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Amino Acids: The Forum for Amino Acid, Peptide and Protein Research (v.26, #3)
Catabolism of polyamines by N. Seiler (pp. 217-233).
Owing to the establishment of cells and transgenic animals which either lack or over-express acetylCoA:spermidine N1-acetyltransferase a major progress was made in our understanding of the role of polyamine acetylation. Cloning of polyamine oxidases of mammalian cell origin revealed the existence of several enzymes with different substrate and molecular properties. One appears to be identical with the polyamine oxidase that was postulated to catalyse the conversion of spermidine to putrescine within the interconversion cycle. The other oxidases are presumably spermine oxidases, because they prefer free spermine to its acetyl derivatives as substrate. Transgenic mice and cells which lack spermine synthase revealed that spermine is not of vital importance for the mammalian organism, but its transformation into spermidine is a vitally important reaction, since in the absence of active polyamine oxidase, spermine accumulates in blood and causes lethal toxic effects.Numerous metabolites of putrescine, spermidine and spermine, which are presumably the result of diamine oxidase-catalysed oxidative deaminations, are known as normal constituents of organs of vertebrates and of urine. Reasons for the apparent contradiction that spermine is in vitro a poor substrate of diamine oxidase, but is readily transformed into N8-(2-carboxyethyl)spermidine in vivo, will need clarification.Several attempts were made to establish diamine oxidase as a regulatory enzyme of polyamine metabolism. However, diamine oxidase has a slow turnover. This, together with the efficacy of the homeostatic regulation of the polyamines via the interconversion reactions and by transport pathways renders a role of diamine oxidase in the regulation of polyamine concentrations unlikely. 4-Aminobutyric acid, the product of putrescine catabolism has been reported to have antiproliferative properties. Since ornithine decarboxylase and diamine oxidase activities are frequently elevated in tumours, it may be hypothesised that diamine oxidase converts excessive putrescine into 4-aminobutyric acid and thus restricts tumour growth and prevents malignant transformation. This function of diamine oxidase is to be considered as part of a general defence function, of which the prevention of histamine and cadaverine accumulation from the gastrointestinal tract is a well-known aspect.
Keywords: Keywords: Polyamines – Putrescine – Spermidine – Spermine – Polyamine oxidase – Diamine oxidase – AcetylCoA:spermidine N1-acetyltransferase (SAT)
Threonine metabolism in Japanese quail liver by S. Akagi; K. Sato; S. Ohmori (pp. 235-242).
In general, threonine is metabolized by reaction catalyzed by threonine-3-dehydrogenase (TDH), threonine dehydratase (TH) or threonine aldolase (TA). The activities of these three enzymes were compared in the liver of Japanese quails and rats. The animals were fed a standard or threonine rich-diet, or fasted for 3 days. The specific activity of TDH in the liver from quail fed a standard diet was 11 times higher than that in the liver from rats fed a standard diet. The TDH activities in the livers of the fasting and 5% threonine-rich diet groups of quail were 3 and 2 times higher than those in the livers from quail fed the standard diet, respectively. The TH activity in the liver of rats fed a standard diet was 14 times higher than that in the liver of quail fed a standard diet. The TH activity in the rat liver after fasting was 2.3 times higher than that of the standard diet control. The activity of TA in the livers of rat and quail were so low that its role in threonine metabolism in both animals seemed to be negligible. These results suggest that threonine is a ketogenic amino acid in the quail liver, while it is a glucogenic in the rat liver.
Keywords: Keywords: Threonine metabolism – Quail – D-Lactate – Methylglyoxal – Threonine-3-dehydrogenase – Threonine hydratase
Endogenous production of hydrogen sulfide in mammals by P. Kamoun (pp. 243-254).
Hydrogen sulfide is one of three gases involved in biological functions and synthesized in vivo. Like NO and CO, it seems to act as a neuromodulator: it modulates NMDA glutamate receptor function. CBS seems to be the only source of hydrogen sulfide in the brain, whereas the liver synthesizes hydrogen sulfide via cystathionase. In the heart, the third pathway for the hydrogen sulfide synthesis, the 3-mercaptopyruvate pathway is used. Only two diseases characterized by alterations of hydrogen sulfide metabolism have been described: decreased hydrogen sulfide synthesis in the brains of Alzheimer’s disease patients and increased hydrogen sulfide synthesis due to the overexpression of CBS in Down syndrome patients.
Keywords: Keywords: Cystathionase – Cystathionine beta synthase – Cystathionine gamma lyase – Down syndrome – Hydrogen sulfide – H2S – Mammals – Mercaptopyruvate sulfurtransferase
Protein levels of genes encoded on chromosome 21 in fetal Down Syndrome brain (Part V): Overexpression of phosphatidyl-inositol-glycan class P protein (DSCR5) by R. Ferrando-Miguel; M. S. Cheon; G. Lubec (pp. 255-261).
Down Syndrome (DS, trisomy 21) is the most common genetic cause of mental retardation. The completed sequencing of genes encoded on chromosome 21 provides excellent basic information, however the molecular mechanisms leading to the phenotype of DS remain to be elucidated. Although overexpression of chromosome 21 encoded genes has been documented information at the protein expression level is mandatory as it is the proteins that carry out function. We therefore decided to evaluated expression level of seven proteins whose genes are encoded on chromosome 21: DSCR4, DSCR5, DSCR6; KIR4.2, GIRK2, KCNE1 and KCNE2 in fetal cortex brain of DS and controls at the early second trimester of pregnancy by Western blotting. β-actin and neuron specific enolase (NSE) were used to normalise cell loss and neuronal loss. DSCR5 (PIG-P), a component of glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT), was overexpressed about twofold, even when levels were normalised with NSE. DSCR6 was overexpressed in addition but when normalised versus NSE, levels were comparable to controls. DSCR4 was not detectable in fetal brain. Potassium channels KIR4.2 and GIRK2 were comparable between DS and controls, whereas KCNE1 and KCNE2 were not detectable. Quantification of these proteins encoded on chromosome 21 revealed that not all gene products of the DS critical region are overexpressed in DS brain early in life, indicating that the DS phenotype cannot be simply explained by the gene dosage effect hypothesis. Overexpression of PIG-P (DSCR5) may lead to or represent impaired glycosylphosphatidylinositol-N-acetylglucosaminyltransferase mediated posttranslational modifications and subsequent anchoring of proteins to the plasma membrane.
Keywords: Keywords: DSCR4 – DSCR5 (PIG-P) – DSCR6 – KIR4.2 – GIRK2 – KCNE1 – KCNE2 – Fetal brain – Protein expression – Immunoblotting
Augmented taurine release is not the mechanism of ischemic preconditioning’s cardioprotection by T. Krieg; X.-M. Yang; J. M. Downey; S. W. Schaffer; M. V. Cohen (pp. 263-266).
In ischemic preconditioning (IPC) a brief ischemic period protects the heart from a subsequent ischemic insult by an unknown mechanism. Osmotic swelling has been proposed to be a major cause of cell death when ischemic tissue is reperfused. The present study tests whether the preconditioned heart during reperfusion might release more taurine, an important osmolyte in the cardiac myocytes, to decrease cellular osmolarity, oppose swelling, and preserve viability. We collected the coronary effluent from isolated rabbit hearts for 10 min before and 10 min after preconditioning with 5 min of global ischemia. The heart then experienced 15 min of global ischemia and effluent was collected during reperfusion for 40 min. A control group was studied similarly but without the preconditioning ischemia. Fifteen min of ischemia was chosen to avoid any taurine release caused by ischemic cell death. Taurine was measured with HPLC. In the IPC group there was a postischemic release over baseline of 5.09 ± 1.51 μmol (approx 3.3% of the total taurine pool), whereas in the control group the release was not significantly different, 5.72 ± 1.67 μmol. The percent of the taurine pool lost from each heart during reperfusion was calculated based on an assumption of a total content of 20 μM taurine/gm wet weight. Since the amount of taurine released by the isolated rabbit heart following ischemia was not different in preconditioned and non-preconditioned hearts, we conclude that reduced swelling through taurine release is not the mechanism of the cardioprotective effects of IPC.
Keywords: Keywords: Cell swelling – Ischemia – Preconditioning – Taurine
Beneficial effects of taurine on serum lipids in overweight or obese non-diabetic subjects by M. Zhang; L. F. Bi; J. H. Fang; X. L. Su; G. L. Da; T. Kuwamori; S. Kagamimori (pp. 267-271).
Taurine has beneficial effects on lipid metabolism in experimental animals fed with high-cholesterol or high fat diets. Whether taurine benefits lipid metabolism in humans has rarely been investigated. The aim of this study was to evaluate the effects of taurine on serum lipids in overweight or obese young adults. Thirty college students (age: 20.3±1.7 years) with a body mass index (BMI) ≥25.0 kg/m2, and with no evidence of diabetes mellitus were selected and assigned to either the taurine group (n=15) or the placebo group (n=15) by double-blind randomization. Taurine 3 g/day or placebo was taken orally for 7 weeks. Triacylglycerol (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and plasma glucose were measured before and after supplementation. The atherogenic index (AI) was calculated as (TC−HDL-C)/HDL-C. There were no differences in any baseline parameter between the two groups. Taurine supplementation decreased TG and AI significantly. Body weight also reduced significantly in the taurine group. These results suggest that taurine produces a beneficial effect on lipid metabolism and may have an important role in cardiovascular disease prevention in overweight or obese subjects.
Keywords: Keywords: Taurine – Obesity – Lipid metabolism – Cardiovascular diseases
Mitochondrial alterations induced by serum amine oxidase and spermine on human multidrug resistant tumor cells by G. Arancia; A. Calcabrini; M. Marra; P. Crateri; M. Artico; A. Martone; F. Martelli; E. Agostinelli (pp. 273-282).
Multidrug resistance (MDR) has been studied extensively because it is one of major problems in cancer chemotherapy. The MDR phenotype is often due to overexpression of P-glycoprotein (P-gp), that acting as an energy-dependent drug efflux pump exports various anticancer drugs out of cells. The major goal of our investigation is to establish whether bovine serum amine oxidase (BSAO), which generates the products H2O2 and aldehyde(s), from the polyamine spermine, is able to overcome MDR of human cancer cells. The cytotoxicity of the products was evaluated in both drug-sensitive (LoVo WT) and drug-resistant (LoVo DX) colon adenocarcinoma cells. A clonogenic cell survival assay demonstrated that LoVo DX cells were more sensitive than LoVo WT cells. Exogenous catalase protected cells against cytotoxicity mainly due to the formation of H2O2. However, spermine-derived aldehyde(s) still induced some cytotoxicity. The cytotoxic effect was totally inhibited in the presence of both enzymes, catalase and NAD-dependent aldehyde dehydrogenase (ALDH). Transmission electron microscopy investigations showed that BSAO and spermine induced evident mitochondria alterations, more pronounced in MDR than in LoVo WT cells. The mitochondrial activity was checked by flow cytometry studies, labelling cells with the probe JC1, that displayed a basal hyperpolarized status of the mitochondria in multidrug-resistant cells. After treatment with amine oxidase in the presence of polyamine-spermine, the cells showed a marked increase in mitochondrial membrane depolarization higher in LoVo DX than in LoVo WT cells. Our findings suggest that toxic oxidation products formed from spermine and BSAO could be a powerful tool in the development of new anticancer treatments, mainly against MDR tumor cells.
Keywords: Keywords: Polyamines – Amine oxidase – Multidrug resistance – Adenocarcinoma – Cytotoxicity – Mitochondria
Synthesis and investigation of a new cyclo (N α-dipicolinoyl) pentapeptide of a breast and CNS cytotoxic activity and an ionophoric specificity by M. Abo-Ghalia; A. Amr (pp. 283-289).
A new acylated cyclopentapeptide namely, Cyclo-(N α-dipicolinoyl)-bis-[L-Leu-DL-Nval]-L-Lys OMe (5) was suggested and synthesized. The structural conception of 5 was rationalized by analogy to the structural features of some known cyclodepsipeptides exemplified by the antibiotic and DNA intercalator actinomycin D (NSC: 3053), the ionophore and anti-HIV enniatin B (NSC: 692895) and the ionophore and antibiotic valinomycin (NSC: 630175).The cyclopeptide 5 was chemically synthesized, starting from its linear tetrapeptide ester precursor 2 by coupling L-lysine methyl ester to the prepared tetrapeptide acid 3 or hydrazide 4 via the mixed anhydride or azide method, respectively.A cytotoxic activity (cell killing) in both breast (NCF7) and CNS (SF-268) cell lines NCI, USA) was realized for 5, while less active cytotoxic profile was determined for 2.Moreover, we have recently reported general ionophoric and sensor characteristics particularly, for Pb (II) ions for both 5 and 2. Correlation between the cytotoxic activity and the ionophoric potency is a matter of future investigations.
Keywords: Keywords: Cyclopeptides – 2,6-Pyridinedicarboxlic acid – Peptide coupling methods – Cytotoxic agents – Ionophores
The facile HPLC enantioresolution of amino acids, peptides on naphthylethylcarbamate-β-cyclodextrin bonded phases using the acetonitrile-based mobile phase after their pre-column derivatization with phenyl isothiocyanate: factors that affect the resolution by S. Chen (pp. 291-298).
A variety of α-amino acids are enantioresolved for the first time on naphthylethylcarbamate-β-cyclodextrin bonded phases (i.e., SN- and RN-β-CD) using the acetonitrile-based mobile phase after their pre-column derivatization with phenyl isothiocyanate in alkaline medium. The resolution is better obtained on RN-β-CD phase and fails to reproduce if the amino acid is N-benzoylated or N-carbobenzyloxylated under the same chromatographic conditions. The enhanced resolution is believed to be due to the re-location of the hydrogen receptor site from sulfur to nitrogen on the isothiocyanyl fragment of derivatizing reagent, which in turn changes the enantioselectivity. Also, the sulfur atom is larger in size and subject to steric hindrance more significantly in comparison with oxygen. The carboxyl group of amino acid is essential toward a satisfactory resolution. The position of the amino group on the backbone affects the resolution as well. Finally, the resolution is either not observed or unsatisfactory in the reversed- or normal phase mode for most of the amino acids examined in this study.
Keywords: Keywords: Phenyl isothiocyanate – Amino acids – Peptides – Enantioresolution
Hoe 140 abolishes the blood pressure lowering effect of taurine in high fructose-fed rats by A. T. A. Nandhini; C. V. Anuradha (pp. 299-303).
High fructose feeding induces moderate increases in blood pressure of normal rats, associated with hyperinsulinemia, insulin resistance and impaired glucose tolerance. Increased vascular resistance, and sodium retention have been proposed to contribute to the blood pressure elevation in this model. Taurine, a sulphur-containing amino acid has been reported to have antihypertensive and antinatriuretic actions. In addition, taurine is shown to increase the excretion of nitrite and kinin availability and hence would be expected to improve the vascular tone. In the present study, the involvement of kinins in the blood pressure lowering effect of taurine was investigated by coadministration of Hoe 140, a kinin B2 receptor antagonist along with taurine. The effects of taurine on plasma and urinary concentrations of sodium and tissue kallikrein activity were studied in high fructose-fed rats. Fructose-fed rats had elevated blood pressure and decreased levels of sodium in urine. Treatment with 2% taurine in drinking water prevented the blood pressure elevation and coadministration of Hoe 140 abolished this effect of taurine in high fructose-fed rats. The findings confirm the antinatriuretic action of taurine and also suggest a role for the kinins in the mechanism of taurine action in diet-induced hypertension.
Keywords: Keywords: Fructose feeding – Hypertension – Kallikrein – Sodium – Taurine