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PubMed1981

The specificity of cathepsin B.

Peptidyl chloromethyl ketones, largely derived from arginine, inactivate cathepsin B (beef spleen) at rates that vary 300 fold according to sequence, but the residue in the P1 position is not responsible for this variation since homoarginine or nitroarginine in this position provide inhibitors as good or better than those containing arginine. Peptidyl chloromethyl ketones containing hydrophobic residues such as phenylalanine or valine in the P2 and P3 position are the most effective inhibitors of the group. Cystamine (bis-aminoethyl disulfide) inactivates cathepsin B by formation of a mixed disulfide. Derivatives of cystamine containing phenylalanine, such as bis-N,N'-Phe-cystamine and bis-N,N'-Ala-Ala-Phe-cystamine are more effective and represent a new class of affinity labels for cathepsin B. Immobilized peptidyl cystamine derivatives can be used for the purification of cathepsin B by covalent affinity chromatography. Cathepsin B from beef spleen has a pronounced carboxydipeptidase action on glucagon as described for the human liver enzyme. This action can be conveniently followed by high pressure liquid chromatography.

Affinity Labels↗
PubMed1976

Effect of selenium compounds on selenium content, growth and 35S-cystine metabolism of skin fibroblasts from normal and cystinotic individuals.

Kidney samples from children with the inborn metabolic disease cystinosis contain 4 times more selenium (Se) than do kidney samples from normal individuals (p = 0.1). However, when cultured skin fibroblasts from cystinotic patients and normal control individuals are incubated in Se-D,L-methionine, Se-D,L-cystine, Se-cystamine X HCl, Se-urea, selenite or in medium without added selenium, only the cystinotic fibroblasts grown in Se-urea or selenite (SeO3=) contain more selenium than do the corresponding normal cells (p less than 0.05). In both types of cultured fibroblasts, the order of descending toxicity per ppm selenium is: Se-urea greater than Se-cystamine greater than Se-cystine greater than or equal to SeO3= much greater than Se-methionine. High (apparently toxic) concentrations of Se-urea and Se-cystamine lower the elevated intracellular free (nonprotein) cystine content of cystinotic fibroblasts to less than 60% of control values; at lower concentrations, these compounds raise the cystine content of these cells to over 140% of control values. Appropriate concentrations of SeO3=, Se-cystine and Se-methionine also elevate the free cystine content of the cystinotic cells. During a 75 minute incubation in 35S-cystine, the incorporation of 35S into the acid precipitable (protein) fraction of both cell types is significantly inhibited by Se-cystamine (approximately 55% control; p less than 0.05). The incorporation of 35S-cystine into glutathione is inhibited by Se-cystine (approximately 40% control) in both fibroblast types (p less than 0.05). In cystinotic cells, Se-cystamine significantly reduces incorporation of 35S-cystine into the cystine pool (40% control) as does SeO3= (67% control; p less than 0.05). Protein and glutathione synthesis in cystinotic fibroblasts are more strongly inhibited by Se-cystine and SeO3=, respectively, than in normal fibroblasts (p less than 0.05). These studies demonstrate that selenium compounds exhibit a different sequence of toxicity in fibroblasts than in the intact animal and that some previously unreported metabolic effects (i.e. inhibition of glutathione synthesis) may contribute to their toxicity.

Amino Acids↗
PubMed1990

Structural studies on the inactivation of gamma-glutamylcysteine synthetase by the disulphide analogues of radioprotective cysteamine derivatives. Effects of aminoalkyl and hydroxyalkyl chain length and beta beta-bis-dimethylation.

Disulphide compounds have been shown to inactivate gamma-glutamylcysteine synthetase, the rate-limiting enzyme for GSH synthesis. Such compounds bind to a cysteine residue at or near the glutamate-binding site of the enzyme. This phenomenon is thought to be responsible for the synergistic toxicity of the thiophosphate radio- and chemo-protective agent WR2721 and the oxygen-radical generator 6-hydroxydopamine (2,4,6-trihydroxyphenethylamine). 6-Hydroxy-dopamine enhances conversion of WR2721 into its disulphide metabolite NN'-bis-(3-aminopropyl)cystamine, which, in turn, paralyses the synthetase. In an effort to identify radio- and chemo-protective thiols and thiol derivatives that do not have this toxicity, we have begun to define the structure-activity relationship that governs inactivation of the enzyme by analogues of WR2721 disulphide. NN'-Bis(aminoalkyl)cystamines and bis(hydroxyalkyl)cystamines with an alkyl chain length of C5 or greater are not inactivators of the synthetase. That this is not due solely to the size of these compounds is shown by the potent inactivation of the enzyme by SAPH3 disulphide, an extremely bulky cystamine analogue. beta beta-Bis-dimethylation of the cystamine portion of the molecule also obviates inactivation. This is almost certainly due to steric interference with disulphide interchange. These findings may facilitate the safe adjunctive use of the thiol counterparts of such compounds with oxygen-radical-generating chemotherapeutic agents, and may shed light on the structure of the region of the synthetase adjacent to the glutamate-binding site.

Animals↗
PubMed1985

Augmentation of in vitro antibody response by disulfide compounds. I. Comparison between intermolecular and intramolecular disulfides.

The following disulfide compounds: 2-hydroxyethyldisulfide (2-MEox), 2-aminoethyldisulfide (cystamine) and oxidized dithiothreitol (DTTox) were found to augment the in vitro antibody response to sheep erythrocytes in murine lymphocytes as effectively as their reduced forms when they were added to the culture medium. We, however, found out that the mode of action of DTTox was greatly different from that of 2-MEox or cystamine. 2-MEox and cystamine showed augmenting effects on the proliferative response to lipopolysaccharide and on the uptake of (35S)-cystine by the lymphocytes. In contrast to these intermolecular disulfides, DTTox, an intramolecular disulfide compound, was found to be inactive in these systems. 2-MEox and cystamine, but not DTTox, were reduced to thiol forms by the intact lymphocytes or by the cell homogenate. Thus, it is likely that DTTox did not behave as the reduced form in the lymphocyte culture in contrast to 2-MEox and cystamine, suggesting that the disulfide form itself plays an important role in augmenting effects of DTTox.

Animals↗
PubMedDate not supplied

[Increased efficacy of radiation protection against fission neutrons using unithiol].

It was found that the combination of unithiol (Sodium salt of 2,3-dimercapto-1-propansulfonic acid) with cystamine and AET diminished their toxicity. The optimum ratio for the antitoxic effect is 0.5 molar equivalent of unithiol per radioprotective 1.0 equivalent of thiol. Animals withstand big doses of protectors well, that gives an opportunity to use increased amounts of cystamine and AET. In the experiments with circular irradiation of male (CBA x C57B1)F1 mice weighing 18-22 g with fission neutrons (the neutron mean energy was 0.85 MeV, the contribution of gamma-quanta to the total was 25%, dose rate was 14 cGy/min) it was shown that the combination of unithiol with cystamine and AET enhances their radioprotective effect: the DRF of cystamine (150 mg/kg)--1.1, and the DRF of the combination of cystamine (300 mg/kg) with unithiol (152 mg/kg)--1.2; the DRF of AET (150 mg/kg)--1.2, the DRF of the combination of AET (300 mg/kg) with unithiol--1.4. Thus, the enhancement of dose of the radioprotectors, which was made possible as a result of their combination with unithiol, leads to enhancement of efficacy of chemical protection against fission neutron irradiation as much as 10-20%. Efficacy of AET is found to be comparable to efficacy of this protector in conditions of X-rays irradiation.

Animals↗
PubMedDate not supplied

[Antiradiation properties of radioprotectors, immunomodulators and agents affecting tissue metabolism in fractionated irradiation].

A comparative study was made of the protective efficacy of the per os administered cystamine and mexamine as well as of immunomodulators: decaris and thymoptin, and agents influencing tissue metabolism, such as glutamevite and phosphate concentrate, in conditions of fractionated gamma irradiation at a time interval between fractions of 7 to 1 days. In experiments with (CBA X C57B1/6)F1 and (DBA X C57B1/6)F1 hybrid mice it was shown that with a single exposure cystamine and mexamine protected 40-50% of animals. With a three-fold exposure once a week the efficacy of cystamine was as high as 70%. With exposure every other day the radioprotective efficacy of cystamine and mexamine dropped down to 28.3%. With daily exposure, cystamine was ineffective. Decaris and phosphate concentrate had a slight and transient effect amounting to 10-20%.

Adjuvants, Immunologic↗
PubMed1987

Inactivation of rat pineal hydroxyindole-O-methyltransferase by disulfide-containing compounds.

Rat pineal hydroxyindole-O-methyltransferase activity in crude homogenates is reduced by treatment with disulfides. Cystamine (IC50 = 128 microM) and selenocystamine (IC50 = 13 microM) are the most potent compounds tested. Reduced cystamine (cysteamine) and diaminohexane are inactive. N,N'-Diacetylcystamine, penicillamine disulfide, and glutathione disulfide are less potent or inactive; but several peptides (oxytocin, vasopressin, and arginine vasotocin) are active. Inactivation by cystamine is time- and temperature-dependent and is accelerated at higher pH. Disulfide treatment of intact pinealocytes also inactivates the enzyme. Addition of dithiothreitol during the enzyme assay completely reactivates inactivated enzyme formed by disulfide treatment of homogenates or intact cells. Rat hydroxyindole-O-methyltransferase is also inactivated in the absence of added disulfides and dissolved O2. This spontaneous inactivation is time-, temperature-, and pH-dependent and can be completely prevented, but not reversed, by dithiothreitol. In contrast to the inhibitory effects of cystamine on the rat enzyme, cystamine does not alter bovine hydroxyindole-O-methyltransferase and increases ovine hydroxyindole-O-methyltransferase activity. The bovine and ovine enzymes do not become inactive in the absence of added disulfides. Together these observations indicate that rat pineal hydroxyindole-O-methyltransferase can be inactivated by a protein thiol:disulfide exchange mechanism. This mechanism may contribute to the physiological regulation of this enzyme in the rat pineal gland but does not appear to be a common feature of pineal hydroxyindole-O-methyltransferase regulation in all species.

Acetylserotonin O-Methyltransferase↗
PubMed1995

Involvement of transglutaminase in the formation of covalent cross-links in the cell wall of Candida albicans.

Activity of the enzyme glutaminyl-peptide--glutamylyl-transferase (EC 2.3.2.13; transglutaminase), which forms the interpeptidic cross-link N epsilon-(gamma-glutamic)-lysine, was demonstrated in cell-free extracts obtained from both the yeast like and mycelial forms of Candida albicans. Higher levels of enzymatic activity were observed in the cell wall fraction, whereas the cytosol contained only trace amounts of activity. Cystamine, a highly specific inhibitor of the enzyme, was used to analyze a possible role of transglutaminase in the organization of the cell wall structure of the fungus. Cystamine delayed protoplast regeneration and inhibited the yeast-to-mycelium transition and the incorporation of proteins into the cell wall. The incorporation of covalently bound high-molecular-weight proteins into the wall was sensitive to cystamine. Proteic epitopes recognized by two monoclonal antibodies, one of which is specific for the mycelial walls of the fungus, were also sensitive to cystamine. These data suggest that transglutaminase may be involved in the formation of covalent bonds between different cell wall proteins during the final assembly of the mature cell wall.

Antibodies, Fungal↗
PubMed1994

Putrescine and paraquat uptake in human lung slices and isolated type II pneumocytes.

Paraquat is accumulated into the lungs of various species by an active uptake system which also appears to mediate the uptake of endogenous polyamines, such as putrescine. The accumulation of putrescine in the human lung has been previously shown to be mainly located in the type II cells. In the present study, we have studied the mutually competitive inhibition of putrescine and paraquat in human lung slices and the inhibition of putrescine by paraquat or cystamine in isolated human type II pneumocytes. Peripheral lung tissue taken from patients undergoing pneumectomy or lobectomy was used. The initial steps of the cell isolation procedure differed from the literature in that the tissue was first sliced in 0.7 mm thick slices, which were washed in phosphate buffered saline without calcium and magnesium (PBS-), followed by incubations with trypsin. The type II cells were purified and isolated by differential adherence on plastic followed by Percoll gradient centrifugation. Uptake was determined 48 hr after cell isolation. The accumulation of radiolabelled putrescine showed saturation kinetics, with the following apparent kinetic parameters: Km 6.7 and 6.2-7.6 microM and Vmax 2.7 and 3.0-3.4 mumol/g prot/hr for slices and isolated cells, respectively. In the presence of paraquat, putrescine uptake was reduced, in both systems, in a manner compatible with competitive inhibition, with calculated inhibition constants (Ki) of 549-614 and 659-895 microM paraquat for slices and isolated cells, respectively. The accumulation of putrescine in isolated human pneumocytes was strongly reduced in the presence of cystamine, with calculated Ki of 3.7 microM cystamine. These data indicate that putrescine, paraquat and cystamine accumulate in the human lung by the same uptake system, but that the affinities for the three substrates differ. The presence of an uptake system for putrescine in cultured human pulmonary type II is probably useful as a functional viability test.

Binding, Competitive↗
PubMed1974

Chemical protection against radiation-induced genetic damage during the period of after-effects of gravity stress.

The protective effect of cystamine (150 mg kg-1) against genetic damage induced by gamma-radiation in germ cells of the CBA line of mice (at doses of 100, 300 and 600 r) was studied. Cystamine reduced the frequency of dominant lethal mutations in sperms, spermatids and spermatocytes. The amount of protection depended on the radiation dose. After cystamine the lethal effect of radiation on the whole organism was reduced 2-3 times. After transverse acceleration (15 g over 10 min) the protective effect of cystamine against dominant lethal mutations induced by radiation (300 r) decreased on the average by 1/3. The action of transverse acceleration alone somewhat reduced the radiosensitivity of germ cells. The administration of the protector and acceleration did not affect the frequency of reciprocal translocations induced by radiation in spermatogonia.

Acceleration↗
PubMed2004

Dependence of Giardia lamblia encystation on novel transglutaminase activity.

Earlier, we found that three protein disulfide isomerases (PDI) from Giardia lamblia (gPDI) also have transglutaminase (TGase) activity in vitro. We now show that differentiating Giardia cells contain isopeptide bonds (epsilon(gamma-glutamyl)lysine), the biological product of TGase activity that results in irreversible crosslinking of proteins in vivo. HPLC analyses showed the highest isopeptide bond content in cells encysting for 21 h, indicating an important role for TGase early in encystation. We were not able to detect isopeptide bonds in water-resistant cysts, possibly because they could not be extracted. One of the hallmarks of early encystation is the formation of encystation secretory vesicles (ESV) that transport nascent cyst wall proteins (CWPs) to the outer cell surface. ImmunoEM and live-cell immunofluorescence assays of encysting parasites revealed that gPDIs 1-3 are located in ESV and that gPDI-2 is also novel in that it is localized on the cell surface. Cystamine, a widely used TGase inhibitor, caused a dose-dependent inhibition of ESV formation by 21 h, thereby preventing development of trophozoites into cysts. Since cystamine (0.5-1 mM) inhibited the TGase activity of recombinant gPDIs 1-3 in vitro, PDIs appear to be the physiologic targets of cystamine. We found that when parasites were treated with cystamine, CWPs were not processed normally. These data suggest that TGase-catalyzed reactions may be needed for either the machinery that processes CWP precursors or their recruitment to ESV.

Animals↗
PubMed1968

The mechanism of disulphide reduction by mitochondria.

1. Cystamine was reduced to the corresponding thiol by rat liver mitochondria, even in the presence of rotenone or antimycin A. 2. The reduction of disulphides was stimulated by the accumulation of NADH or by the addition of NADH to osmotically ;shocked' mitochondria. 3. Energy made available by oxidative phosphorylation was not essential for the reduction of disulphides. 4. Cystamine was not reduced during the oxidation of NADH by ultrasonically treated particles, which had lost their capacity for oxidation of alpha-oxo acids. 5. In intact mitochondria, arsenite and other inhibitors of vicinal dithiols caused a decrease in the capacity for reduction of disulphides concomitantly with an inhibition of the oxidation of alpha-oxo acids. 6. Isolated lipoamide dehydrogenase reduced cystamine at the expense of NADH, provided that lipoic acid was also present. 7. It is concluded that in mitochondria the reduction of cystamine and related disulphides is probably brought about by interaction with reduced lipoic acid, generated by the alpha-oxo acid dehydrogenase complexes during the oxidation of alpha-oxo acids or by reaction of lipoamide dehydrogenase with NADH.

Animals↗
PubMedDate not supplied

[The role of cell hypoxia in the effect of radiation protectors].

In experiment with mice, rats and dogs the intimate relationship has been established between radioprotective efficiency of indraline, cystamine and mexamine and its properties to enhance succinate dehydrogenase (SDG) activity of blood lymphocytes (r = 0.95). In that analysis modifying effect of normobaric hyperoxia has been estimated. Mice and dogs were correspondingly irradiated with gamma-60Co-rays in the dose 8.33 and 3.16 Gy. In the investigation involving mice, dogs and men the effect-dose dependence of aggravating of the SDG activity was linear for indraline, but not for cystamine. In man hypoxic hypoxia with air-hypoxic mixture containing 10% of oxygen has initiated rise of the SDG activity being twice as smaller as the one when indraline in the dose of 100 mg administrated. Hyperoxia suppressed radioprotective properties of indraline, cystamine and mexamine in the ED50 in term of DRF by twice and didn't virtually influenced on that in the optimum radioprotective doses. Hyperoxia and alpha-adrenoblocator tropaphene also suppressed the SDG response to indraline. In vitro experiment cystamine and adrenaline held stimulating action on SDG of blood lymphocytes. The role of pharmacological stimulation of cell respiration and cell hypoxia relating with the one in mechanism of radioprotective effect of the radioprotector of two dissimilar groups was discussed.

5-Methoxytryptamine↗
PubMed1979

Spleen lipids: effect of whole body gamma irradiation and radioprotective chemicals.

Effect of whole body gamma irradiation (1200 r) on spleen lipid metabolism of male and female rats 24 hrs and 48 hrs after irradiation and the effect of radioprotective chemicals vis. AET, serotonin, their mixture and cystamine on radiation induced changes in spleen lipid metabolism has been studied. In male rats both 24 and 48 hrs after irradiation a significant increase in spleen total lipids, cholesterol, phospholipids, phosphatidylethanolamine and phosphatidylcholine was observed. Administration of AET before irradiation prevented the changes in spleen total lipids and cholesterol but not in phospholipids, which was prevented by prior administration of both serotonin and the mixture of serotonin and AET. In female rats 24 hrs after irradiation only spleen total lipids showed an increase which was prevented by prior administration of cystamine. In male rats, 24 hrs after irradiation the incorporation of NaH2 32PO4 (counts/min/ug PLP and counts/min/g spleen) into spleen total phospholipids, phosphatidylcholine and phosphatidylethanolamine was reduced and this was corrected by prior administration of AET. Serotonin and the mixture of serotonin + AET did not protect the specific activity of phosphatidy choline. In female rats irradiation increased the incorporation of NaH2 32PO4 into phosphatidylcholine, which was not prevented by prior administration of cystamine. The fatty acid composition of spleen lipid of female rats was profoundly altered 24 hrs after irradiation. Palmitic acid and oleic acid showed an increase whereas arachidonic and fatty acid above arachidonic acid showed an decrease, which were corrected by administration of cystamine before irradiation.

Animals↗
PubMed1983

Inactivation of cathepsin B by active site-directed disulfide exchange. Application in covalent affinity chromatography.

The ability of cystamine, bis-N-aminoethyl disulfide, to inactivate cathepsin B by disulfide exchange is considerably enhanced by the addition of hydrophobic residues which apparently occupy secondary binding sites in the extended active center of the protease. For example, a peptidyl cystamine derivative such as symmetrical Gly-Phe-cystamine is substrate-like and promotes the disulfide exchange by affinity labeling. The effectiveness of this type of reagent is dependent on the peptidyl sequence. The inactivation is more rapid with increasing pH in the narrow range studied, pH 5-7, and is completely reversed by added thiols. 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. Pork liver cathepsin B thus obtained was a mixture of single chain and double chain forms as found by other methods.

Animals↗
PubMed1980

The concentrations of SH-groups in some radiosensitive tissues after the administration of radioprotectors in rats.

The changes in the concentrations of total, nonprotein and protein SH-groups were spectrophotometrically determined in the small intestine and bone marrow of the rats 10, 20, 30 and 60 min after the administration of protective doses of cystamine (50 mg/kg), mexamine (10 mg/kg) or of a mixture of cystamine with mexamine (20 + 10 mg/kg). Cystamine caused an increase in the concentration of mainly nonprotein thiols, whereas the mexamine administration increased the protein SH-groups (mainly between the 20th and 30th min after treatment). The radioprotective mixture led to the most pronounced increase at the 10-min interval. This increase at the 10- and 20-min intervals was more pronounced (or identical) than after cystamine or mexamine administered as a single agent. If the SH-concentration should correspond to the degree of radioprotection, then the phenomenon observed would indicate the usefulness of the mixture administered.

Animals↗
PubMedDate not supplied

[Changes in the content and fractional composition of blood plasma nucleic acids in radiation lesions. The effect of radioprotectors].

The content of DNA in blood plasma increased in early stages after irradiation (2 and 5 h), the low-molecular DNA (160-180 bp) being revealed as opposed to intact animals. Protection of gamma-irradiated rats by cystamine or gammaphos enhanced this phenomenon. The injections of cystamine and gammaphos to nonirradiated animals stimulated DNA ejection into blood stream in 2 h only with normalization by 5 h. Cystamine was the most effective, and in experiment with non-irradiated animals the low-molecular DNA was detected for cystamine only.

Amifostine↗
PubMedDate not supplied

Evidence for the involvement of sulfhydryl groups in the expression of antitumor activity of streptococcal acid glycoprotein (SAGP) purified from crude extract of Streptococcus pyogenes.

An acidic glycoprotein (SAGP), purified from crude extract (CE) of Streptococcus pyogenes, inhibits the growth of murine fibrosarcoma (Meth A) cells in vitro and prolongs the life span of mice inoculated with the same cells. This study revealed that the growth inhibitory activity of SAGP on Meth A cells in vitro was lowered in the presence of sulfhydryl-oxidizing agents such as cystamine and 5, 5'-dithiobis (2-nitrobenzoic acid) in a dose dependent manner. The activity of SAGP was also diminished by pretreatment of SAGP with cystamine. Inactivation of SAGP by cystamine was reversed by dithiothreitol. Furthermore, the effect of CE on prolonging the life span of Meth A-bearing mice was reduced by the administration of cystamine. These findings suggest that SH-groups are involved in the expression of anti-tumor activity of SAGP or CE in vitro and in vivo.

3T3 Cells↗