We studied the kinetics of the reaction of N-acetyl-l-cysteine (NAC or RSH) with cupric ions at an equimolar ratio of the reactants in aqueous acid solution (pH 1.4−2) using UV/Vis absorption and circular dichroism (CD) spectroscopies. Cu2+ showed a strong catalytic effect on the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) radical (ABTSr) consumption and autoxidation of NAC. Difference spectra revealed the formation of intermediates with absorption maxima at 233 and 302 nm (ε302/Cu > 8 × 103 M−1 cm−1) and two positive Cotton effects centered at 284 and 302 nm. These intermediates accumulate during the first, O2-independent, phase of the NAC autoxidation. The autocatalytic production of another chiral intermediate, characterized by two positive Cotton effects at 280 and 333 nm and an intense negative one at 305 nm, was observed in the second reaction phase. The intermediates are rapidly oxidized by added ABTSr; otherwise, they are stable for hours in the reaction solution, undergoing a slow pH- and O2-dependent photosensitive decay. The kinetic and spectral data are consistent with proposed structures of the intermediates as disulfide-bridged dicopper(I) complexes of types cis-/trans-CuI2(RS)2(RSSR) and CuI2(RSSR)2. The electronic transitions observed in the UV/Vis and CD spectra are tentatively attributed to Cu(I) → disulfide charge transfer with an interaction of the transition dipole moments (exciton coupling). The catalytic activity of the intermediates as potential O2 activators via Cu(II) peroxo-complexes is discussed. A mechanism for autocatalytic oxidation of Cu(I)−thiolates promoted by a growing electronically coupled −[CuI2(RSSR)]n− polymer is suggested. The obtained results are in line with other reported observations regarding copper-catalyzed autoxidation of thiols and provide new insight into these complicated, not yet fully understood systems. The proposed hypotheses point to the importance of the Cu(I)−disulfide interaction, which may have a profound impact on biological systems.

Centre of Experimental Medicine of Slovak Academy of Sciences Dúbravská cesta 9 841 04 Bratislava Slovakia

Department of Chemical Engineering Faculty of Chemical Engineering University of Chemistry and Technology Prague Technická 5 166 28 Praha 6 Czech Republic

Department of Physical and Theoretical Chemistry Faculty of Natural Sciences Comenius University Mlynská dolina Ilkovičova 6 842 15 Bratislava Slovakia

Global Change Research Institute Czech Academy of Sciences Bělidla 986 4a 603 00 Brno Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo náměstí 542 2 160 00 Praha 6 Czech Republic

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Pfaff A.R., Beltz J., King E., Ercal N. Medicinal thiols: Current status and new perspectives. Mini-Rev. Med. Chem. 2020;20:513–529. doi: 10.2174/1389557519666191119144100. PubMed DOI PMC

Samuni Y., Goldstein S., Dean O.M., Berk M. The chemistry and biological activities of N-acetylcysteine. Biochim. Biophys. Acta-Gen. Subj. 2013;1830:4117–4129. doi: 10.1016/j.bbagen.2013.04.016. PubMed DOI

Dhouib I.E., Jallouli M., Annabi A., Gharbi N., Elfazaa S., Lasram M.M. A minireview on N-acetylcysteine: An old drug with new approaches. Life Sci. 2016;151:359–363. doi: 10.1016/j.lfs.2016.03.003. PubMed DOI

Zheng J., Lou J.R., Zhang X.-X., Benbrook D.M., Hanigan M.H., Lind S.E., Ding W.-Q. N-Acetylcysteine interacts with copper to generate hydrogen peroxide and selectively induce cancer cell death. Cancer Lett. 2010;298:186–194. doi: 10.1016/j.canlet.2010.07.003. PubMed DOI PMC

Valachova K., Juranek I., Rapta P., Valent I., Soltes L. On infusion of high-dose ascorbate in treating cancer: Is it time for N-acetylcysteine pretreatment to enhance susceptibility and to lower side effects? Med. Hypotheses. 2019;122:8–9. doi: 10.1016/j.mehy.2018.10.006. PubMed DOI

Mlejnek P., Dolezel P., Maier V., Kikalova K., Skoupa N. N-Acetylcysteine dual and antagonistic effect on cadmium cytotoxicity in human leukemia cells. Environ. Toxicol. Pharmacol. 2019;71:103213. doi: 10.1016/j.etap.2019.103213. PubMed DOI

Amini A., Masoumi-Moghaddam S., Morris D.L. Utility of Bromelain and N-Acetylcysteine in Treatment of Peritoneal Dissemination of Gastrointestinal Mucin-Producing Malignancies. Springer International Publishing; Cham, Switzerland: 2016.

Pedre B., Barayeu U., Ezerina D., Dick T.P. The mechanism of action of N-acetylcysteine (NAC): The emerging role of H2S and sulfane sulfur species. Pharmacol. Ther. 2021;228:107916. doi: 10.1016/j.pharmthera.2021.107916. PubMed DOI

Aldini G., Altomare A., Baron G., Vistoli G., Carini M., Borsani L., Sergio F. N-Acetylcysteine as an antioxidant and disulphide breaking agent: The reasons why. Free Radic. Res. 2018;52:751–762. doi: 10.1080/10715762.2018.1468564. PubMed DOI

Aruoma O., Halliwell B., Hoey B., Butler J. The antioxidant action of N-acetylcysteine—Its reaction with hydrogen-peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic. Biol. Med. 1989;6:593–597. doi: 10.1016/0891-5849(89)90066-X. PubMed DOI

Ezerina D., Takano Y., Hanaoka K., Urano Y., Dick T.P. N-Acetyl cysteine functions as a fast-acting antioxidant by triggering intracellular HS and sulfane sulfur production. Cell Chem. Biol. 2018;25:447. doi: 10.1016/j.chembiol.2018.01.011. PubMed DOI PMC

Sprong R., Winkelhuyzen-Janssen A., Aarsman C., van Oirschot J., van der Bruggen T., van Asbeck B. Low-dose N-acetylcysteine protects rats against endotoxin-mediated oxidative stress, but high-dose increases mortality. Am. J. Respir. Crit. Care Med. 1998;157:1283–1293. doi: 10.1164/ajrccm.157.4.9508063. PubMed DOI

Oikawa S., Yamada K., Yamashita N., Tada-Oikawa S., Kawanishi S. N-acetylcysteine, a cancer chemopreventive agent, causes oxidative damage to cellular and isolated DNA. Carcinogenesis. 1999;20:1485–1490. doi: 10.1093/carcin/20.8.1485. PubMed DOI

Childs A., Jacobs C., Kaminski T., Halliwell B., Leeuwenburgh C. Supplementation with vitamin C and N-acetyl-cysteine increases oxidative stress in humans after an acute muscle injury induced by eccentric exercise. Free Radic. Biol. Med. 2001;31:745–753. doi: 10.1016/S0891-5849(01)00640-2. PubMed DOI

Sagrista M., Garcia A., De Madariaga M., Mora M. Antioxidant and pro-oxidant effect of the thiolic compounds N-acetyl-l-cysteine and glutathione against free radical-induced lipid peroxidation. Free Radic. Res. 2002;36:329–340. doi: 10.1080/10715760290019354. PubMed DOI

Saez G., Thornalley P., Hill H., Hems R., Bannister J. The production of free-radicals during the autoxidation of cysteine and their effect on isolated rat hepatocytes. Biochim. Biophys. Acta. 1982;719:24–31. doi: 10.1016/0304-4165(82)90302-6. PubMed DOI

Vansteveninck J., Vanderzee J., Dubbelman T. Site-specific and bulk-phase generation of hydroxyl radicals in the presence of cupric ions and thiol compounds. Biochem. J. 1985;232:309–311. doi: 10.1042/bj2320309. PubMed DOI PMC

Kachur A., Koch C., Biaglow J. Mechanism of copper-catalyzed autoxidation of cysteine. Free Radic. Res. 1999;31:23–34. doi: 10.1080/10715769900300571. PubMed DOI

Burkitt M. A critical overview of the chemistry of copper-dependent low density lipoprotein oxidation: Roles of lipid hydroperoxides, alpha-tocopherol, thiols, and ceruloplasmin. Arch. Biochem. Biophys. 2001;394:117–135. doi: 10.1006/abbi.2001.2509. PubMed DOI

Wu M.-S., Lien G.-S., Shen S.-C., Yang L.-Y., Chen Y.-C. N-acetyl-l-cysteine enhances fisetin-induced cytotoxicity via induction of ROS-independent apoptosis in human colonic cancer cells. Mol. Carcinog. 2014;53:E119–E129. doi: 10.1002/mc.22053. PubMed DOI

Qanungo S., Wang M., Nieminen A. N-acetyl-L-cysteine enhances apoptosis through inhibition of nuclear factor-kappa B in hypoxic murine embryonic fibroblasts. J. Biol. Chem. 2004;279:50455–50464. doi: 10.1074/jbc.M406749200. PubMed DOI

Rakshit S., Bagchi J., Mandal L., Paul K., Ganguly D., Bhattacharjee S., Ghosh M., Biswas N., Chaudhuri U., Bandyopadhyay S. N-Acetyl cysteine enhances imatinib-induced apoptosis of Bcr-Abl(+) cells by endothelial nitric oxide synthase-mediated production of nitric oxide. Apoptosis. 2009;14:298–308. doi: 10.1007/s10495-008-0305-7. PubMed DOI

Andreou A., Trantza S., Filippou D., Sipsas N., Tsiodras S. COVID-19: The potential role of copper and N-acetylcysteine (NAC) in a combination of candidate antiviral treatments against SARS-COV-2. In Vivo. 2020;34:1567–1588. doi: 10.21873/invivo.11946. PubMed DOI PMC

Mathews A., Walker S. The action of metals and strong salt solutions on the spontaneous oxidation of cystein. J. Biol. Chem. 1909;6:299–312. doi: 10.1016/S0021-9258(18)91608-X. DOI

Harrison D. The catalytic action of traces of iron and copper on the anaerobic oxidation of sulphydryl compounds. Biochem. J. 1927;21:335–346. doi: 10.1042/bj0210335. PubMed DOI PMC

Stricks W., Kolthoff I. Polarographic investigations of reactions in aqueous solutions containing copper and cysteine (cystine). 1. Cuprous copper and cysteine in ammoniacal medium—The dissociation constant of cuprous cysteinate. J. Am. Chem. Soc. 1951;73:1723–1727. doi: 10.1021/ja01148a087. DOI

Klotz I., Czerlinski G., Fiess H. A mixed-valence copper complex with thiol compounds. J. Am. Chem. Soc. 1958;80:2920–2923. doi: 10.1021/ja01545a002. DOI

Hemmerich P., Beinert H., Vanngard T. Complex formation between copper and organic disulfides. Angew. Chem. Int. Ed. 1966;5:422–423. doi: 10.1002/anie.196604222. DOI

Cavallini D., Demarco C., Dupre S., Rotilio G. Copper catalyzed oxidation of cysteine to cystine. Arch. Biochem. Biophys. 1969;130:354–361. doi: 10.1016/0003-9861(69)90044-7. PubMed DOI

Peisach J., Blumberg W. A mechanism for action of penicillamine in treatment of Wilsons disease. Mol. Pharmacol. 1969;5:200–209. PubMed

Hanaki A., Kamide H. Autoxidation of cysteine catalyzed by copper in glycylglycine buffer. Chem. Pharm. Bull. 1975;23:1671–1676. doi: 10.1248/cpb.23.1671. PubMed DOI

Vortisch V., Kroneck P., Hemmerich P. Model studies on coordination of copper in enzymes. 4. Structure and stability of cuprous complexes with sulfur-containing ligands. J. Am. Chem. Soc. 1976;98:2821–2826. doi: 10.1021/ja00426a025. DOI

Birker P., Freeman H. Structure, properties, and function of a copper(I)-copper(II) complex of D-penicillamine–pentathallium(I) μ8-chloro-dodeca(D-penicillaminato)-octacuprate(I)hexacuprate(II) normal-hydrate. J. Am. Chem. Soc. 1977;99:6890–6899. doi: 10.1021/ja00463a019. PubMed DOI

Lappin A., Mcauley A. Reactions between copper(II) and 2-mercaptosuccinic acid in aqueous perchlorate solution. J. Chem. Soc.-Dalton Trans. 1978:1606–1609. doi: 10.1039/dt9780001606. DOI

Zwart J., Vanwolput J., Koningsberger D. The mechanism of the copper-ion catalyzed autoxidation of cysteine in alkaline-medium. J. Mol. Catal. 1981;12:85–101. doi: 10.1016/0304-5102(81)80021-1. DOI

Pecci L., Montefoschi G., Musci G., Cavallini D. Novel findings on the copper catalysed oxidation of cysteine. Amino Acids. 1997;13:355–367. doi: 10.1007/BF01372599. DOI

Gilbert B., Silvester S., Walton P. Spectroscopic, kinetic and mechanistic studies of the influence of ligand and substrate concentration on the activation by peroxides of CuI-thiolate and other CuI complexes. J. Chem. Soc.-Perkin Trans. 2. 1999:1115–1121. doi: 10.1039/a901179j. DOI

Itoh S., Nagagawa M., Fukuzumi S. Fine tuning of the interaction between the copper(I) and disulfide bond. Formation of a bis(mu-thiolato)dicopper(II) complex by reductive cleavage of the disulfide bond with copper(I) J. Am. Chem. Soc. 2001;123:4087–4088. doi: 10.1021/ja0157200. PubMed DOI

Rigo A., Corazza A., di Paolo M., Rossetto M., Ugolini R., Scarpa M. Interaction of copper with cysteine: Stability of cuprous complexes and catalytic role of cupric ions in anaerobic thiol oxidation. J. Inorg. Biochem. 2004;98:1495–1501. doi: 10.1016/j.jinorgbio.2004.06.008. PubMed DOI

Seko H., Tsuge K., Igashira-Kamiyama A., Kawamoto T., Konno T. Autoxidation of thiol-containing amino acid to its disulfide derivative that links two copper(II) centers: The important role of auxiliary ligand. Chem. Commun. 2010;46:1962–1964. doi: 10.1039/B913989C. PubMed DOI

Ording-Wenker E.C.M., Siegler M.A., Lutz M., Bouwman E. Catalytic catechol oxidation by copper complexes: Development of a structure-activity relationship. Dalton Trans. 2015;44:12196–12209. doi: 10.1039/C5DT01041A. PubMed DOI

Buzuk M., Brinic S., Vladislavic N., Bralic M., Buljac M., Roncevic I.S. Real-time monitoring of “self-oxidation” of cysteine in presence of Cu2+: Novel findings in the oxidation mechanism. Mon. Chem. 2016;147:359–367. doi: 10.1007/s00706-015-1577-6. DOI

Ngamchuea K., Batchelor-McAuley C., Compton R.G. The copper(II)-catalyzed oxidation of glutathione. Chem.-Eur. J. 2016;22:15937–15944. doi: 10.1002/chem.201603366. PubMed DOI

Maiti B.K., Maia L.B., Moro A.J., Lima J.C., Cordas C.M., Moura I., Mourer J.J.G. Unusual reduction mechanism of copper in cysteine-rich environment. Inorg. Chem. 2018;57:8078–8088. doi: 10.1021/acs.inorgchem.8b00121. PubMed DOI

Cook A.W., Jones Z.R., Wu G., Teat S.J., Scott S.L., Hayton T.W. Synthesis and characterization of “atlas-sphere” copper nanoclusters: New insights into the reaction of Cu2+ with thiols. Inorg. Chem. 2019;58:8739–8749. doi: 10.1021/acs.inorgchem.9b01140. PubMed DOI

Hu Z.-E., Li J., Wu Z.-N., Wei Y.-J., Liu Y.-H., Wang N., Yu X.-Q. One-pot synthesis-biocompatible copper-tripeptide complex as a nanocatalytic medicine to enhance chemodynamic therapy. ACS Biomater. Sci. Eng. 2021;7:1394–1402. doi: 10.1021/acsbiomaterials.0c01678. PubMed DOI

Ehrenberg L., Harmsringdahl M., Fedorcsak I., Granath F. Kinetics of the copper-catalyzed and iron-catalyzed oxidation of cysteine by dioxygen. Acta Chem. Scand. 1989;43:177–187. doi: 10.3891/acta.chem.scand.43-0177. DOI

Zanzen U., Bovenkamp-Langlois L., Klysubun W., Hormes J., Prange A. The interaction of copper ions with Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli: An X-ray absorption near-edge structure (XANES) spectroscopy study. Arch. Microbiol. 2018;200:401–412. doi: 10.1007/s00203-017-1454-2. PubMed DOI

Macomber L., Rensing C., Imlay J.A. Intracellular copper does not catalyze the formation of oxidative DNA damage in Escherichia coli. J. Bacteriol. 2007;189:1616–1626. doi: 10.1128/JB.01357-06. PubMed DOI PMC

Milne L., Nicotera P., Orrenius S., Burkitt M. Effects of glutathione and chelating-agents on copper-mediated DNA oxidation—Prooxidant and antioxidant properties of glutathione. Arch. Biochem. Biophys. 1993;304:102–109. doi: 10.1006/abbi.1993.1327. PubMed DOI

Pham A.N., Xing G., Miller C.J., Waite T.D. Fenton-like copper redox chemistry revisited: Hydrogen peroxide and superoxide mediation of copper-catalyzed oxidant production. J. Catal. 2013;301:54–64. doi: 10.1016/j.jcat.2013.01.025. DOI

Valent I., Topolska D., Valachova K., Bujdak J., Soltes L. Kinetics of ABTS derived radical cation scavenging by bucillamine, cysteine, and glutathione. Catalytic effect of Cu2+ ions. Biophys. Chem. 2016;212:9–16. doi: 10.1016/j.bpc.2016.02.006. PubMed DOI

Inoue Y. Asymmetric photochemical-reactions in solution. Chem. Rev. 1992;92:741–770. doi: 10.1021/cr00013a001. DOI

Harada N., Nakanishi K. Circular Dichroic Spectroscopy: Exciton Coupling in Organic Stereochemistry. University Science Books; Mill Valley, CA, USA: 1983.

Scott S., Chen W., Bakac A., Espenson J. Spectroscopic parameters, electrode-potentials, acid ionization-constants, and electron-exchange rates of the 2,2’-azinobis(3-ethylbenzothiazoline-6-sulfonate) radicals and ions. J. Phys. Chem. 1993;97:6710–6714. doi: 10.1021/j100127a022. DOI

Packer J. The radiation chemistry of thiols. In: Patai S., editor. The Chemistry of the Thiol Group, Part 2. Wiley; London, UK: 1974. pp. 481–517.

Bagiyan G., Koroleva I., Soroka N. Formation conditions of mononuclear copper(I) complexes with aminothiols. Zhurnal Neorg. Khimii. 1978;23:416–424.

Hanaki A. Interaction of biologically relevant Cu(II)-peptide and cysteine—Transient complexes with Cu(II)N3S and Cu(II)N2S2 chromophores. Chem. Lett. 1980;9:629–630. doi: 10.1246/cl.1980.629. DOI

Mezyk S., Armstrong D. Kinetics of oxidation of Cu(I) complexes of cysteine and penicillamine—Nature of intermediates and reactants at pH 10.0. Can. J. Chem.-Rev. Can. Chim. 1989;67:736–745. doi: 10.1139/v89-112. DOI

Wilson E., Martin R. Penicillamine deprotonations and interactions with copper ions. Arch. Biochem. Biophys. 1971;142:445–454. doi: 10.1016/0003-9861(71)90508-X. PubMed DOI

Demarco C., Dupre S., Crifo C., Rotilio G., Cavallini D. Copper-catalyzed oxidation of thiomalic acid. Arch. Biochem. Biophys. 1971;144:496–502. doi: 10.1016/0003-9861(71)90354-7. PubMed DOI

Hanaki A., Funahashi Y., Odani A. Ternary Cu(II) complexes, Cu(H-1L)(ACys(-)) and Cu(H-2L)(ACys(-)); L = peptides, ACys(-) = N-acetyl-cysteinate. Analogous complexes to the intermediates in the transport of Cu(II) from Cu(H-2L) to cysteine. J. Inorg. Biochem. 2006;100:305–315. doi: 10.1016/j.jinorgbio.2005.11.017. PubMed DOI

Sharma R., Pal M., Mishra K.K. Entropy-controlled Cu(II)-catalyzed oxidation of N-acetyl-l-cysteine by methylene blue in acidic medium. Z. Phys. Chem. 2017;231:1093–1109. doi: 10.1515/zpch-2016-0853. DOI

Morgan M.T., Nguyen L.A.H., Hancock H.L., Fahrni C.J. Glutathione limits aquacopper(I) to sub-femtomolar concentrations through cooperative assembly of a tetranuclear cluster. J. Biol. Chem. 2017;292:21558–21567. doi: 10.1074/jbc.M117.817452. PubMed DOI PMC

Amundsen A., Whelan J., Bosnich B. Biological analogs—Nature of binding-sites of copper-containing proteins. J. Am. Chem. Soc. 1977;99:6730–6739. doi: 10.1021/ja00462a042. PubMed DOI

Solomon E.I. Spectroscopic methods in bioinorganic chemistry: Blue to green to red copper sites. Inorg. Chem. 2006;45:8012–8025. doi: 10.1021/ic060450d. PubMed DOI

Sakurai H., Yokoyama A., Tanaka H. Studies on the sulfur-containing chelating agents. XXIX. Reaction of cysteamine and its related compounds with copper. Chem. Pharm. Bull. 1970;18:2373–2385. doi: 10.1248/cpb.18.2373. DOI

Graf L., Fallab S. Zum reaktionsmechanismus von oxydasen. Experientia. 1964;20:46–47. doi: 10.1007/BF02146037. PubMed DOI

Blumberg W., Peisach J. Bis(thiosemicarbazone) and other nitrogen and sulfur ligated complexes of copper(2) J. Chem. Phys. 1968;49:1793–1802. doi: 10.1063/1.1670309. DOI

Bagiyan G., Koroleva I., Soroka N., Ufimtsev A. Kinetics of the catalytic oxidation reactions of thiol compounds in aqueous solutions in the presence of copper ions. Kinet. Catal. 2004;45:372–380. doi: 10.1023/B:KICA.0000032171.81652.91. DOI

Davis F., Gilbert B., Norman R., Symons M. Electron-spin resonance studies. 66. Characterization of copper(II) complexes in the oxidation of D-penicillamine, L-cysteine, and related sulfur-containing-compounds. J. Chem. Soc.-Perkin Trans. 2. 1983:1763–1771. doi: 10.1039/p29830001763. DOI

Hanaki A. Kinetic-studies on the role of dioxygen in the copper-catalyzed autoxidation of cysteine. Bull. Chem. Soc. Jpn. 1995;68:831–837. doi: 10.1246/bcsj.68.831. DOI

Eigen M., Wilkins R. Mechanisms of inorganic reactions. Adv. Chem. Ser. 1965;49:55.

Pasquarello A., Petri I., Salmon P., Parisel O., Car R., Toth E., Powell D., Fischer H., Helm L., Merbach A. First solvation shell of the Cu(II) aqua ion: Evidence for fivefold coordination. Science. 2001;291:856–859. doi: 10.1126/science.291.5505.856. PubMed DOI

Ottersen T., Warner L., Seff K. Synthesis and crystal-structure of a dimeric cyclic copper(I)-aliphatic disulfide complex—Cyclo-di-mu-bis[2-(N,N-dimethylamino)ethyl] disulfide-dicopper(I) tetrafluoroborate. Inorg. Chem. 1974;13:1904–1911. doi: 10.1021/ic50138a023. DOI

Warner L., Ottersen T., Seff K. Synthesis and crystal-structure of a polymeric copper(I) aliphatic disulfide complex—(bis[2-(2-pyridyl)ethyl] disulfide)copper(I) perchlorate. Inorg. Chem. 1974;13:2819–2826. doi: 10.1021/ic50142a012. DOI

Ohta T., Tachiyama T., Yoshizawa K., Yamabe T., Uchida T., Kitagawa T. Synthesis, structure, and H2O2-dependent catalytic functions of disulfide-bridged dicopper(I) and related thioether-copper(I) and thioether-copper(II) complexes. Inorg. Chem. 2000;39:4358–4369. doi: 10.1021/ic000018a. PubMed DOI

Neuba A., Haase R., Meyer-Klaucke W., Floerke U., Henkel G. A halide-induced copper(I) disulfide/copper(II) thiolate interconversion. Angew. Chem. Int. Ed. 2012;51:1714–1718. doi: 10.1002/anie.201102714. PubMed DOI

Ording-Wenker E.C.M., van der Plas M., Siegler M.A., Bonnet S., Bickelhaupt F.M., Guerra C.F., Bouwman E. Thermodynamics of the CuII μ-thiolate and CuI disulfide equilibrium: A combined experimental and theoretical study. Inorg. Chem. 2014;53:8494–8504. doi: 10.1021/ic501060w. PubMed DOI

Lee D.-H., Hatcher L.Q., Vance M.A., Sarangi R., Milligan A.E., Sarjeant A.A.N., Incarvito C.D., Rheingold A.L., Hodgson K.O., Hedman B., et al. Copper(I) complex O2-reactivity with a N3S thioether ligand: A copper-dioxygen adduct including sulfur ligation, ligand oxygenation, and comparisons with all nitrogen ligand analogues. Inorg. Chem. 2007;46:6056–6068. doi: 10.1021/ic700541k. PubMed DOI

Eickman N., Himmelwright R., Solomon E. Geometric and electronic-structure of oxyhemocyanin—Spectral and chemical correlations to met apo, half met, met, and dimer active-sites. Proc. Natl. Acad. Sci. USA. 1979;76:2094–2098. doi: 10.1073/pnas.76.5.2094. PubMed DOI PMC

Panijpan B. Chirality of disulfide bond in biomolecules. J. Chem. Educ. 1977;54:670–672. doi: 10.1021/ed054p670. DOI

Kuhn W. The physical significance of optical rotatory power. Trans. Faraday Soc. 1930;26:0293–0307. doi: 10.1039/tf9302600293. DOI

Wakabayashi M., Yokojima S., Fukaminato T., Shiino K., Irie M., Nakamura S. Anisotropic dissymmetry factor, g: Theoretical investigation on single molecule chiroptical spectroscopy. J. Phys. Chem. A. 2014;118:5046–5057. doi: 10.1021/jp409559t. PubMed DOI

Dixon M., Tunnicliffe H. The oxidation of reduced glutathione and other sulphydryl compounds. Proc. R. Soc. Lond. Ser. B. 1923;94:266–297. doi: 10.1098/rspb.1923.0005. DOI

Cavallini D., Demarco C., Dupre S. Luminol chemiluminescence studies of oxidation of cysteine and other thiols to disulfides. Arch. Biochem. Biophys. 1968;124:18–26. doi: 10.1016/0003-9861(68)90299-3. PubMed DOI

Elwell C.E., Gagnon N.L., Neisen B.D., Dhar D., Spaeth A.D., Yee G.M., Tolman W.B. Copper-oxygen complexes revisited: Structures, spectroscopy, and reactivity. Chem. Rev. 2017;117:2059–2107. doi: 10.1021/acs.chemrev.6b00636. PubMed DOI PMC

Koval I.A., Gamez P., Belle C., Selmeczi K., Reedijk J. Synthetic models of the active site of catechol oxidase: Mechanistic studies. Chem. Soc. Rev. 2006;35:814–840. doi: 10.1039/b516250p. PubMed DOI

Karlin K.D., Itoh S., Rokita S. Copper-Oxygen Chemistry. Wiley; Hoboken, NJ, USA: 2011. Wiley Series of Reactive Intermediates in Chemistry and Biology.

Solomon E.I., Heppner D.E., Johnston E.M., Ginsbach J.W., Cirera J., Qayyum M., Kieber-Emmons M.T., Kjaergaard C.H., Hadt R.G., Tian L. Copper active sites in biology. Chem. Rev. 2014;114:3659–3853. doi: 10.1021/cr400327t. PubMed DOI PMC

Kroneck P.M.H. Walking the seven lines: Binuclear copper A in cytochrome c oxidase and nitrous oxide reductase. J. Biol. Inorg. Chem. 2018;23:27–39. doi: 10.1007/s00775-017-1510-z. PubMed DOI

Lee Y., Lee D.-H., Sarjeant A.A.N., Karlin K.D. Thiol-copper(I) and disulfide-dicopper(I) complex O2-reactivity leading to sulfonate-copper(II) complex or the formation of a cross-linked thioether-phenol product with phenol addition. J. Inorg. Biochem. 2007;101:1845–1858. doi: 10.1016/j.jinorgbio.2007.06.016. PubMed DOI

Yamauchi O., Seki H. Dioxygen absorption by a 2-1 copper(II)-disulfide system—Partial incorporation of oxygen-atoms from dioxygen upon copper(II)-catalyzed disulfide bond-cleavage to sulfinate. Chem. Lett. 1982;11:1241–1244. doi: 10.1246/cl.1982.1241. DOI

Karlin K., Kaderli S., Zuberbuhler A. Kinetics and thermodynamics of copper(I)/dioxygen interaction. Acc. Chem. Res. 1997;30:139–147. doi: 10.1021/ar950257f. DOI

Naumova M., Khakhulin D., Rebarz M., Rohrmueller M., Dicke B., Biednov M., Britz A., Espinoza S., Grimm-Lebsanft B., Kloz M., et al. Structural dynamics upon photoexcitation-induced charge transfer in a dicopper(I)-disulfide complex. Phys. Chem. Chem. Phys. 2018;20:6274–6286. doi: 10.1039/C7CP04880G. PubMed DOI

Solomon E., Sundaram U., Machonkin T. Multicopper oxidases and oxygenases. Chem. Rev. 1996;96:2563–2605. doi: 10.1021/cr950046o. PubMed DOI

Solomon E.I., Augustine A.J., Yoon J. O2 Reduction to H2O by the multicopper oxidases. Dalton Trans. 2008;30:3921–3932. doi: 10.1039/b800799c. PubMed DOI PMC

Casuso P., Carrasco P., Loinaz I., Grande H.J., Odriozola I. Converting drugs into gelators: Supramolecular hydrogels from N-acetyl-l-cysteine and coinage-metal salts. Org. Biomol. Chem. 2010;8:5455–5458. doi: 10.1039/c0ob00311e. PubMed DOI

Ueno Y., Tachi Y., Itoh S. Interconversion between bis(μ-thiolato)dicopper(II) and disulfide-bridged dicopper(I) complexes mediated by chloride ion. J. Am. Chem. Soc. 2002;124:12428–12429. doi: 10.1021/ja027397m. PubMed DOI

Thomas A.M., Lin B.-L., Wasinger E.C., Stack T.D.P. Ligand noninnocence of thiolate/disulfide in dinuclear copper complexes: Solvent-dependent redox isomerization and proton-coupled electron transfer. J. Am. Chem. Soc. 2013;135:18912–18919. doi: 10.1021/ja409603m. PubMed DOI

Lee T., Notari R. Kinetics and mechanism of captopril oxidation in aqueous-solution under controlled oxygen partial-pressure. Pharm. Res. 1987;4:98–103. doi: 10.1023/A:1016406716989. PubMed DOI

Bagiyan G., Koroleva I., Soroka N., Ufimtsev A. Oxidation of thiol compounds by molecular oxygen in aqueous solutions. Russ. Chem. Bull. 2003;52:1135–1141. doi: 10.1023/A:1024761324710. DOI

Kachur A., Koch C., Biaglow J. Mechanism of copper-catalyzed oxidation of glutathione. Free Radic. Res. 1998;28:259–269. doi: 10.3109/10715769809069278. PubMed DOI

Soorkia S., Dehon C., Kumar S.S., Pedrazzani M., Frantzen E., Lucas B., Barat M., Fayeton J.A., Jouvet C. UV photofragmentation dynamics of protonated cystine: Disulfide bond rupture. J. Phys. Chem. Lett. 2014;5:1110–1116. doi: 10.1021/jz500158j. PubMed DOI

Dance I. Formation and X-ray structure of hexa(tert-butylthiolato)pentacuprate(I) monoanion. J. Chem. Soc.-Chem. Commun. 1976:68–69. doi: 10.1039/c39760000068. DOI

Blower P., Dilworth J. Thiolato-complexes of the transition-metals. Coord. Chem. Rev. 1987;76:121–185. doi: 10.1016/0010-8545(87)85003-8. DOI

Fujisawa K., Imai S., Kitajima N., Moro-oka Y. Preparation, spectroscopic, characterization, and molecular structure of copper(I) aliphatic thiolate complexes. Inorg. Chem. 1998;37:168–169. doi: 10.1021/ic971317b. DOI

Zeevi S., Tshuva E.Y. Synthesis and X-ray characterization of mono- and polynuclear thiolatocopper(I) complexes: The effect of steric bulk on coordination number and nuclearity. Eur. J. Inorg. Chem. 2007;2007:5369–5376. doi: 10.1002/ejic.200700710. DOI

Ferrara S.J., Mague J.T., Donahue J.P. Synthesis and structures of cuprous triptycylthiolate complexes. Inorg. Chem. 2012;51:6567–6576. doi: 10.1021/ic300124n. PubMed DOI

Yam V., Lam C., Fung W., Cheung K. Syntheses, photophysics, and photochemistry of trinuclear copper(I) thiolate and hexanuclear copper(I) selenolate complexes: X-ray crystal structures of [Cu6(µ-dppm)4(µ3-SePh)4](BF4)2 and [Cu6{µ-(Ph2P)2NH}4(µ3-SePh)4](BF4)2. Inorg. Chem. 2001;40:3435–3442. doi: 10.1021/ic0012322. PubMed DOI

Butler I., Schoonen M., Rickard D. Removal of dissolved-oxygen from water—A comparison of 4 common techniques. Talanta. 1994;41:211–215. doi: 10.1016/0039-9140(94)80110-X. PubMed DOI

Kizek R., Vacek J., Trnkova L., Jelen F. Cyclic voltammetric study of the redox system of glutathione using the disulfide bond reductant tris(2-carboxyethyl)phosphine. Bioelectrochemistry. 2004;63:19–24. doi: 10.1016/j.bioelechem.2003.12.001. PubMed DOI

Pountney D., Schauwecker I., Zarn J., Vasak M. Formation of mammalian Cu8-metallothionein in vitro: Evidence for the existence of 2 Cu(I)4-thiolate clusters. Biochemistry. 1994;33:9699–9705. doi: 10.1021/bi00198a040. PubMed DOI

Tarasava K., Loebus J., Freisinger E. Localization and spectroscopic analysis of the Cu(I) binding site in wheat metallothionein Ec-1. Int. J. Mol. Sci. 2016;17:371. doi: 10.3390/ijms17030371. PubMed DOI PMC

Ford P., Vogler A. Photochemical and photophysical properties of tetranuclear and hexanuclear clusters of metals with d10 and s2 electronic configurations. Acc. Chem. Res. 1993;26:220–226. doi: 10.1021/ar00028a013. DOI

Artells E., Palacios O., Capdevila M., Atrian S. In vivo-folded metal-metallothionein 3 complexes reveal the Cu-thionein rather than Zn-thionein character of this brain-specific mammalian metallothionein. FEBS J. 2014;281:1659–1678. doi: 10.1111/febs.12731. PubMed DOI

Scheller J.S., Irvine G.W., Wong D.L., Hartwig A., Stillman M.J. Stepwise copper(I) binding to metallothionein: A mixed cooperative and non-cooperative mechanism for all 20 copper ions. Metallomics. 2017;9:447–462. doi: 10.1039/C7MT00041C. PubMed DOI

Casas-Finet J., Hu S., Hamer D., Karpel R. Spectroscopic characterization of the copper(I)-thiolate cluster in the DNA-binding domain of yeast ACE1 transcription factor. FEBS Lett. 1991;281:205–208. doi: 10.1016/0014-5793(91)80394-I. PubMed DOI

Subedi P., Paxman J.J., Wang G., Ukuwela A.A., Xiao Z., Heras B. The Scs disulfide reductase system cooperates with the metallochaperone CueP in Salmonella copper resistance. J. Biol. Chem. 2019;294:15876–15888. doi: 10.1074/jbc.RA119.010164. PubMed DOI PMC

Yoon B.-Y., Yeom J.-H., Kim J.-S., Um S.-H., Jo I., Lee K., Kim Y.-H., Ha N.-C. Direct ROS scavenging activity of CueP from Salmonella enterica serovar Typhimurium. Mol. Cells. 2014;37:100–108. doi: 10.14348/molcells.2014.2238. PubMed DOI PMC

Goebl C., Morris V.K., van Dam L., Visscher M., Polderman P.E., Hartlmueller C., de Ruiter H., Hora M., Liesinger L., Birner-Gruenberger R., et al. Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A. Redox Biol. 2020;28:101316. doi: 10.1016/j.redox.2019.101316. PubMed DOI PMC

Werner T.E.R., Bernson D., Esbjoerner E.K., Rocha S., Wittung-Stafshede P. Amyloid formation of fish beta-parvalbumin involves primary nucleation triggered by disulfide-bridged protein dimers. Proc. Natl. Acad. Sci. USA. 2020;117:27997–28004. doi: 10.1073/pnas.2015503117. PubMed DOI PMC

Morgada M.N., Abriata L.A., Cefaro C., Gajda K., Banci L., Vila A.J. Loop recognition and copper-mediated disulfide reduction underpin metal site assembly of Cu-A in human cytochrome oxidase. Proc. Natl. Acad. Sci. USA. 2015;112:11771–11776. doi: 10.1073/pnas.1505056112. PubMed DOI PMC

Osterberg R., Ligaarden R., Persson D. Copper(I) complexes of penicillamine and glutathione. J. Inorg. Biochem. 1979;10:341–355. doi: 10.1016/S0162-0134(00)80200-7. PubMed DOI

Corazza A., Harvey I., Sadler P. H-1,C-13-NMR and X-ray absorption studies of copper(I) glutathione complexes. Eur. J. Biochem. 1996;236:697–705. doi: 10.1111/j.1432-1033.1996.0697d.x. PubMed DOI

Koenigsberger L.-C., Koenigsberger E., Hefter G., May P.M. Formation constants of copper(I) complexes with cysteine, penicillamine and glutathione: Implications for copper speciation in the human eye. Dalton Trans. 2015;44:20413–20425. doi: 10.1039/C5DT02129D. PubMed DOI

Kroneck P. Models for electron-paramagnetic resonance nondetectable copper in blue oxidases—Binuclear copper(II) complex with oxidized glutathione. J. Am. Chem. Soc. 1975;97:3839–3841. doi: 10.1021/ja00846a059. PubMed DOI

Miyoshi K., Sugiura Y., Ishizu K., Iitaka Y., Nakamura H. Crystal-structure and spectroscopic properties of violet glutathione-copper(II) complex with axial sulfur coordination and 2 copper sites via a disulfide bridge. J. Am. Chem. Soc. 1980;102:6130–6136. doi: 10.1021/ja00539a027. DOI

Huet J., Jouini M., Abello L., Lapluye G. Structural study of copper oligopeptide complexes. 1. Oxidized glutathione Cu(II) system. J. Chim. Phys. - Chim. Biol. 1984;81:505–511. doi: 10.1051/jcp/1984810505. DOI

Pedersen J., Steinkuhler C., Weser U., Rotilio G. Copper-glutathione complexes under physiological conditions: Structures in solution different from the solid state coordination. Biometals. 1996;9:3–9. doi: 10.1007/BF00188083. PubMed DOI

Shtyrlin V., Zyavkina Y., Ilakin V., Garipov R., Zakharov A. Structure, stability, and ligand exchange of copper(II) complexes with oxidized glutathione. J. Inorg. Biochem. 2005;99:1335–1346. doi: 10.1016/j.jinorgbio.2005.03.008. PubMed DOI

Burkitt M., Duncan J. Effects of trans-resveratrol on copper-dependent hydroxyl-radical formation and DNA damage: Evidence for hydroxyl-radical scavenging and a novel, glutathione-sparing mechanism of action. Arch. Biochem. Biophys. 2000;381:253–263. doi: 10.1006/abbi.2000.1973. PubMed DOI

Hrabarova E., Valachova K., Rychly J., Rapta P., Sasinkova V., Malikova M., Soltes L. High-molar-mass hyaluronan degradation by Weissberger’s system: Pro- and anti-oxidative effects of some thiol compounds. Polym. Degrad. Stabil. 2009;94:1867–1875. doi: 10.1016/j.polymdegradstab.2009.05.007. DOI

Aliaga M.E., Lopez-Alarcon C., Garcia-Rio L., Martin-Pastor M., Speisky H. Redox-changes associated with the glutathione-dependent ability of the Cu(II)-GSSG complex to generate superoxide. Bioorg. Med. Chem. 2012;20:2869–2876. doi: 10.1016/j.bmc.2012.03.027. PubMed DOI