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PubMed1990

Urinary polyamine excretion measured by a simple enzymatic method is clinically useful as an expression of hepatic regeneration in liver diseases.

Polyamines have been known to play an important role in hepatic regeneration. In the present study, we measured the amount of urinary polyamine excretion in various liver diseases using a simple enzymatic method. Urinary polyamine excretion was elevated above the normal range in 21 out of 47 cases with fulminant hepatic failure, acute hepatitis, chronic active hepatitis, and liver cirrhosis. No change, however, was observed in 11 patients with chronic inactive hepatitis. In fulminant hepatic failure, two patients with urinary polyamine concentrations above 100 mumoles/g.cr. recovered, while two patients with concentrations of 56.2 and 26.7 mumoles/g.cr., died. In acute hepatitis, urinary polyamine excretion was significantly less in the recovery stage compared with the acute stage. When insulin and glucagon infusion therapy was performed in patients with liver cirrhosis without ascites, urinary polyamine excretion was significantly elevated after three days. These results suggest that measuring the amount of polyamine in urine is clinically useful for monitoring hepatic regeneration.

Biogenic Polyamines↗

PubMed1990

Effect of endogenous and exogenous polyamines on organic cation transport in rabbit renal plasma membrane vesicles.

The effect of several polyamines on the transport of organic cations [N1-[3H]methylnicotinamide (NMN), [3H]NMN and 3H-tetraethylammonium, ([3H]TEA)] in rabbit renal brush border (BBMV) and basolateral membrane vesicles (BLMV) was studied using a rapid filtration assay. Under pH-driven conditions in BBMV, [3H]NMN transport was cis inhibited approximately 30% by the naturally occurring polyamines (cadaverine, putrescine, spermine and spermidine) and nearly 90% by methylglyoxal bis(guanylhydrazone) (MGBG), a synthetic polyamine, mepiperphenidol and cimetidine, classical organic cation transport inhibitors. In the absence of a pH gradient, the capability of these agents to block [3H]NMN transport was diminished. The capability of these compounds to translocate the membrane was assessed by examining the phenomenon of counterflow. TEA, mepiperphenidol and MGBG produced trans stimulation of TEA uptake, whereas putrescine did not. Kinetic studies revealed that both putrescine and MGBG affected the Km value for TEA transport while having a minimal effect on the Vmax value. These results are most consistent with competitive inhibition. The specificity of polyamine inactivation of organic cation transport was assessed by examining what effect they had on the transport of another brush border transporter, D-glucose. These agents did not inhibit D-glucose transport. In addition, the effect of polyamines on the transport of organic cations in BLMV was studied. Only MGBG, cimetidine and mepiperphenidol inhibited organic cation transport. The results indicate that endogenous polyamines cis inhibited the organic cation transporter in BBMV competitively, whereas the exogenous polyamine MGBG cis inhibited competitively and produced trans stimulation. In contrast in BLMV, only MGBG was an effective inhibitor.

Animals↗

PubMed1989

Polyamines, molecules necessary for cell division, colocalize with peptide growth factors.

The naturally occurring polyamines spermidine and spermine are necessary for cell division and growth. By restaining experiments, using three independent polyamine cytochemical methods, together with peptide immunocytochemistry, we show that substantial amounts of polyamines occur in a number of peptide growth factor-producing cell types. These include submandibular granular convoluted duct cells producing epidermal growth factor (EGF), pancreatic islet cells producing insulin and anterior pituitary cells producing growth hormone (GH). Other cell types in these tissues display only weak or no polyamine reactivity. Also blood platelets, known to contain platelet-derived growth factor (PDGF), are strongly stained for polyamines. Moreover, in EGF cells, insulin cells and blood platelets, polyamines are clearly localized in secretory granules. The possibility that polyamines may be coreleased and act in concert with peptide growth factors is discussed.

Animals↗

PubMed1989

Major increases in spermidine/spermine-N1-acetyltransferase activity by spermine analogues and their relationship to polyamine depletion and growth inhibition in L1210 cells.

As an antiproliferative strategy, we are using bis(ethyl) derivatives of spermine to suppress polyamine biosynthetic enzyme activity and, thereby, deplete intracellular polyamine pools. Since certain of these analogues have recently been shown to potently increase spermidine/spermine-N1-acetyltransferase activity, we have investigated the relationship of this effect to growth inhibition and polyamine depletion. The cellular effects of N1,N12-bis(ethyl)spermine (BESPM) and two of its homologues, N1,N11-bis(ethyl)norspermine (BENSPM) and N1,N14-bis(ethyl)homospermine (BEHSPM), were compared in L1210 cells following treatments at equimolar concentrations (2 microM) and at concentrations (0.5 microM BEHSPM; 2 microM BESPM, and 20 microM BENSPM) producing comparable intracellular concentrations (2600-3000 pmol/10(6) cells) of the analogues. At 2 microM, BENSPM increased total polyamine N-acetyltransferase activity by 15-fold, BESPM, by 7-fold, and BEHSPM, by only 1.5-fold. These differences were much more exaggerated at comparable intracellular concentrations, where BENSPM increased enzyme activity 31-fold, BESPM, 7-fold, and BEHSPM had no effect. This rank order in effectiveness sharply contrasted effects on cell growth and interference with polyamine biosynthesis, which correlated more with intracellular accumulation of the analogues. At 2 microM, BEHSPM was most effective in suppressing ornithine and S-adenosylmethionine decarboxylases, depleting polyamine pools, and inhibiting cell growth, followed by BESPM and then by BENSPM. Thus, the data indicate that, in L1210 cells, the large increases in spermidine/spermine-N1-acetyltransferase activity produced by the analogues do not appear to contribute significantly to polyamine depletion or to be causally related to inhibition of cell growth. These studies also identify BENSPM as the most potent modulator of spermidine/spermine-N1-acetyltransferase activity thus far studied in cell culture systems. To a large extent, its greater effectiveness over BESPM seems to be attributable to a major increase in prolongation of enzyme half-life (3.9 versus 1.3 h), presumably due to enzyme stabilization caused by differential binding of the analogues at the enzyme active site.

Acetyltransferases↗

PubMed1987

Cytotoxic response of the relatively difluoromethylornithine-resistant human lung tumor cell line NCI H157 to the polyamine analogue N1,N8-bis(ethyl)spermidine.

Difluoromethylornithine (DFMO), an enzyme activated irreversible inhibitor of ornithine decarboxylase (ODC), depletes intracellular putrescine, and spermidine (Spd), but not spermine, and generally leads to an inhibition of cell proliferation, without cell death, in both normal and neoplastic cells. This is the case with a culture line of human large cell undifferentiated lung cancer, NCI H157, which will survive indefinitely in DFMO containing medium and ultimately actually grows through the DFMO block. We now provide evidence that a Spd analogue, N1,N8-bis(ethyl)spermidine (BES) also suppresses ODC activity in H157 cells but leads not only to complete depletion of putrescine and Spd but also reduces intracellular spermine to 20-30% of control levels. This depletion of polyamines is accompanied by a rapid decrease in cell proliferation and ultimately cell death. The cell death resulting from BES treatment is in direct contrast to results obtained with DFMO and occurs at concentrations of less than 10 microM, whereas 5 mM DFMO is required to maintain growth inhibition in NCI H157. The observed suppression of ODC activity by BES is consistent with mechanisms by which Spd itself regulates ODC activity. Our data suggest that although both agents, DFMO and BES, interfere with polyamine metabolism, the differential sensitivities to these agents indicate susceptibility to polyamine depletion may be agent and cell type specific. Such differences may be related to the different requirement of individual cell types for polyamines and different regulatory events in polyamine biosynthesis. These differences may be exploitable in the treatment of neoplastic disease with polyamine analogues or inhibitors of polyamine biosynthesis.

Carcinoma, Non-Small-Cell Lung↗

PubMed1988

Urinary polyamines as markers of cardiac allograft rejection. A clinical evaluation.

Histologic evaluation of endomyocardial biopsy specimens is the current method of monitoring rejection after cardiac transplantation. Unfortunately, this technique gives a discontinuous evaluation of the recipient immunologic status. A noninvasive marker of immunologic activation and of allograft rejection that would permit a more continuous monitoring than the biopsy technique would be clinically useful. Urinary polyamine excretion reflects cellular proliferation or degeneration and, as a marker of cellular metabolic activity, may also reflect lymphocyte proliferation and organ rejection. From July 1985 to December 1986, urinary polyamines were studied in 18 patients during hospitalization for heart and heart-lung transplantation. Endomyocardial biopsy was performed twice a week and histologic rejection was characterized by standard criteria. Urinary specimens were collected daily and analyzed for polyamines by high-pressure liquid chromatography. Concentrations of acetylputrescine and total urinary polyamines were significantly higher before the 20 rejection episodes than before the 80 biopsies yielding negative results. So that their clinical usefulness could be evaluated, an elevation of polyamines and a daily level variability of 28% or more was chosen to indicate increased metabolic cellular activity and to predict rejection in the next 8 days. On the basis of these definitions, the sensitivity of polyamine assays to predict rejection was 85%, the specificity 88%, and the positive predictive value 79%. Therefore, serial measurements of urinary polyamines may provide daily information on the recipient's immunologic status after cardiac transplantation.

Adult↗

PubMed1987

Comparison of DNA interstrand cross-linking and strand breakage by 1,3-bis(2-chloroethyl)-1-nitrosourea in polyamine-depleted and control human adenocarcinoma cells.

Recent evidence from our laboratory and from others suggested that pretreatment with alpha-difluoromethylornithine (DFMO) sensitizes some human and rodent tumor cell lines to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Many human tumor cells are resistant to chloroethylnitrosourea-induced DNA interstrand cross-linking and cell kill due to their high levels of the DNA repair protein O6-alkylguanine DNA alkyltransferase. We therefore investigated DFMO-mediated sensitization to BCNU in BCNU-sensitive and -resistant cells. Colony formation assays were used to compare BCNU cytotoxicity in DFMO-pretreated and control cultures of two colon tumor lines, HT-29 cells, which have high alkyltransferase levels and thus are BCNU-resistant, and BE cells, which are deficient in this repair capacity and thus are BCNU-sensitive. Polyamine depletion significantly enhanced BCNU cytotoxicity only for the repair-proficient HT-29 cell line. BE cells were 40-fold more sensitive to BCNU than were HT-29 cultures. However, in BE cells, no effect of polyamine depletion was found on cellular response to BCNU treatment at 72 h after DFMO treatment. Reverse-phase high-performance liquid chromatography assays of polyamine concentrations in cell extracts verified that DFMO produced comparable degrees of polyamine depletion for both cell lines. DNA alkaline elution analysis was used to monitor BCNU-induced formation of DNA single strand breaks, DNA interstrand cross-links, and DNA-protein cross-links. Equal concentrations of BCNU produced similar levels of strand breaks and DNA-protein cross-links in DFMO-pretreated and control cultures for both cell lines. These data suggest that DNA in polyamine-deficient HT-29 and BE cells is not more accessible to BCNU than is DNA in controls. No DNA interstrand cross-links were detected in either DFMO-pretreated or control HT-29 cells after BCNU treatment. Further, in BE cells which accumulate BCNU-induced DNA interstrand cross-links, no increase in the measureable levels of cross-links resulted from polyamine deficiency. Our observations suggest that mechanisms other than increased DNA interstrand cross-link formation may be mediating the enhanced efficacy of BCNU in polyamine-deficient HT-29 cell cultures. Our findings may also imply that cellular targets for BCNU other than DNA damage may be responsible for DFMO-induced chemosensitization in the repair-proficient cells.

Adenocarcinoma↗

PubMed1988

Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy.

The polyamine-biosynthetic pathway represents an inviting target for the development of agents inhibiting carcinogenesis and tumor growth. Polyamines play an essential role in the proliferation and development of mammalian cells. Deranged polyamine metabolism may be an important factor in carcinogenesis. Depletion of polyamines inhibits growth of neoplastic cells in vitro and in animal models. Several different classes of other anticancer agents may under some conditions exert enhanced effects when polyamine levels are depleted. Some suitable inhibitors of polyamine production are currently available and other promising compounds are presently being tested. It should soon prove possible to block polyamine biosynthesis at every step in the pathway. The use of these inhibitors alone and combined either with each other or with other antitumor agents will enable a full examination of the potential of this approach.

Animals↗

PubMed1988

Control of ornithine decarboxylase activity in alpha-difluoromethylornithine-resistant L1210 cells by polyamines and synthetic analogues.

The regulation of ornithine decarboxylase (ODC) activity by the polyamine derivatives N1,N8-bis(ethyl)-spermidine and N1,N12-bis(ethyl)spermine was studied using a line of L1210 cells resistant to alpha-difluoromethylornithine (D-R cells), which contain very high levels of ODC, and a synthetic mRNA prepared from a plasmid containing an insert corresponding to ODC mRNA adjacent to an SP6 RNA polymerase promoter. Studies in which ODC protein was labeled in the D-R cells by exposure to [35S]methionine indicated that the polyamine derivatives and their physiological counterparts led to an increased rate of degradation of ODC and to a rapid reduction in ODC synthesis without affecting the content of ODC mRNA. Direct evidence that the polyamine derivatives act by inhibiting the translation of the ODC mRNA was obtained by studying their effects on the translation of ODC mRNA in reticulocyte lysates. This translation was strongly inhibited by the addition of N1,N8-bis(ethyl)spermidine, spermidine, N1,N12-bis(ethyl)spermine, or spermine but was not affected much by putrescine. The inhibition of the translation of ODC mRNA by either of the bis(ethyl) polyamine derivatives occurred at concentrations which stimulated total protein synthesis showing the selectivity of the reduction in ODC. The effects of polyamine derivatives and polyamines on translation of the plasmid-derived ODC mRNA were identical with those found with the D-R L1210 cell mRNA. This synthetic ODC mRNA lacks 261 bases of the 5'-leader sequences and 200 bases plus the poly(A) section from the 3'-nontranslated sequence. Therefore, these regions appear not to influence sensitivity of the ODC mRNA to inhibition of translation by polyamine derivatives.

Animals↗

PubMed1988

[The clinical value of urinary polyamine analysis in urological disease].

To study the clinical usefulness of the determination of urinary polyamine levels, voluntary urine of several urological diseases including 56 bladder tumor patients was analyzed by high performance liquid chromatography. The obtained values were adjusted by the concentration of urinary creatinine and expressed as the unit of mumol/g creatinine (mumol/g Cr) From the measurement of 8 normal adults, the normal upper limit of each polyamine was decided by mean + 2SD, and the limit for total polyamine was 59.1 mumol/g Cr, putrescine 38.1 mumol/g Cr, spermidine 16.6 mumol/g Cr and spermine 9.2 mumol/g Cr, respectively. In the patients with non-neoplastic benign urological disease, the polyamine levels were statistically not different from those of the normal adults. In the case of bladder tumor, the urinary levels of total polyamine, putrescine and spermine were significantly elevated compared with the control group. The true positive rate of this determination in bladder tumor patients was 26/56 (46%) by total polyamine level, 21/56 (38%), by putrescine level, 11/56 (56%) by spermidine level and 16/56 (29%) by spermine level. Grade or stage of the bladder tumor did not have any significant correlation with the urinary polyamine level. This determination would not be included in routine clinical examinations due to the difficulty of measurement, difference of urine sampling and lack of high sensitivity and specificity.

Biomarkers, Tumor↗

PubMed1987

[Urine levels of polyamine in patients with or without cancer].

The urine levels of polyamine (total amount of putrescine, spermidine and cadaverine) were measured in patients with or without cancer by simple enzymatic assay method. In 148 control healthy adults, the urine levels of polyamine were 23.1 +/- 7.1 mumole/g. creatinine, whereas among 52 patients with benign diseases, the level in only 5 patients was slightly higher than normal level. The polyamine levels in 170 patients with cancer was 46.1 +/- 50.6 mumole/g. creatinine, which was about 2-times higher than normal level. In the patients with cancer of the stomach or the colon and rectum, the increase in polyamine level appeared to be correlated with the clinical stage of tumor. Following successful surgical resection of cancer, the polyamine level increased in one week transitorily after operation but gradually decreased to normal level within 5 weeks. Whereas following unsuccessful surgical resection of cancer, the polyamine value maintained high levels. The evidence suggests that the measurement of the urine level of polyamine is useful for the diagnosis of cancer or the clinical stage of tumor, and it will be helpful in the evaluation of therapeutic effects and prognosis.

Adult↗

PubMed1985

Urinary polyamines as a tumor marker.

We recently established a new simple enzymatic assay method for measuring total urinary polyamines. To evaluate the clinical usefulness of measuring total urinary polyamines as a tumor marker, we have applied this method to the assay of polyamines in the urine of cancer patients. Elevation above 3 SD of the normal mean was found in 116 of the 181 patients with cancer (stomach 49/72 [68.1%], colon 22/32 [68.8%], lung 16/24 [66.7%], blood 15/27 [55.6%], liver 3/14 [21.4%], gallbladder 4/4 [100%], and esophagus 7/8 [87.5%]). Total urinary polyamine levels were determined before and after surgery in 36 patients with gastrointestinal cancer (stomach 22 and colon 14). Urinary polyamine levels fell to within the normal range after successful surgery in 23 of 30 patients who had showed elevated levels of urinary polyamines before surgery. Our data indicate that the determination of total urinary polyamines by our new assay may be useful as a tumor marker.

Humans↗

PubMed1980

Cerebrospinal fluid polyamines in patients with Glioblastoma multiforme and anaplastic astrocytoma.

Eighteen cerebrospinal fluid polyamine determinations in 12 patients with glioblastoma multiforme and 76 determinations in 37 patients with anaplastic astrocytoma were evaluated. Cerebrospinal fluid polyamine levels showed no significant relationship to the degree of malignancy or to enhanced tumor volume or volume of tumor central low density as determined by contrast-enhanced computerized tomography. A significant correlation was found between polyamine levels and the proximity of the tumor to the cerebral ventricles. Polyamine levels were correlated with clinical status as determined by neurological examination, radionuclide scan, and computerized tomography. Compared with those of stable patients, cerebrospinal fluid polyamine levels were significantly elevated in patients with recurrent tumors; however, elevation of polyamine levels did not appear to precede tumor recurrence. A large fraction of the results were false-positive or false-negative results. In contrast to our findings in patients with medulloblastoma, it appears that cerebrospinal fluid polyamine levels determinations may be of little use for monitoring tumor progression in patients with glioblastoma multiforme and anaplastic astrocytoma.

Astrocytoma↗

PubMed1983

Influence of polyamine depletion caused by alpha-difluoromethylornithine, an enzyme-activated irreversible inhibitor of ornithine decarboxylase, on alkylation- and carbamoylation-induced cytotoxicity in 9L rat brain tumor cells in vitro.

Using a colony-forming efficiency assay, we studied the effect of polyamine depletion on the cytotoxicity of four nitrosoureas with different capacities to alkylate and/or carbamoylate biomolecules. 9L rat brain tumor cells were treated with 10 mM alpha-difluoromethylornithine for 48 hr before a 1-hr treatment with nitrosoureas. The cytotoxicity of 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose, which alkylates and subsequently cross-links DNA but does not carbamoylate, was significantly increased by depletion of intracellular polyamines; the dose enhancement ratio of 1.3 is identical to that found for 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl-1-nitrosourea in previous studies. Addition of exogenous putrescine to polyamine-depleted 9L cells 24 hr before treatment prevented this phenomenon. In contrast, the cytotoxicity of 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea, which carbamoylates only, was significantly decreased in polyamine-depleted cells. This compound alone reduced intracellular polyamine levels. Polyamine depletion did not affect the cytotoxicity of the monoalkylating nitrosoureas N-ethyl-N-nitrosourea and N-methyl-N-nitrosourea. Thus, polyamine depletion apparently potentiates the cytotoxicity only of chloroethylnitrosoureas that alkylate and cross-link.

Animals↗

PubMed1984

Kinetics of activation of casein kinase II by polyamines and reversal of 2,3-bisphosphoglycerate inhibition.

The effects of polyamines on the catalytic activity of casein kinase II have been studied. Of the three polyamines tested (putrescine, spermidine, and spermine), spermine was the most effective at stimulating the enzyme. When physiological concentrations of potassium and magnesium were utilized, 50% activation was observed at 0.28 mM spermine or 0.70 mM spermidine. With mixtures of spermine and spermidine at physiological concentrations for the reticulocyte (0.04 and 1.06 mM, respectively), a 2.5-fold stimulation of casein kinase II activity was observed. In general, stimulation of the enzyme was dependent on salt concentration and it was necessary to hold ionic strength constant in order to separate specific activation by the polyamines from general salt activation. Optimum activation by polyamines was observed at low ionic strength and physiological concentrations of Mg2+. When beta-casein and eukaryotic initiation factors 2 or 3 were used as substrates, up to 3.5-fold stimulation of casein kinase II was observed. In the absence of polyamine, half-saturation of the enzyme by Mg2+ was observed at 1-3 mM MgCl2, a concentration much higher than required for ATP-Mg2+ complex formation. This dependence of the enzyme on Mg2+ was greatly diminished in the presence of spermine. Spermine decreased the apparent Km for casein and increased the maximum velocity of the reaction. Spermidine and spermine also effectively reversed inhibition by 2,3-bisphosphoglycerate. The significant activation by polyamines observed under conditions similar to those measured for the red cell suggest that the polyamines, spermidine and to a lesser extent spermine, function to regulate casein kinase II in vivo.

2,3-Diphosphoglycerate↗

PubMed1982

Decreased cytotoxicity of cis-diamminedichloroplatinum(II) by alpha-difluoromethylornithine depletion of polyamines in 9L rat brain tumor cells in vitro.

Before treatment with the cytotoxic drug cis-dichlorodiammineplatinum(II) (cis-platinum), 9L rat brain gliosarcoma cells grown in vitro were depleted of intracellular polyamines by alpha-difluoromethylornithine (DFMO; 10 mM, 48 hr), an enzyme-activated, irreversible inhibitor of the polyamine-synthetic enzyme ornithine decarboxylase. In contrast to studies that showed that the cytotoxicity of 1,3-bis (2-chloroethyl)-1-nitrosourea as measured by colony-forming efficiency is enhanced by DFMO depletion of intracellular polyamines, the cytotoxicity of cis-platinum was significantly decreased in polyamine-depleted 9L cells. At 10, 1, and 0.1% survival levels, the dose modification factors were 2.0 to 2.1. Addition of exogenous putrescine to polyamine-depleted 9L cells 24 hr before treatment with cis-platinum partially reversed this phenomenon. When 9L cells were treated either with DFMO and cis-platinum or with DFMO, putrescine, and cis-platinum for 1 hr, a time period that is too short for DFMO to affect intracellular polyamine levels, the cytotoxicity of cis-platinum was decreased, but to a significantly lesser extent than by the 48-hr DFMO pretreatment. Putrescine alone did not alter the cytotoxic effect of cis-platinum when administered either 24 or 1 hr before treatment. DFMO appears to affect cis-platinum cytotoxicity by two different mechanisms, the first mediated through polyamine depletion and the second through a direct interaction with cis-platinum.

Animals↗

PubMed1977

Insulin-like effects of polyamines in fat cells. Mediation by H2O2 formation.

Significant amounts of H2O2 were produced when the polyamines, spermine, or spermidine were incubated with a Krebs-Ringer phosphate buffer that contained bovine serum albumin (Fraction V). This effect was specific for certain amines and could be prevented by treatment of the albumin fraction with isoniazid or aminoguanidine. These features suggest that H2O2 is formed during oxidative deamination of the polyamines catalized by spermine oxidase, a known contaminant of Fraction V bovine serum albumin. The insulin-like effects elicited by polyamines in fat cells (e.g. enhancement of glucose transport and inhibition of cAMP-mediated lipolysis) were dependent on H2O2 production. Incubation of cells with catalase or treatment of the albumin fraction with isoniazid abolished the stimulation of glucose uptake by polyamines but did not alter the stimulatory effects of insulin or vitamin K5. The H2O2 generating activity was partially separated from the albumin by gel filtration; only those fractions which formed H2O2 provided support for the activation of glucose transport by polyamines. Also, the time needed to activate glucose uptake was markedly shortened by incubation of the albumin buffer with the polyamines before addition of the cells. These findings indicate that the polyamines do not themselves mimic the actions of insulin but that the insulin-like effects result from the formation of H2O2 which has been shown to stimulate glucose transport.

Adipose Tissue↗

PubMed1993

Polyamine-like actions of peptides derived from conantokin-G, an N-methyl-D-aspartate (NMDA) antagonist.

Conantokins-T and -G are highly conserved polypeptides derived from Conus venoms. The N-methyl-D-aspartate (NMDA) antagonist properties of these compounds have been attributed to a potent noncompetitive inhibition of polyamine responses. Substitution of the highly conserved gamma-carboxyglutamate residues as well as modification of the N and C termini of conantokin-G abolished the inhibition of polyamine responses at the NMDA receptor complex. However, several of these modified polypeptides closely mimicked the neurochemical profile of polyamines at the NMDA receptor complex. One of these derivatives, Tyr0-conantokin-G, was found to be the most potent compound exhibiting polyamine-like actions at the NMDA receptor complex described to date, approximately 7-fold more potent than spermine. Circular dichroism studies demonstrate a significant alpha-helical content in conantokin-G (27% in aqueous medium). However, this alpha-helicity is not sufficient for the NMDA antagonist action of the parent peptide and is neither necessary nor sufficient for the polyamine-like behavior of several conantokin-G analogs. The modified conantokin-G derivatives described in this report should be useful probes for examining the role of both polyamines and the polyamine recognition site in the operation of the NMDA receptor complex.

Amino Acid Sequence↗