Disease relevance of Decarboxycystine

• When treatment began after the appearance of abnormal movements, cystamine extended survival, reduced associated tremor and abnormal movements and ameliorated weight loss [1].
• Administration of cystamine in vivo partially corrects susceptibility to malaria in A/J mice, as measured by reduced blood parasitemia and decreased mortality [2].
• These results show that cystamine potently suppresses HIV replication in human cells by contemporaneously blocking at least two independent steps of the viral life cycle, without affecting cell viability, suggesting that this compound may represent a new possibility towards the treatment of HIV-1 infection [3].
• Cystamine does not affect viral transcription, translation or protein processing; indeed, all HIV proteins are present in a pattern similar to that of nontreated cells [3].
• Instead, cystamine interferes with the orderly assembly of HIV virions, as shown by electron microscopy analysis, that reveals only defective viral particles in treated cells [3].

Psychiatry related information on Decarboxycystine

• Cystamine treatment is neuroprotective in the YAC128 mouse model of Huntington disease [4].

High impact information on Decarboxycystine

• The apoptotic cell death was partially suppressed by the transglutaminase inhibitors cystamine and monodansyl cadaverine (but not putrescine), suggesting involvement of a transglutaminase reaction and providing a potential basis for the development of therapeutic measures for CAG-repeat expansion diseases [5].
• Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine [1].
• Cystamine given intraperitoneally entered brain where it inhibited TGase activity [1].
• This protection is reversible by administration of cystamine or bisphenol A diglycidyl ether, a peroxisome proliferator-activated receptor (PPAR)gamma antagonist [6].
• Oral administration of cystamine reversed all aspects of the deficient phenotype [7].

Chemical compound and disease context of Decarboxycystine

• The inhibitory effects of cystamine on HIV-1 did not appear to be caused by toxicity to CBMDM or lymphocytes because there was no change in cell viability or cellular DNA synthesis as evaluated by trypan blue dye exclusion and [3H]-thymidine incorporation at doses of cystamine that inhibit the virus [8].
• In contrast, pretreatment of the cells with antipain or leupeptin, two inhibitors of Ca2+-activated proteases, abolished the stimulation of proteolysis by cystamine and also protected the cells from cystamine toxicity [9].
• In contrast, tyrosinase activity in an amelanotic melanoma cell line (MM96L) was rapidly inhibited without consumption of cystamine/cysteamine, in association with the generation of free thiol in the culture medium, and could be enhanced by the cystine transport inhibitor, glutamate [10].
• In studies to determine whether pigmentation can be regulated physiologically by thiols, human melanoma cells (MM418c5) and melanocytes were found to become depigmented when cultured continuously in 50 microM cystamine [10].
• Here, we investigated the effects of cystamine, which has shown neuroprotection in animal models of Huntington's disease, in a parkinsonian mouse generated by the toxin MPTP [11].

Biological context of Decarboxycystine

• The exact contribution of the interrelated factors in cystamine inhibition of sickling (changes in oxygen affinity, mean corpuscular hemoglobin concentration, and minimum gelling concentration) has yet to be determined [12].
• The combined pharmacological treatment with mithramycin and cystamine down-regulates ESET gene expression and reduces hypertrimethylation of histone H3 (K9) [13].
• This protection is correlated with reduced apoptosis and inflammation and is reversed by treating mutant animals with cystamine [14].
• Treatment with cystamine prior to DMN administration completely abolished the depression of protein synthesis and reduced by more than 90% the methylation by [14C]DMN of purine bases in liver DNA [15].
• The enzyme is potently inactivated by cystamine, which apparently interacts with a sulfhydryl group at the active site to form a mixed disulfide [16].

Anatomical context of Decarboxycystine

• We have investigated the effects of cystamine on the replication of human immunodeficiency virus (HIV) in human lymphocytes and macrophages, the natural targets of HIV in vivo [3].
• Treatment of chronically infected macrophages with cystamine, at a concentration (500 microM) that did not show any cytotoxic or cytostatic effects, strongly decreased (> 80%) HIV-p24 antigen production and completely abolished the production of infectious viral particles [3].
• Pantethine and cystamine deplete cystine from cystinotic fibroblasts via efflux of cysteamine-cysteine mixed disulfide [17].
• Furthermore, both pantethine and cystamine act by generating the mixed disulfide of cysteamine and cysteine in the lysosomes, which is then rapidly excreted from the cells [17].
• Inhibition of erythrocyte sickling by cystamine, a thiol reagent [12].

Associations of Decarboxycystine with other chemical compounds

• Radioactivity in cytoplasmic glutathione was, however, increased by cystamine or pantethine [17].
• The inhibitors of TG2, cystamine and monodansyl cadaverine, abolished the ability of the T47D cell membrane preparation to phosphorylate IGFBP-3 [18].
• It has been suggested by several studies that cystamine labels an active site Cys residue essential for catalysis [19].
• The findings suggest that a sulfhydryl group at the active site interacts with the chloroketones and with cystamine and that the chloroketone inhibitors and cystamine bind to the enzyme as glutamine analogs [20].
• Our results suggest that the perturbation of intracellular Ca2+ homeostasis by cystamine is caused by the inhibition of Ca2+ efflux associated with the formation of cystamine-protein mixed disulfides in the plasma membrane and that subsequent cytotoxicity results from Ca2+-activation of a nonlysosomal proteolytic system [9].
• We demonstrate that cysteamine, the FDA-approved reduced form of cystamine, is neuroprotective in HD mice by increasing BDNF levels in brain [21].

Gene context of Decarboxycystine

• This novel bifunctional enzyme, referred to as gamma-GCS-GS, has been characterized in terms of catalytic activity, substrate specificity, and inhibition by GSH, cystamine, and transition state analog sulfoximines [22].
• Moreover, administration of the transglutaminase inhibitor cystamine delays the onset of pathology in the R6/2 HD mouse model [23].
• However, the contribution of tTG inhibition towards the therapeutic effects of cystamine has not been determined, as this compound likely has multiple mechanisms of action in the R6/2 mouse [23].
• Cystamine also inhibited LPS-induced TNF production in MDM [24].
• The inhibitory effects of latent TGF-beta1 on MS-9 cell proliferation were restored by addition of either TGF-beta1 neutralizing antibody or cystamine, a transglutaminase inhibitor [25].

Analytical, diagnostic and therapeutic context of Decarboxycystine

• Cystamine also decreased HIV-1 protein expression in CBMDM as determined by indirect immunofluorescence assay [8].
• Immobilization of the peptidyl cystamine derivatives provided an effective and rapid procedure for the covalent chromatography of cathepsin B following ammonium sulfate fractionation of beef spleen or pork liver homogenates, replacing the need for ion exchange chromatography [26].
• These results provide strong evidence for neuroprotective properties of cystamine in this animal model of Parkinson's disease [11].
• A limited incubation of oxidized (pretreated with the disulfide cystamine) Rubisco from Chlamydomonas reinhardtii with subtilisin or proteinase K generated fragments of molecular mass about 53 kDa (band I in SDS-PAGE) and 47 kDa (band II) derived from the large subunit (55 kDa) of the enzyme [27].
• Lung slices from both tumoral tissue and non-tumoral tissue, obtained from patients undergoing surgery for lung cancer, were incubated with radiolabelled putrescine at both 37 degrees C and 4 degrees C. The accumulation of putrescine was evaluated by its apparent kinetic parameters, in the presence or absence of cystamine, and by autoradiography [28].

References