A8 gene, encoding the zinc transporter ZnT8 which is expressed highly selectively on the secretory granule of pancreatic islet β and α cells, as affecting the risk of Type 2 Diabetes. Here, we review the regulation and roles of Zn 2+ ions in islet cells, the mechanisms through which SLC30A8 variants might affect glucose homeostasis and diabetes risk, and the novel technologies including recombinant targeted zinc probes and knockout mice which have been developed to explore these questions. Abbreviation ISG: Insulin Secreting Granules; T2D: Type 2 Diabetes; T1D: Type 1 Diabetes; 2 Diabetes mellitus is a common metabolic disease, affecting approximately 9% of the adult population worldwide. It is characterized by high circulating glucose levels over a prolonged period of time which leads to long-term health complications [1]. Type 1 Diabetes (T1D) involves the autoimmune destruction of insulin-secreting β cells while Type 2 Diabetes (T2D) is linked to both a decrease of insulin release and deficient hormone action on targeted organs [2].The links among Zn 2+ , diabetes and insulin were established in the 1930s, a decade after the discovery of the hormone, when a study showed crystallized insulin contains Zn 2+ and that Zn 2+ , along with other metal ions, could reversibly trigger insulin crystallization [3]. Zinc was later demonstrated to prolong insulin action when co-injected with the hormone [4].These early studies, as well as much more recent findings showing association between T2D risk and the inheritance of gene variants encoding a critical β cell Zn 2+ transporter, ZnT8[5] have generated considerable interest in the role of Zn 2+ in diabetes aetiology and as a possible therapeutic target [6]. Zinc and the diabetic patientScott and Fisher were the first to report a direct link between zinc and diabetes in patients.While assessing the insulin content in the pancreas of diabetic patients compared to nondiabetic cadavers, they showed that in the former group zinc content was reduced by 75 % [7].Epidemiological studies also demonstrated that diabetes and whole body zinc status are associated [8][9][10][11]. In T1D and T2D patients, serum zinc levels are significantly decreased [9][10][11], this being associated with an increased zinc urinary loss [8].Zinc may have important anti-oxidant properties, as it acts as a cofactor of the superoxide dismutase enzyme which regulates the detoxification of reactive oxygen species, regulating the expression and protecting against the oxidative stress induced by chronic hyperglycaemia (for review, [12]). Furthermore, zinc inhibits alpha-ketoglutarate-dependent mitochondrial respiration suggesting that Zn 2+ can interfere with mitochondrial antioxidant production and may also stimulate production of reactive oxygen [13].Zinc supplementation h...

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Section: Zinc and The Diabetic Patientmentioning

confidence: 99%

Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

152

104

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“…Amino acids could also be identified on the homodimerization surface of the dimer. It is known from previous mechanistic studies [15,[55][56][57] which residues take part in the catalytic action of LADH. On this ground, we filtered further the residue displacement plots (see above), mapped the original crystal structure and identified individual atomic distances that represent these specific interactions and areas of the protein.…”

Section: Structure Mappingmentioning

confidence: 99%

Molecular dynamics study of the structural basis of dysfunction and the modulation of reactive oxygen species generation by pathogenic mutants of human dihydrolipoamide dehydrogenase

Ambrus

Ádám-Vizi

2013

Archives of Biochemistry and Biophysics

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Human dihydrolipoamide dehydrogenase (LADH, E3) is a component in the pyruvate-, alpha-ketoglutarate-and branched-chain ketoacid dehydrogenase complexes and in the glycine cleavage system. The pathogenic mutations of LADH cause severe metabolic disturbances, called E3 deficiency that often involve cardiological and neurological symptoms and premature death. Our laboratory has recently shown that some of the known pathogenic mutations augment the reactive oxygen species (ROS) generation capacity of LADH, which may contribute to the clinical presentations. A recent report concluded that elevated oxidative stress generated by the above mutants turns the lipoic acid cofactor on the E2 subunits dysfunctional. In the present contribution we generated by molecular dynamics (MD) simulation the conformation of LADH that is proposed to be compatible with ROS generation. We propose here for the first time the structural changes, which are likely to turn the physiological LADH conformation to its ROS-generating conformation. We also created nine of the pathogenic mutants of the ROS-generating conformation and again used MD simulation to detect structural changes that the mutations induced in this LADH conformation. We propose the structural changes that may lead to the modulation in ROS generation of LADH by the pathogenic mutations.

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“…In vitro, DLDH can act as a diaphorase (Massey, et al, 1960) that is capable of transferring electrons from NADH to electron acceptors such as cytochrome c (Igamberdiev, et al, 2004) and ubiquinone (Olsson, et al, 1999, Xia, et al, 2001, and to electron-accepting dyes such as 2,6-dichlorophenolindophenol (DCPIP) (Patel, et al, 1995) and nitroblue tetrazolium (NBT) (Scouten andMcManus, 1971, Sokatch, et al, 1981). While DLDH itself may be a source of reactive oxygen species (Bando and Aki, 1991, Gazaryan, et al, 2002, Sreider, et al, 1990, Tahara, et al, 2007, it is also capable of scavenging nitric oxide (Igamberdiev, et al, 2004) and can serve as an antioxidant by protecting other proteins against oxidative inactivation by 4-hydroxyl-2-nonenal (Korotchkina, et al, 2001). Moreover, DLDH can also act as a proteolytic enzyme when the stability of its homodimer is altered (Babady, et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Changes in dihydrolipoamide dehydrogenase expression and activity during postnatal development and aging in the rat brain

Thangthaeng

Forster

2008

Mechanisms of Ageing and Development

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Brain energy metabolism is increased during postnatal development and diminished in neurodegenerative diseases linked to senescence. The objective of this study was to determine if these conditions could involve postnatal or senescence-related shifts in activity or expression of dihydrolipoamide dehydrogenase (DLDH), a key mitochondrial oxidoreductase. Rats ranging from 10 to 60 days of age were used in studies of postnatal development, whereas rats aged 5 or 30 months were used in the aging studies. The expression of DLDH was determined by Western blot analysis using anti-DLDH antibodies and DLDH diaphorase activity was measured by an in-gel activity staining method using nitroblue tetrazolium (NBT)/NADH. Activity of DLDH dehydrogenase was measured as NAD + oxidation of dihydrolipoamide. When these measures were considered in separate groups of 10-, 20-, 30-, or 60-day-old rats, all three showed an increase between 10 and 20 days of age. However, dehydrogenase activity of DLDH showed a further, progressive increase from 20 days to adulthood, in the absence of any further change in DLDH expression or diaphorase activity. No age-related decline in DLDH activity or expression was evident over the period from 5 to 30 months of age. Moreover, aging did not render DLDH more susceptible to oxidative inactivation by mitochondria-generated reactive oxygen species (ROS). Taken together, results of the present study indicate that (1) brain DLDH expression and activity undergo independent postnatal maturational increases; (2) Senescence does not confer any detectable change in the activity of DLDH or its susceptibility to inactivation by mitochondrial oxidative stress.

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Zinc Is a Potent Inhibitor of Thiol Oxidoreductase Activity and Stimulates Reactive Oxygen Species Production by Lipoamide Dehydrogenase

Cited by 155 publications

References 33 publications

Zinc and diabetes

Zinc and diabetes

Molecular dynamics study of the structural basis of dysfunction and the modulation of reactive oxygen species generation by pathogenic mutants of human dihydrolipoamide dehydrogenase

Changes in dihydrolipoamide dehydrogenase expression and activity during postnatal development and aging in the rat brain

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