Browse
Submit Data
Databases
API
Help

Dataset Information

13 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of S-adenosylmethionine decarboxylase and diamine oxidase activities by analogues of methylglyoxal bis(guanylhydrazone) and their cellular uptake during lymphocyte activation.

ABSTRACT: Several congeners of methylglyoxal bis(guanylhydrazone) were tested for their ability to inhibit eukaryotic putrescine-activated S-adenosylmethionine decarboxylase (EC 4.1.1.50) and intestinal diamine oxidase (EC 1.4.3.6). All the compounds tested, namely methylglyoxal bis(guanylhydrazone), ethylglyoxal bis(guanylhydrazone), dimethylglyoxal bis(guanylhydrazone) and the di-N"-methyl derivative of methylglyoxal bis(guanylhydrazone), were strong inhibitors of both yeast and mouse liver adenosylmethionine decarboxylase activity in vitro. The enzyme from both sources was most powerfully inhibited by ethylglyoxal bis(guanylhydrazone). All the diguanidines likewise inhibited diamine oxidase activity in vitro. The maximum intracellular concentrations of the ethyl and dimethylated analogues achieved in activated lymphocytes were only about one-fifth of that of the parent compound. However, both derivatives appeared to utilize the polyamine-carrier system, as indicated by competition experiments with spermidine.

SUBMITTER: Janne J

PROVIDER: S-EPMC1153427 | biostudies-other | 1984 Mar

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Specific inhibition of the enzymic decarboxylation of S-adenosylmethionine by methylglyoxal bis(guanylhydrazone) and related substances.

Project description:Methylglyoxal bis(guanylhydrazone) {1,1'-[(methylethanediylidene)-dinitrilo]diguanidine} is a very potent inhibitor of putrescine-activated S-adenosylmethionine decarboxylases from many different mammalian tissues, including sublines of mouse L1210 leukaemia that are resistant to the drug as well as sublines that are sensitive. The inhibition of purified rat ventral prostate S-adenosylmethionine decarboxylase is competitive with respect to the S-adenosylmethionine substrate, and is much greater in the presence than in the absence of the activator putrescine. Inhibition by the drug depends, among other things, on the nature of the aliphatic amines that can serve as stimulators of rat prostate S-adenosylmethionine decarboxylase. Effects of some congeners of methylglyoxal bis(guanylhydrazone) on the enzyme are described.

| S-EPMC1166290 | biostudies-other

Methylglyoxal-bis-guanylhydrazone inhibits osteopontin expression and differentiation in cultured human monocytes.

Project description:Monocyte activation and polarization play essential roles in many chronic inflammatory diseases. An imbalance of M1 and M2 macrophage activation (pro-inflammatory and alternatively activated, respectively) is believed to be a key aspect in the etiology of these diseases, thus a therapeutic approach that regulates macrophage activation could be of broad clinical relevance. Methylglyoxal-bis-guanylhydrazone (MGBG), a regulator of polyamine metabolism, has recently been shown to be concentrated in monocytes and macrophages, and interfere with HIV integration into the DNA of these cells in vitro. RNA expression analysis of monocytes from HIV+ and control donors with or without MGBG treatment revealed the only gene to be consistently down regulated by MGBG to be osteopontin (OPN). The elevated expression of this pro-inflammatory cytokine and monocyte chemoattractant is associated with various chronic inflammatory diseases. We demonstrate that MGBG is a potent inhibitor of secreted OPN (sOPN) in cultured monocytes with 50% inhibition achieved at 0.1 ?M of the drug. Furthermore, inhibition of OPN RNA transcription in monocyte cultures occurs at similar concentrations of the drug. During differentiation of monocytes into macrophages in vitro, monocytes express cell surface CD16 and the cells undergo limited DNA synthesis as measured by uptake of BrdU. MGBG inhibited both activities at similar doses to those regulating OPN expression. In addition, monocyte treatment with MGBG inhibited differentiation into both M1 and M2 classes of macrophages at non-toxic doses. The inhibition of differentiation and anti-OPN effects of MGBG were specific for monocytes in that differentiated macrophages were nearly resistant to MGBG activities. Thus MGBG may have potential therapeutic utility in reducing or normalizing OPN levels and regulating monocyte activation in diseases that involve chronic inflammation.

| S-EPMC5851547 | biostudies-literature

Inhibition of HIV Expression and Integration in Macrophages by Methylglyoxal-Bis-Guanylhydrazone.

Project description:UnlabelledMacrophages are a target for infection with HIV and represent one of the viral reservoirs that are relatively resistant to current antiretroviral drugs. Here we demonstrate that methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine analog and potent S-adenosylmethionine decarboxylase inhibitor, decreases HIV expression in monocytes and macrophages. MGBG is selectively concentrated by these cells through a mechanism consistent with active transport by the polyamine transporter. Using a macrophage-tropic reporter virus tagged with the enhanced green fluorescent protein, we demonstrate that MGBG decreases the frequency of HIV-infected cells. The effect is dose dependent and correlates with the production of HIV p24 in culture supernatants. This anti-HIV effect was further confirmed using three macrophage-tropic primary HIV isolates. Viral life cycle mapping studies show that MGBG inhibits HIV DNA integration into the cellular DNA in both monocytes and macrophages.ImportanceOur work demonstrates for the first time the selective concentration of MGBG by monocytes/macrophages, leading to the inhibition of HIV-1 expression and a reduction in proviral load within macrophage cultures. These results suggest that MGBG may be useful in adjunctive macrophage-targeted therapy for HIV infection.

| S-EPMC4645666 | biostudies-literature

Inhibition of pig kidney diamine oxidase by substrate analogues.

Project description:1. The oxidation of p-dimethylaminomethylbenzylamine was followed spectrophotometrically by measuring the change in E(250) caused by the p-dimethylaminomethylbenzaldehyde produced. 2. This reaction was inhibited by substrate analogues such as isothiouronium, guanidino, dimethylsulphonium and trimethylammonium compounds. 3. The inhibition by both mono- and bis-onium compounds has been studied and a comprehensive theory is developed to explain both the type and degree of inhibition produced.

| S-EPMC1173761 | biostudies-other

Stimulation of ornithine decarboxylase activity and inhibition of S-adenosyl-L-methionine decarboxylase activity in leukaemic mice by methylglyoxal bis(guanylhydrazone).

Project description:Administration of methylglyoxal bis(guanylhydrazone) to leukaemic mice results in an early depression followed by a marked elevation of S-adenosyl-l-methionine decarboxylase activity. Further, there is an early prolonged increase in the activity of ornithine decarboxylase, the initial enzyme in the polyamine biosynthetic pathway. Because of the profound effects of methylglyoxal bis(guanylhydrazone) in vivo on the polyamine biosynthetic pathway, the drug can no longer be considered a specific inhibitor of spermidine synthesis.

| S-EPMC1166065 | biostudies-other

New insights into the design of inhibitors of human S-adenosylmethionine decarboxylase: studies of adenine C8 substitution in structural analogues of S-adenosylmethionine.

Project description:S-adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation process. The crystal structures of the enzyme with various inhibitors at the active site have shown that the adenine base of the ligands adopts an unusual syn conformation when bound to the enzyme. To determine whether compounds that favor the syn conformation in solution would be more potent AdoMetDC inhibitors, several series of AdoMet substrate analogues with a variety of substituents at the 8-position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. The biochemical analysis indicated that an 8-methyl substituent resulted in more potent inhibitors, yet most other 8-substitutions provided no benefit over the parent compound. To understand these results, we used computational modeling and X-ray crystallography to study C(8)-substituted adenine analogues bound in the active site.

| S-EPMC2652407 | biostudies-literature

Diamine oxidase and polyamine oxidase activities in normal and transformed cells.

Project description:1. The activity of diamine oxidase (EC 1.4.3.6) in normal rat kidney cells and in normal rat kidney cells transformed by avian sarcoma virus (B77 strain) growing in tissue culture varies with the stage of growth. There is an initial stimulation of activity by 24h after seeding, followed by a steep decline during exponential growth (48-72h). Enzyme activity decreases even further as the cells reach saturation density (confluence) after 4 days in culture when the activity in normal rat kidney cells is twice as high as that in transformed cells. 2. Differences of about the same order of magnitude are observed between transformed human cells HeLa, HEp2 (a human epithelioid carcinoma) and normal human fibroblasts, in chicken cells between normal myeloblasts and leukaemic myeloblasts, and in rats between biopsy material from normal mammary tissue and 9,10-dimethylbenz[a]anthracene-induced mammary tumours. 3. Polyamine oxidase activity also varies with the growth of transformed rat kidney cells, but shows no significant variation with the growth of normal rat kidney cells between 24 and 96h after seeding. The activity in cells at confluence is from 3- to 5-fold lower in the transformed than in the normal rat kidney cells. 4. A similar 5-10-fold decrease in activity has been found in 9,10-dimethylbenz[a]anthracene-induced mammary tumours in rats and in human oesophageal tumours. 5. Possible reasons for these observations and the contribution of these two enzymes to cellular putrescine concentrations are discussed.

| S-EPMC1186366 | biostudies-other

The inhibition of human placental diamine oxidase by substrate analogues.

Project description:1. The oxidation of p-dimethylaminomethylbenzylamine by purified placental diamine oxidase was followed by measuring the change in E(250) caused by the production of p-dimethylaminomethylbenzaldehyde. 2. The inhibition of this reaction by substrate analogues such as isothiouronium, guanidinium, dimethylsulphonium and trimethylammonium compounds was extensively studied. 3. The type and degree of inhibition by mono- and bis-onium compounds is described, and a theory is developed to explain the type of inhibition produced.

| S-EPMC1166265 | biostudies-other

Intracellular putrescine and spermidine deprivation induces increased uptake of the natural polyamines and methylglyoxal bis(guanylhydrazone).

Project description:Inhibition of polyamine synthesis by alpha-difluoromethylornithine in cultured Ehrlich ascites-carcinoma cells rapidly enhanced the uptake of exogenous putrescine, spermidine and spermine from the culture medium. In tumour cells exposed to the drug for 2 days, the intracellular concentration of spermidine was decreased to less than 10% of that found in untreated cells. However, the strikingly stimulated transport system brought the concentration of spermidine to the control values in less than 2h after supplementation of the cells with micromolar concentrations of the polyamine. In the absence of polyamine deprivation, tumour cells did not accumulate extracellular polyamines to any appreciable extent. Ascites-tumour cells deprived of putrescine and spermidine likewise concentrated methylglyoxal bis(guanylhydrazone) [1,1'-[methylethanedylidine)dinitrilo]diguanidine] at a greatly enhanced rate. A previous "priming of tumour cells with difluoromethylornithine followed by an exposure of the cells to methylglyoxal bis(guanylhydrazone) resulted in a marked and rapid anti-proliferative effect.

| S-EPMC1162421 | biostudies-other

Crenarchaeal arginine decarboxylase evolved from an S-adenosylmethionine decarboxylase enzyme.

Project description:The crenarchaeon Sulfolobus solfataricus uses arginine to produce putrescine for polyamine biosynthesis. However, genome sequences from S. solfataricus and most crenarchaea have no known homologs of the previously characterized pyridoxal 5'-phosphate or pyruvoyl-dependent arginine decarboxylases that catalyze the first step in this pathway. Instead they have two paralogs of the S-adenosylmethionine decarboxylase (AdoMetDC). The gene at locus SSO0585 produces an AdoMetDC enzyme, whereas the gene at locus SSO0536 produces a novel arginine decarboxylase (ArgDC). Both thermostable enzymes self-cleave at conserved serine residues to form amino-terminal beta-domains and carboxyl-terminal alpha-domains with reactive pyruvoyl cofactors. The ArgDC enzyme specifically catalyzed arginine decarboxylation more efficiently than previously studied pyruvoyl enzymes. alpha-Difluoromethylarginine significantly reduced the ArgDC activity of purified enzyme, and treating growing S. solfataricus cells with this inhibitor reduced the cells' ratio of spermidine to norspermine by decreasing the putrescine pool. The crenarchaeal ArgDC had no AdoMetDC activity, whereas its AdoMetDC paralog had no ArgDC activity. A chimeric protein containing the beta-subunit of SSO0536 and the alpha-subunit of SSO0585 had ArgDC activity, implicating residues responsible for substrate specificity in the amino-terminal domain. This crenarchaeal ArgDC is the first example of alternative substrate specificity in the AdoMetDC family. ArgDC activity has evolved through convergent evolution at least five times, demonstrating the utility of this enzyme and the plasticity of amino acid decarboxylases.

| S-EPMC2533785 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data