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At least 19 recordsLinked to original sources

PubMed1975

Effect of iodoacetate on the bone marrow immunocompetence of AKR mice.

Studies were conducted to determine whether the sulfhydryl inhibitor, sodium iodoacetate, administered to preleukemic AKR mice and to mature C3H mice altered the immunocompetence of their bone marrow. Parameters investigated included the splenic plaque-forming capacity directed to sheep erythrocytes of bone marrow transferred from iodoacetate-treated aanimals to irradiated syngeneic recipients and the mitogenic responsiveness of bone marrow cells from untreated and iodoacetate-treated preleukemic AKR mice to phytohemagglutinin and concanavalin A. The administration of two 0.5-ml doses of 10 mM iodoacetate to preleukemic AKR mice and to C3H mice resulted in a significant increase in bone marrow immunocompetence. Irradiated mice given marrow transplants from iodoacetate-treated syngeneic donors exhibited greater numbers of plaque-forming cells directed against sheep erythrocytes than did recipients of marrow from control animals. This effect was abrogated when the donor marrow was previously treated in vitro with rabbit antimouse brain serum and the complement to remove thymus-derived lymphocytes. The mitogenic responsiveness of marrow cultures from iodoacetate-treated AKR mice to phytohemagglutinin was similar to that observed for control mice, while the response to concanavalin A was decreased. These findings suggest that the administration of iodoacetate potentiated the immunocompetence of bone marrow by affecting thymus-derived cells.

Animals↗

PubMed1978

The stimulus-secretion coupling of glucose-induced insulin release XXVI. Are the secretory and fuel functions of glucose dissociable by iodoacetate?

Iodoacetate inhibits glyceraldehyde-3-phosphate dehydrogenase activity in pancreatic islets and causes a time- and dose-related inhibition of glucose oxidation and lactate output by the islets. High concentrations of the drug (0.3 mM or more) fail to affect Ba2+-induced insulin secretion but inhibit glucose-stimulated proinsulin biosynthesis, 45Ca net uptake and insulin release. A mixture of fumarate, glutamate, and pyruvate, the oxidation of which is only partially reduced by iodoacetate, fails to protect the B-cell against the inhibitory effect of the drug. These findings are compatible with the view that glycolysis plays an essential role in the process of glucose-induced insulin release. At low concentrations of iodoacetate (up to 0.2 mM), the reduction in glucose metabolism coincides with a partial inhibition of proinsulin biosynthesis. However, the expected reduction in 45Ca net uptake and subsequent insulin release is masked by a concomitant facilitating action of iodoacetate, possibly due to interference with native ionophoretic processes. It is concluded that iodoacetate is not an adequate tool to dissociate, if they are dissociable, the fuel and secretory functions of glucose.

Animals↗

PubMed1977

Effect of iodoacetate on T lymphocytes of young AKR mice.

The influence of sulphydryl inhibitor iodoacetate on properties characteristically associated with T-lymphocytes was examined in young AKR mice. Thymocytes from mice receiving 100 microgram of iodoacetate showed a decrease in cortisone sensitivity, and responded more vigorously to phytohemagglutinin (PHA). Spleen cells from treated mice also exhibited greater reactivity to both PHA and concanavalin A (Con A). The uptake of 14C-iodoacetate by the thymus, spleen, lymph nodes, bone marrow, liver and kidneys also was investigated. One hour, 2 h and 18 h after the intraperiotoneal injection of 10-3 M iodoacetate, the thymus demonstrated a higher incorporation of the labelled compound than did the spleen, lymph nodes or other organs examined. These findings provide further evidence to indicate that the immuno-enhancement observed following iodoacetate treatment is related to its effect on T lymphocytes.

Animals↗

PubMed1977

Rat intestinal phosphodiesterase II. Properties of the highly purified enzyme and its inactivation by iodoacetic acid.

A highly purifed preparation of rat intestinal phosphodiesterase II (oligonucleate 3'-nucleotidohydrolase, EC 3.1.4.18) has been studied using a synthetic substrate, thymidine 3'(2,4-dinitrophenyl) phosphate. The enzyme was most active between pH 6.1 and pH 6.7 and was inhibited by Cu2+ and Zn2+ but unaffected by EDTA, Mg2+, Co2+, and Ni2+. The reaction rate decreased at high levels of enzyme because of competitive inhibition by deoxythymidine 3'-phosphate, a reaction product, which showed a Ki of 2-10(-5) M. The molecular weight of the enzyme by gel-filtration was 150 000-170 000. In electrofocusing experiments multiple peaks of activity were found at pH 3.4, 4.2-4.5and 7.2. Polyacrylamide gel electrophoresis of freshly purified phosphodiesterase II showed up to 10 protein bands in the gels. If the preparations were stored at 4 degrees C for some time only one or two bands appeared. Investigation of the reaction of rat intestinal phosphodiesterase II with a number of possible phosphodiesterase substrates indicated that the enzyme required a nucleoside 3'-phosphoryl residue for the initiation of hydrolysis. Thus compounds such as NAD, ATP, bis-(p-nitrophenyl)phosphate, thymidine 5'-(p-nitrophenyl)phosphate, glycerylphosphorylcholine, guanylyl-(2' leads to 5')-adenosine and 3',5'-cyclic AMP which contain phosphodiester bonds, nevertheless were not substrates for the enzyme. The enzyme was inhibited reverisbly by p-chloromercuribenzoate and p-chloromercuriphenylsulfonate and inactivated irreversibly by iodoacetic acid. Activity of the phosphodiesterase II was reduced to 50% by incubation with 2.0-10(-3)--5.0-10(-3) M iodoacetate for 20--30 min at 24 degrees C at pH 5.0--6.1. Iodoacetamide had no effect. The degree of inactivation by iodoacetate was reduced by the presence of a substrate for the enzyme or, more effectively by deoxythymidine 3'-phosphate, a competitive inhibitor. It is concluded that iodoacetic acid alkylates an essential residue at the active centre of the enzyme.

Animals↗

PubMed1977

Glutamine active site of formylglycinamide ribonucleotide amidotransferase. 1. Labeling of the enzyme with iodoacetate.

A two-step method for labeling the glutamine active site of formyglycinamide ribonucleotide (FGAR) amidotransferase from chicken liver has been developed in which reaction of all other reactive groups with unlabeled iodoacetate is followed by specific labeling of the glutamine site with radioactive reagent. A study of the reaction as a function of duration, temperature, and pH of the incubation as well as concentration of iodoacetate has revealed that two nonessential groups of the enzyme react in the presence of glutamine and that this modified enzyme is relatively resistant to further carboxymethylation. When this modified enzyme was incubated with radioactive iodoacetate in the presence of FGAR, ATP, and Mg2+ after removal of glutamine by dialysis, about 1 mol of radioactive iodoacetate was incorporated per mol of enzyme with inactivation. This method permits labeling of the active site for glutamine without the use of glutamine analogues.

Animals↗

PubMed1976

Effects of iodoacetate and fluoride on islate respiration and insulin biosynthesis.

Fluoride and iodoacetate inhibited the oxidation of glucose by islets of Langerhans isolated from the rat pancreas. Fifty % inhibition occurred with either 17 mM fluoride or 0.5 mM iodoacetate. The rate of insulin biosynthesis was more strongly inhibited by these inhibitors, especially fluoride. Fifty % inhibition occurred with approximately 1.5 mM fluoride. At high concentrations of iodoacetate and fluoride, the inhibitory effect on insulin synthesis was not reversed to a significant degree by the addition of pyruvate in the incubation medium. In addition to inhibiting the glycolysis and depriving islets of energy essential for the biosynthesis of insulin, fluoride probably exerts a direct inhibitory influence on the biosynthetic mechanism. A separate experiment with [6-14C]glucose indicated that 0.2 mM iodoacetate does not inhibit glycolysis completely.

Animals↗

PubMed1975

Iodoacetate and iodoacetamide-induced alterations of pancreatic alpha- and beta-cell responses.

Iodoacetate and iodoacetamide were compared as to their capacity to block islet glycolysis and interfere with glucose inhibition of glucagon release and glucose stimulation of insulin release. Glycolysis was measured in isolated rat islet by the rate of lactate formation from 27 mM glucose. Hormone release was investigated by perfusing isolated rat pancreas with a 10 mM mixture of 19 amino acids, with and without 5 mM glucose. In perfusion experiments, lactate (2.5 mM) and pyruvate (0.5 mM) were present to provide alternate source of energy independent of glycolysis. Iodoacetate was about twice as potent as iodoacetamide in blocking glycolysis in islets, 0.2 and 0.5 mM, respectively being needed for complete inhibition of lactate production. Levels of either agent lower than 0.05 mM did not affect lactate accumulation. Iodoacetate, at the level which completely inhibited glycolysis did not interfere with the permissive action of glucose for insulin release. In contrast, iodoacetamide at a level (0.05 mM) which had no effect on lactate production, changed the response of the beta-cell dramatically: amino acids now released insulin even in the absence of glucose and insulin release by 5 mM glucose alone was greatly augmented. Both thiol reagents at 0.025 mM concentration completely prevented glucose from suppressing amino acid stimulated glucagon release, iodoacetamide being more potent than iodoacetate. These data indicate that the opposite physiological actions of glucose in alpha and beta-cells are in each case dissociable from the fuel function of the sugar molecule, and the results best support the concept that glucose and thiol reagents effect insulin and glucagon secretion by acting on sulfhydryl groups related to receptor sites in the alpha-and beta-cell membrane.

Amino Acids↗

PubMed1976

Alkylation of cysteinyl residues of pig heart NAD-specific isocitrate dehydrogenase by iodoacetate.

Pig heart NAD-specific isocitrate dehydrogenase is inactivated by reaction with iodoacetate at pH 6.0. Loss of activity can be attributed to the formation of 1-2 mol of carboxymethyl-cysteine per peptide chain. The rate of inactivation is markedly decreased by the combined addition of Mn2+ and isocitrate, but not by alpha-ketoglutarate, the coenzyme NAD or the allosteric activator ADP. The substrate concentration dependence of the decreased rate of inactivation yields a dissociation constant of 1.6 mM for the enzyme-manganous-dibasic isocitrate complex, a value that is 50 times higher than the Km for this substrate. This result suggests that in protecting the enzyme against iodoacetate, isocitrate may bind to a region distinct from the catalytic site. Isocitrate and Mn2+ also prevent thermal denaturation, with an affinity for the enzyme close to that observed for the iodoacetate-sensitive site. The alkylatable cysteine residues may contribute to a manganous-isocitrate binding site which is responsible for stabilizing an active conformation of the enzyme.

Animals↗

PubMed1977

Iodoacetate-induced inhibition and enhancement of spontaneous leukemia in AKR mice.

Either inhibition or enhancement of the spontaneous lymphoma exhibited by AKR mice was observed after treatment with different dosages of the sulfhydryl inhibitor, sodium iodoacetate. Treatment of the mice at 3 or 6 months of age with five ip injections of 0.10 mg of iodoacetate at 5-day intervals significnatly extended the survival of the animals. A single administration of this dosage elevated the responses of splenic lymphocytes to the T-cell mitogens phytohemagglutinin (PHA) and concanavalin A (Con A), and resulted in higher PHA and Con A response ratios than were noted for age-matched controls. Conversely, groups of 3- or 6-month-old AKR mice, subjected to the same regimen but with 0.01-mg dosages, exhibited an apparent accelerated development of the leukemia and survived for significantly shorter periods. In general, splenic lymphocytes harvested from mice given a single 0.01-mg treatment of iodoacetate were not as reactive as were control cell cultures when exposed to the T-cell mitogens.

Animals↗

PubMed1977

Effects of iodoacetate, mannoheptulose and 3-O-methyl glucose on the secretory function and metabolism of isolated pancreatic islets.

The ability of iodoacetate, mannoheptulose, and 3-O-methyl glucose to alter islet cell metabolism and glucose-stimulated insulin secretion was examined. A method for the sequential analysis of the releasing and fuel function of glucose in isolated islets was applied. Insulin release was measured by radioimmunoassay and the metabolism of glucose by determining the rate of tritiated water production from [5-3H]glucose and lactate accumulation. It was found that iodoacetate, in the range of 0.2-1.0 mM, inhibited the metabolism of glucose linearly while release was not blocked until metabolism was reduced by 30-40%. The KI for both processes, release and metabolism, was the same. Pyruvate did not protect against or reverse the effects of iodoacetate. Mannoheptulose inhibited both release and metabolism half-maximally at about 5 mM when 27.5 mM glucose was used as the stimulatory agent. A mannoheptulose-resistant component of glucose metabolism, amounting to 30% of the maximal rate was observed. 3-O-Methyl glucose had no effect on insulin release but reduced glucose utilization and lactate production from low glucose. The results are discussed in light of the two prevailing hypotheses explaining glucose induced insulin release, i.e., the receptor and the metabolism hypotheses.

Animals↗

PubMed1975

Sodium iodoacetate as an antiglycolytic agent in blood samples.

We evaluated the effect of sodium iodoacetate on glycolysis in a series of randomly selected blood samples from patients. Glucose values for serum and for serum with added sodium fluoride (2.5 g/liter) or sodium iodoacetate (2 g and 0.5 g/liter) were compared at room temperature. Respective declines in glucose values averaged 170, 40, 30, and 30 mg/liter after 24 h. Iodoacetate-preserved (0.5 g/liter) samples showed no visible hemolysis. Results of determinations of urea with urease and of other tests on SMA 12/60 (Technicon) panels were unaffected.

Autoanalysis↗

PubMed1975

The structure of dihydrofolate reductase. Identification of methionine residues carboxymethylated by iodoacetate with loss of catalytic activity.

Dihydrofolate reductase from the amethopterin-resistant mutant (strain A) of Streptococcus faecium var. Durans was reacted with iodo[14C]acetate according to three procedures; (a) in the absence of an inhibitor, (b) in the presence of aminopterin, and (c) in absence of inhibitor, but after treatment with unlabeled iodoacetate in presence of aminopterin. The first and last procedures resulted in the loss of approximately 90% of the catalytic activity, whereas in the presence of aminopterin essentially no activity was lost. Peptides were produced from all three labeled proteins by tryptic digestion after citraconylation of the lysine residues. From the amino acid compositions and partial amino acid sequences of these peptides the position of all modified methionines in the sequence was determined. The extent of labeling at each methionine, in enzyme labeled in the different procedures, indicated that methionines 28 and 50 may be at the binding site for inhibitors and that residue 50 is less accessible to iodoacetate than is residue 28. It is likely that carboxymethylation of residue 28 is responsible for the loss of enzyme activity.

Aminopterin↗

PubMed1977

Metabolic control of circulation. Effects of iodoacetate and fluoroacetate.

The circulatory effects of selective metabolic inhibition of glycolysis and of the tricarboxylic acid cycle by iodoacetate and fluoroacetate were studied in intact chloralose-anesthetized dogs. Pulmonary arterial blood pressure and vascular resistance increased after administration of both inhibitors, but neither systemic hemodynamics nor myocardial contractility changed significantly. Coronary blood flow did not change after iodoacetate administration but increased four- to five-fold after fluoroacetate. Administration of normal saline had no effect on any of the parameters. The changes in pulmonary arterial blood pressure and coronary blood flow after fluoroacetate were not mediated via the autonomic nerves or adrenergic neurohumors because they still occurred after autonomic nervous system inhibition. Neither myocardial oxygen consumption nor left ventricular work changed. A selective increase in myocardial blood flow also occurred in conscious dogs after fluoroacetate administration; hepatic artery flow was reduced, but other organ flows did not change significantly. These results indicate that pulmonary pressor and coronary dilator effects may be produced in intact dogs by selective metabolic blockade, in the absence of reduced oxygen supply or impairment in the electron transport system. These results also suggest that the increases in pulmonary arterial blood pressure, coronary blood flow, and cardiac output that occur during hypoxia probably are related to separate metabolic events in the tissue.

Animals↗

PubMed1992

Structural and metabolic changes in articular cartilage induced by iodoacetate.

The chemically induced injury to articular cartilage, caused by two successive intra-articular injections of sodium iodoacetate, has been used in studies on the effects of anti-inflammatory and of potentially chondroprotective agents. It has been assumed that the injurious effects are caused by inhibition of the glycolytic pathway. In the present study this inhibition has been shown to be greater than expected from in vitro studies, and to influence equally other oxidative pathways. However, the response is clearly not a simple one in that some of the surface chondrocytes, and synovial lining cells in close proximity to the cartilage, show virtually no inhibition.

Animals↗

PubMed1976

Changes of some enzymatic activities in iodoacetate-treated microconidiating cultures of Neurospora crassa.

In iodoacetate-treated microconidating cultures of Neurospora crassa, mycelial yield, sucrose consumption and ethanol production are reduced. The specific activity of glyceraldehyde-3-phosphate dehydrogenase is sharply decreased while the specific activities of glucose-6-phosphate dehydrogenase and of 6-phosphogluconate dehydrogenase are stimulated. A polyphenoloxidase is induced in the microconidiating cultures.

Catechol Oxidase↗

PubMed1975

Inhibition of thiamine transport in anaerobic baker's yeast by iodoacetate, 2,4-dinitrophenol N,N'-dicyclohexylcarbodiimide and fatty acids.

1. [14C]Thiamine uptake by baker's yeast (Saccharomyces cerevisiae) was strongly inhibited by 0.2 mM iodoacetate, 0.2 mM 2,4-dinitrophenol and 0.1 mM N,N'-dicyclohexylcarbodiimide under anaerobic conditions. 2. The inhibition of anaerobic [14C]thiamine uptake by these inhibitors was accompanied by almost parallel decreases in the ATP level of the yeast cells. 3. On the other hand, the short-chain fatty acids inhibited [14C]thiamine uptake to a large extent, without greatly affecting the intracellular ATP level. This suggests that the acids primarily block the use of energy from ATP for the transport rather than the fermentation process. 4. Caproate, which has a most pronounced inhibitory effect on [14C]thiamine uptake, significantly prevented the dissipation of an energized membrane state of yeast cells necessary for the active transport of thiamine. 5. Possible ways in which the inhibitors may affect thiamine uptake were discussed.

Adenosine Triphosphate↗

PubMed1978

Caffeine contracture and iodoacetate rigor in frog skeletal muscle. A comparison.

Frog sartorius muscle treated with 5.0 mM or greater caffeine exhibits stiffness similar to that obtained from muscle in iodoacetate rigor. The data provide quantitative evidence that suggests that caffeine at irreversible contracture-producing concentrations somehow induces a rigor or rigorlike state in skeletal muscle.

Animals↗

PubMed1978

Probe of beta-galactosidase structure with iodoacetate. Differential reactivity of thiol groups in wild-type and mutant forms of beta-galactosidase.

Carboxymethylation with 14 C-labeled iodoacetate of cysteine residues in wild-type beta-galactosidase from Escherichia coli and in a defective beta-galactosidase from deletion mutant strain M15 was investigated in order to determine accessible positions in the tetrameric wild-type form and the dimeric mutant M15 protein. The extent of carboxymethylation, the effects on biological activity, antibody activation, physical stability, and the labeling of particular residues were studied. The results distinguish three groups of spatial relationships for cysteine residues in the protein, define possible regions for subunit interactions, and confirm that no cysteine residue is specifically involved in catalysis. Residue 1019 and to a lesser extent 498 are accessible in the tetrameric protein and probably represent exposed areas. In the M15 protein, these two, and three additional residues, at 76,387 and 600, were found to react significantly with reagent. One or more of the latter are suggested to be in the dimer-dimer interface. Complementation and activation by antibody are inhibited by carboxymethylation of M15 protein.

Binding Sites, Antibody↗