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Cysteine/Glutathione Deficiency: A Significant and Treatable Corollary of Disease

ABSTRACT: Glutathione (GSH) deficiency may play a pivotal role in a variety of apparently unrelated clinical conditions and diseases. Orally administered N-acetylcysteine (NAC), which replenishes the cysteine required for GSH synthesis, has been tested in a large number of randomized placebo-controlled trials involving these diseases and conditions. This chapter focused on developing a base of evidence suggesting that NAC administration improves disease by increasing cysteine and/or GSH in a variety of diseases, thereby implying a significant role for GSH deficiency in the clinical basis of many diseases. To develop this base of evidence, we systematically selected studies which considered the hypothesis that the therapeutic efficacy for NAC is an indication that cysteine and/or GSH deficiency is a pathophysiological part of the diseases studied. In this manner we focus this chapter on explaining the biological mechanisms of NAC therapy in a wide variety of disorders and demonstrate its ubiquitous role in improving disease that involves disrupted GSH and/or cysteine metabolism. Electronic supplementary material The online version of this article (10.1007/978-981-10-5311-5_20) contains supplementary material, which is available to authorized users.

SUBMITTER: Frye R

PROVIDER: S-EPMC7120747 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Project description:The complex formation between silver(I) and cysteine (H2Cys), penicillamine (H2Pen), and glutathione (H3Glu) in alkaline aqueous solution was examined using extended X-ray absorption fine structure (EXAFS) and (109)Ag NMR spectroscopic techniques. The complexes formed in 0.1 mol dm(-3) Ag(I) solutions with cysteine and penicillamine were investigated for ligand/Ag(I) (L/Ag) mole ratios increasing from 2.0 to 10.0. For the series of cysteine solutions (pH 10-11) a mean Ag-S bond distance of 2.45 ± 0.02 Å consistently emerged, while for penicillamine (pH 9) the average Ag-S bond distance gradually increased from 2.40 to 2.44 ± 0.02 Å. EXAFS and (109)Ag NMR spectra of a concentrated Ag(I)-cysteine solution (C(Ag(I)) = 0.8 mol dm(-3), L/Ag = 2.2) showed a mean Ag-S bond distance of 2.47 ± 0.02 Å and δ((109)Ag) 1103 ppm, consistent with prevailing, partially oligomeric AgS3 coordinated species, while for penicillamine (C(Ag(I)) = 0.5 mol dm(-3), L/Ag = 2.0) the mean Ag-S bond distance of 2.40 ± 0.02 Å and δ((109)Ag) 922 ppm indicate that mononuclear AgS2 coordinated complexes dominate. For Ag(I)-glutathione solutions (C(Ag(I)) = 0.01 mol dm(-3), pH ∼11), mononuclear AgS2 coordinated species with a mean Ag-S bond distance of 2.36 ± 0.02 Å dominate for L/Ag mole ratios from 2.0 to 10.0. The crystal structure of the silver(I)-cysteine compound (NH4)Ag2(HCys)(Cys)·H2O (1) precipitating at pH ∼10 was solved and showed a layer structure with both AgS3 and AgS3N coordination to the cysteinate ligands. A redetermination of the crystal structure of Ag(HPen)·H2O (2) confirmed the proposed digonal AgS2 coordination environment to bridging thiolate sulfur atoms in polymeric intertwining chains forming a double helix. A survey of Ag-S bond distances for crystalline Ag(I) complexes with S-donor ligands in different AgS2, AgS2(O/N), and AgS3 coordination environments was used, together with a survey of (109)Ag NMR chemical shifts, to assist assignments of the Ag(I) coordination in solution.

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Cysteine/Glutathione Deficiency: A Significant and Treatable Corollary of Disease

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