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Chemical Compound Review

AG-G-44657     2-(3,5- dimethylphenyl)disulfanyl- 1,4...

Synonyms: AC1Q7EAL, CTK5C2164, AR-1D4474, AC1L2UC5, A835729, ...
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Disease relevance of Disulfides


Psychiatry related information on Disulfides

  • The cleavage of inter-chain disulfides of both Id and anti-Id caused the predominant generation of cyclic dimers at the expense of larger aggregates, suggesting with regard to already published data that the hinge located interheavy-chain disulfides are essential for the strain [6].

High impact information on Disulfides

  • Disulfides generated de novo within Ero1p are transferred to protein disulfide isomerase and then to substrate proteins by dithiol-disulfide exchange reactions [7].
  • FTR, the key electron/thiol transducer enzyme in this pathway, is unique in that it can reduce disulfides by an iron-sulfur cluster, a property that is explained by the tight contact of its active-site disulfide and the iron-sulfur center [8].
  • Mixed disulfides can also be detected between PDI and the ER precursor of carboxypeptidase Y (CPY) [9].
  • The results provide strong support for the hypothesis that protein disulfides can be reduced during physiologic antigen processing [10].
  • These results lead us to suggest that the formation of intramolecular disulfides during early biogenesis serves to prevent nonspecific associations between nascent polypeptides [11].

Chemical compound and disease context of Disulfides


Biological context of Disulfides

  • These disulfides, which in protein mutagenesis experiments were shown to be essential for the associated peptidyl-prolyl isomerase activity, are unique to chloroplast FKBPs and are absent in animal and yeast counterparts [16].
  • The molecular conformation is determined by four disulfides in the head and one at the tip of the long loop, by a triple-stranded beta-pleated sheet involving this loop, and by hydrophobic interactions stabilizing the other two loops [17].
  • The widely touted analytical figures of merit for FTMS in fact have translated into clarity when analyzing PTMs from phosphorylations to disulfides, oxidations, methylations, acetylations, and even exotic PTMs found in the biosynthesis of antibiotics and other natural products [18].
  • In contrast to changes characteristic of oxidative stress, the efflux of glutathione in bile from diabetic animals was significantly decreased, whereas hepatic mixed disulfides were unchanged, and the hepatic gamma-glutamyltransferase activity was considerably increased [19].
  • The kinetics of precipitation fits the empirical equation 1n(t2/t1) = nù(c1/c2), where t is the time to reach half-maximum turbidity for concentration c. The effect of mild reduction of interchain disulfides on the kinetics and extent of precipitation have also been determined [20].

Anatomical context of Disulfides

  • Generating disulfides enzymatically: reaction products and electron acceptors of the endoplasmic reticulum thiol oxidase Ero1p [21].
  • In addition, the monoamines induced an elevation in protein mixed disulfides within mitochondria [22].
  • To identify proteins undergoing glutathionylation (formation of protein-glutathione mixed disulfides) in human T cell blasts, we radiolabeled the glutathione pool with (35)S, exposed cells to the oxidant diamide, and analyzed cellular proteins by two-dimensional electrophoresis [23].
  • In marine-archaeological oak timbers of the Mary Rose large amounts of reduced sulfur compounds abound in lignin-rich parts such as the middle lamella between the cell walls, mostly as thiols and disulfides, whereas iron sulfides and elemental sulfur occur in separate particles [24].
  • Thus, GDCF and MDNCF have a similar gross secondary structure because of the loops formed by the clustered disulfides, and their different leukocyte specificities are most likely determined by the large differences in primary sequence [25].

Associations of Disulfides with other chemical compounds

  • Formation of mixed disulfides between glutathione and the cysteines of some proteins (glutathionylation) has been suggested as a mechanism through which protein functions can be regulated by the redox status [26].
  • Once formed, disulfides between the transmembrane regions are unusually resistant to reduction by low molecular weight thiols in the presence of denaturants like SDS [27].
  • NAC pretreatment augmented integrin alpha-4-dependent fibronectin adhesion and aggregation of Jurkat cells without changing its expression by fluorescence-activated cell sorter, suggesting that reduction of surface disulfides can affect proteins function [28].
  • The concentrations of methanethiol-mixed disulfides were substantially lower than those previously observed in healthy subjects after an oral methionine load or in a patient with a deficiency in methionine adenosyltransferase, the latter without causing encephalopathy [5].
  • Here, we present evidence indicating that subsequent reduction of surface protein disulfides with N-acetyl-L-cysteine (NAC) further augments the immunogenic potential of PCL-modified tumor cells both in vitro and in vivo [29].

Gene context of Disulfides

  • Herein we demonstrate that nitric oxide and other thiol oxidants can inhibit the autokinase activity of rat JAK2 in vitro, presumably through oxidation of crucial dithiols to disulfides within JAK2 [30].
  • A thiol/disulfide oxidoreductase component of the GSH system, glutaredoxin (Grx), is involved in the reduction of GSH-based mixed disulfides and participates in a variety of cellular redox pathways [31].
  • Thus, Grx1 and Grx2 function differently in the cell, and we suggest that glutaredoxins may act as one of the primary defenses against mixed disulfides formed following oxidative damage to proteins [32].
  • Acute cadmium exposure inactivates thioltransferase (Glutaredoxin), inhibits intracellular reduction of protein-glutathionyl-mixed disulfides, and initiates apoptosis [33].
  • Mutation of the 3 cysteine residues allowed DmGCLM to associate with DmGCLC, but inhibited the formation of intersubunit disulfides [34].

Analytical, diagnostic and therapeutic context of Disulfides


  1. Examination of calf prochymosin accumulation in Escherichia coli: disulphide linkages are a structural component of prochymosin-containing inclusion bodies. Schoemaker, J.M., Brasnett, A.H., Marston, F.A. EMBO J. (1985) [Pubmed]
  2. Inhibition of human immunodeficiency virus infection by agents that interfere with thiol-disulfide interchange upon virus-receptor interaction. Ryser, H.J., Levy, E.M., Mandel, R., DiSciullo, G.J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  3. Methanethiol metabolism and its role in the pathogenesis of hepatic encephalopathy in rats and dogs. Blom, H.J., Chamuleau, R.A., Rothuizen, J., Deutz, N.E., Tangerman, A. Hepatology (1990) [Pubmed]
  4. Sulfhydryl group quantitation of hepatoma and liver microsomal fractions. Stratman, F.W., Hochberg, A.A., Zahlten, R.N., Morris, H.P. Cancer Res. (1975) [Pubmed]
  5. The role of methanethiol in the pathogenesis of hepatic encephalopathy. Blom, H.J., Ferenci, P., Grimm, G., Yap, S.H., Tangerman, A. Hepatology (1991) [Pubmed]
  6. Physiochemical features of monoclonal idiotype-anti-idiotype complexes: importance of inter-chain disulfides for size distribution patterns and molecular geometries. Gronski, P., Bauer, R., Bodenbender, L., Boland, P., Engel, J., Harthus, H.P., Kanzy, E.J., Walter, G., Zilg, H., Seiler, F.R. Behring Inst. Mitt. (1990) [Pubmed]
  7. Structure of Ero1p, source of disulfide bonds for oxidative protein folding in the cell. Gross, E., Kastner, D.B., Kaiser, C.A., Fass, D. Cell (2004) [Pubmed]
  8. Redox signaling in chloroplasts: cleavage of disulfides by an iron-sulfur cluster. Dai, S., Schwendtmayer, C., Schürmann, P., Ramaswamy, S., Eklund, H. Science (2000) [Pubmed]
  9. Ero1p oxidizes protein disulfide isomerase in a pathway for disulfide bond formation in the endoplasmic reticulum. Frand, A.R., Kaiser, C.A. Mol. Cell (1999) [Pubmed]
  10. Reduction of disulfide bonds during antigen processing: evidence from a thiol-dependent insulin determinant. Jensen, P.E. J. Exp. Med. (1991) [Pubmed]
  11. Early disulfide bond formation prevents heterotypic aggregation of membrane proteins in a cell-free translation system. Yilla, M., Doyle, D., Sawyer, J.T. J. Cell Biol. (1992) [Pubmed]
  12. The use of cysteinyl peptides to effect portage transport of sulfhydryl-containing compounds in Escherichia coli. Boehm, J.C., Kingsbury, W.D., Perry, D., Gilvarg, C. J. Biol. Chem. (1983) [Pubmed]
  13. Protein disulfide-isomerase is a substrate for thioredoxin reductase and has thioredoxin-like activity. Lundström, J., Holmgren, A. J. Biol. Chem. (1990) [Pubmed]
  14. The autotrophic pathway of acetogenic bacteria. Role of CO dehydrogenase disulfide reductase. Pezacka, E., Wood, H.G. J. Biol. Chem. (1986) [Pubmed]
  15. Identification of an NADH-linked disulfide reductase from Bacillus megaterium specific for disulfides containing pantethine 4',4''-diphosphate moieties. Swerdlow, R.D., Green, C.L., Setlow, B., Setlow, P. J. Biol. Chem. (1979) [Pubmed]
  16. Structural analysis uncovers a role for redox in regulating FKBP13, an immunophilin of the chloroplast thylakoid lumen. Gopalan, G., He, Z., Balmer, Y., Romano, P., Gupta, R., Héroux, A., Buchanan, B.B., Swaminathan, K., Luan, S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  17. Three-dimensional structure of the "long" neurotoxin from cobra venom. Walkinshaw, M.D., Saenger, W., Maelicke, A. Proc. Natl. Acad. Sci. U.S.A. (1980) [Pubmed]
  18. Detection and localization of protein modifications by high resolution tandem mass spectrometry. Meng, F., Forbes, A.J., Miller, L.M., Kelleher, N.L. Mass spectrometry reviews. (2005) [Pubmed]
  19. Changes in hepatic glutathione metabolism in diabetes. McLennan, S.V., Heffernan, S., Wright, L., Rae, C., Fisher, E., Yue, D.K., Turtle, J.R. Diabetes (1991) [Pubmed]
  20. Study of the kinetic and structural properties of a monoclonal immunoglobulin G cryoglobulin. Scoville, C.D., Turner, D.H., Lippert, J.L., Abraham, G.N. J. Biol. Chem. (1980) [Pubmed]
  21. Generating disulfides enzymatically: reaction products and electron acceptors of the endoplasmic reticulum thiol oxidase Ero1p. Gross, E., Sevier, C.S., Heldman, N., Vitu, E., Bentzur, M., Kaiser, C.A., Thorpe, C., Fass, D. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  22. Parkinson disease: a new link between monoamine oxidase and mitochondrial electron flow. Cohen, G., Farooqui, R., Kesler, N. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  23. Glutathionylation of human thioredoxin: a possible crosstalk between the glutathione and thioredoxin systems. Casagrande, S., Bonetto, V., Fratelli, M., Gianazza, E., Eberini, I., Massignan, T., Salmona, M., Chang, G., Holmgren, A., Ghezzi, P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  24. Sulfur accumulation in the timbers of King Henry VIII's warship Mary Rose: a pathway in the sulfur cycle of conservation concern. Sandström, M., Jalilehvand, F., Damian, E., Fors, Y., Gelius, U., Jones, M., Salomé, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  25. Complete amino acid sequence of a human monocyte chemoattractant, a putative mediator of cellular immune reactions. Robinson, E.A., Yoshimura, T., Leonard, E.J., Tanaka, S., Griffin, P.R., Shabanowitz, J., Hunt, D.F., Appella, E. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  26. Identification by redox proteomics of glutathionylated proteins in oxidatively stressed human T lymphocytes. Fratelli, M., Demol, H., Puype, M., Casagrande, S., Eberini, I., Salmona, M., Bonetto, V., Mengozzi, M., Duffieux, F., Miclet, E., Bachi, A., Vandekerckhove, J., Gianazza, E., Ghezzi, P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  27. Disulfide cross-linking studies of the transmembrane regions of the aspartate sensory receptor of Escherichia coli. Lynch, B.A., Koshland, D.E. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  28. Redox regulation of surface protein thiols: identification of integrin alpha-4 as a molecular target by using redox proteomics. Laragione, T., Bonetto, V., Casoni, F., Massignan, T., Bianchi, G., Gianazza, E., Ghezzi, P. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  29. Effective elimination of lung metastases induced by tumor cells treated with hydrostatic pressure and N-acetyl-L-cysteine. Goldman, Y., Peled, A., Shinitzky, M. Cancer Res. (2000) [Pubmed]
  30. Nitric oxide and thiol redox regulation of Janus kinase activity. Duhé, R.J., Evans, G.A., Erwin, R.A., Kirken, R.A., Cox, G.W., Farrar, W.L. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  31. Identification and characterization of a new mammalian glutaredoxin (thioltransferase), Grx2. Gladyshev, V.N., Liu, A., Novoselov, S.V., Krysan, K., Sun, Q.A., Kryukov, V.M., Kryukov, G.V., Lou, M.F. J. Biol. Chem. (2001) [Pubmed]
  32. The yeast Saccharomyces cerevisiae contains two glutaredoxin genes that are required for protection against reactive oxygen species. Luikenhuis, S., Perrone, G., Dawes, I.W., Grant, C.M. Mol. Biol. Cell (1998) [Pubmed]
  33. Acute cadmium exposure inactivates thioltransferase (Glutaredoxin), inhibits intracellular reduction of protein-glutathionyl-mixed disulfides, and initiates apoptosis. Chrestensen, C.A., Starke, D.W., Mieyal, J.J. J. Biol. Chem. (2000) [Pubmed]
  34. The modifier subunit of Drosophila glutamate-cysteine ligase regulates catalytic activity by covalent and noncovalent interactions and influences glutathione homeostasis in vivo. Fraser, J.A., Kansagra, P., Kotecki, C., Saunders, R.D., McLellan, L.I. J. Biol. Chem. (2003) [Pubmed]
  35. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Takagi, J., Petre, B.M., Walz, T., Springer, T.A. Cell (2002) [Pubmed]
  36. Synthesis of proteins by native chemical ligation. Dawson, P.E., Muir, T.W., Clark-Lewis, I., Kent, S.B. Science (1994) [Pubmed]
  37. Identification and purification of a sperm surface protein with a potential role in sperm-egg membrane fusion. Primakoff, P., Hyatt, H., Tredick-Kline, J. J. Cell Biol. (1987) [Pubmed]
  38. The human growth hormone receptor. Secretion from Escherichia coli and disulfide bonding pattern of the extracellular binding domain. Fuh, G., Mulkerrin, M.G., Bass, S., McFarland, N., Brochier, M., Bourell, J.H., Light, D.R., Wells, J.A. J. Biol. Chem. (1990) [Pubmed]
  39. Physical characterization of the procollagen module of human thrombospondin 1 expressed in insect cells. Misenheimer, T.M., Huwiler, K.G., Annis, D.S., Mosher, D.F. J. Biol. Chem. (2000) [Pubmed]
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