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Amino Acids: The Forum for Amino Acid, Peptide and Protein Research (v.25, #1)

Peptides with anticancer use or potential by Y. L. Janin (pp. 1-40).

This review is an attempt to illustrate the diversity of peptides reported for a potential or an established use in cancer therapy. With 612 references, this work aims at covering the patents and publications up to year 2000 with many inroads in years 2001–2002. The peptides are classed according to four categories of effective (or plausible) biological mechanisms of action: receptor-interacting compounds; inhibitors of protein-protein interaction; enzymes inhibitors; nucleic acid-interacting compounds. The fifth group is made of the peptides for which no mechanism of action has been found yet. Incidentally this work provides an overview of many of the modern targets of anticancer research.

Keywords: Keywords: Peptides; Antitumor

Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: Challenging the gene dosage effect hypothesis (Part IV) by M. S. Cheon; K. S. Shim; S. H. Kim; A. Hara; G. Lubec (pp. 41-47).

Down syndrome (DS) is the most frequent genetic disorder with mental retardation and caused by trisomy 21. Although the molecular mechanisms of the various phenotypes of DS could be due to overexpression of gene(s) on chromosome 21, several groups have challenged this gene dosage effect hypothesis. The near completion of the sequencing of human chromosome 21 provides unprecedented opportunities to understand the molecular pathology of DS, however, functional information on gene products is limited so far. We therefore evaluated the levels of six proteins whose genes are encoded on chromosome 21 (trefoil factor 1, trefoil factor 2, trefoil factor 3, coxsackie virus and adenovirus receptor, carbonyl reductase 1 and interferon-α receptor) in fetal cerebral cortex from DS and controls at the early second trimester using Western blot analysis. None of the investigated proteins showed overexpression in DS compared to controls suggesting that these proteins are not involved in abnormal development of fetal DS brain and that DS phenotype can not be simply explained by the gene dosage effect hypothesis. We are systematically quantifying all proteins whose genes are encoded on chromosome 21 and these studies may provide a better understanding of genotype-phenotype correlation in DS.

Keywords: Keywords: Carbonyl reductase 1; Chromosome 21; Coxsackievirus and adenovirus receptor; Down syndrome; Interferon-α receptor; Trefoil factor

Proteomic analysis of the cerebrospinal fluid of patients with schizophrenia by L. Jiang; K. Lindpaintner; H.-F. Li; N.-F. Gu; H. Langen; L. He; M. Fountoulakis (pp. 49-57).

We applied proteomics technologies to analyze the cerebrospinal fluid of patients with schizophrenia. Such an analysis can result in the identification of proteins, which may play a role in the disease progress and thus lead to the discovery of clues of the etiology of schizophrenia. Cerebrospinal fluid from patients and controls was analyzed by two-dimensional gels and the proteins were identified by matrix-assisted laser desorption ionization mass spectrometry (MS) in the MS and MS/MS mode. 54 different gene products were identified, which were mainly plasma proteins. The level of apolipoprotein A-IV was significantly decreased in the schizophrenic patients compared to that in the controls. Little is known about the function of this apolipoprotein in the central nervous system. The levels of certain other proteins, like haptoglobin, fibrinogen, complement component 3, and Gc-globulin, were altered in the disease group as well, however, the changes did not reach a statistical significance.

Keywords: Keywords: Apolipoprotein A-IV; Central nervous system; Cerebrospinal fluid; Proteomics; Schizophrenia

Electrochemical assay of human haemoglobin S-nitrosylation by nitrosocysteine by C. P. Palmerini; R. Palombari; G. Arienti (pp. 59-62).

Oxyhaemoglobin (oxyHb) and methaemoglobin (metHb) react with S-nitrosocysteine (CysNO) to form nitroso derivatives. We test this reaction with a new method for evaluating transnitrosation reaction. The assay exploits an amperometric sensor developed in our laboratory. The results we obtain are in good agreement with those reported by others, although at much higher sensitivity, indicating the suitability of the method for examining high-mass nitroso compounds.The S-nitrosylation of oxyHb at a CysNO/haem ratio of 1 : 1 is about 5% in 60 min. In the same experimental conditions, the nitrosylation of met-Hb reaches 25%. OxyHb and metHb derivatize by 50% in 60 min upon using a CysNO/haem ratio of 10 : 1.The oxidation of haem iron occurs at ratios of haem/CysNO of 1 : 5 or higher.We conclude that CysNO transfers NO⁺ both to metHb and oxyHb.We propose that NO transfer in RBC may occur through transnitrosation reactions between high and low-mass nitrosothiols.

Keywords: Keywords: Cysteine; Nitrosocysteine; Haemoglobin; Methaemoglobin; Oxyhaemoglobin

A hypothesis on the biochemical mechanism of BH₄-responsiveness in phenylalanine hydroxylase deficiency by R. Steinfeld; A. Kohlschütter; K. Ullrich; Z. Lukacs (pp. 63-68).

We describe six children with tetrahydrobiopterin (BH₄) responsive phenylalanine hydroxylase (PAH) deficiency. All patients carry two mutant alleles in the PAH gene. Cofactor deficiency was excluded. The effect of BH₄ administration was studied by correlating different oral BH₄ doses with plasma phenylalanine levels under defined protein intake. Our results indicate that oral BH₄ supplementation may be used as long-term treatment for individuals with BH₄-responsive PAH deficiency, either without or in combination with a less restrictive diet. Previous in vitro studies have demonstrated that BH₄ inhibits PAH tetramers but activates PAH dimers. This may indicate, that BH₄-responsiveness results from BH₄ induced stabilization of mutant PAH dimers. In addition, interindividual differences in the cellular folding apparatus may determine the tertiary structure and the amount of mutant PAH dimers and hence may account for divergent BH₄-responsiveness reported for the same PAH genotype.

Keywords: Keywords: BH4-responsive PKU; Tetrahydrobiopterin; Mechanism

Plasma amino acids concentration in amyotrophic lateral sclerosis patients by J. Ilżecka; Z. Stelmasiak; J. Solski; S. Wawrzycki; M. Szpetnar (pp. 69-73).

Previous investigations showed an impairment of amino acids (AA) metabolism in amyotrophic lateral sclerosis (ALS). It was hypothesized that excitatory AA may play an important role in the etiopathogenesis of this disease. The aim of the study was to determine plasma AA concentrations in ALS patients, and to examine the relationship between AA and the clinical state of ALS patients, the type of ALS onset and the duration of the disease. The study involved 20 ALS patients and 30 control group people. The AA analysis was performed by ion – exchange chromatography on an automatic AA analyser. The results showed significantly decreased concentrations of valine, isoleucine, leucine, tyrosine and aspartate in the plasma of the whole group of ALS patients compared to the control group, and a significantly decreased concentration of arginine in the patients with a long duration of ALS compared to the patients with a short duration. The clinical state of ALS patients significantly influenced only plasma alanine concentration. Other plasma AA concentrations were not significantly associated with clinical parameters of the disease. Our study confirms that metabolic abnormalities concerning AA exist in ALS patients. However, the normal plasma glutamate concentration observed in this study in the whole group of ALS patients compared to the controls does not exclude that this excitatory AA may play a role in neurodegeneration in ALS.

Keywords: Keywords: Amyotrophic lateral sclerosis; Neurodegeneration; Plasma amino acids

Regulation of L-leucine transport in rat kidney by dexamethasone and triiodothyronine by M. Schwertfeger; K. Pissowotzki; Ch. Fleck; P. M. Taylor (pp. 75-83).

We have investigated the transport mechanisms involved in the stimulation of renal tubular reabsorption of large amino acids by glucocorticoids in vivo through the examination of activity and expression of specific transport systems L and y⁺L for L-leucine in membrane preparations of rat kidneys. Kidneys were removed from adult female Wistar rats treated with dexamethasone or triiodothyronine, and the fractions of brush-border and basolateral membranes were isolated by density gradient centrifugation. Functional analysis of L-leucine uptake using rapid filtration technique revealed induction of a sodium-dependent, arginine-inhibitable system y⁺L transport component in the basolateral membrane in the dexamethasone-treated group. A minor sodium-independent, BCH-inhibitable, system L transport component was unaffected by glucocorticoids. L-leucine uptake remained unaffected in the triiodothyronine-treated group. Expression of both subunits of the system y⁺L transporter was increased in dexamethasone-treated rat kidneys: Western blot analysis showed a significant (46%) increase of 4F2hc protein abundance in the basolateral membrane fraction and competitive RT-PCR revealed an almost 4-times induced expression of y⁺LAT1 mRNA. Our results indicate that system y⁺L in rat kidney is regulated by glucocorticoids. We suggest that enhancement of both 4F2 heavy chain and y⁺LAT1 light chain is necessary for induction of this transport system in the kidney.

Keywords: Keywords: Amino acid transport; Kidney; Glucocorticoid hormones; Thyroid hormones; Leucine

Leucine supplementation does not enhance acute strength or running performance but affects serum amino acid concentration by H. T. Pitkänen; S. S. Oja; H. Rusko; A. Nummela; P. V. Komi; P. Saransaari; T. Takala; A. A. Mero (pp. 85-94).

This study described the effect of leucine supplemen-tation on serum amino acid concentration during two different exercise sessions in competitive male power athletes. The subjects performed a strength exercise session (SES; n = 16; 26 ± 4 years) or a maximal anaerobic running exercise session (MARE; n = 12; 27 ± 5 years) until exhaustion twice at a 7-day interval. The randomized subjects consumed drinks containing leucine (100 mg × kg/body weight before and during SES or 200 mg × kg/body weight before MARE) or placebo. Blood specimens taken 10 min before (B) and after (A) the sessions were analyzed for serum amino acids. In SES the concentration of leucine was distinctly higher in the leucine supplemented group than in the placebo group in both B (p < 0.001) and A (p < 0.001) samples. The leucine concentration decreased in placebo but not in the leucine supplemented group following the exercise session. Isoleucine (p = 0.017) and valine (p = 0.006) concentration decreased more in the leucine supplemented group than in placebo in A samples. In MARE the concentration of leucine was higher in the leucine supplemented group than in placebo in both B (p < 0.001) and A (p < 0.001) samples and increased (p < 0.001) in the supplemented group following the session. Isoleucine (p = 0.020) and valine (p = 0.006) concentration decreased in the supplemented group in A samples. There were no differences in a counter movement jump after SES or in the running performance in MARE between the leucine supplemented group and placebo. These findings indicate that consuming leucine before or before and during exercise sessions results in changes in blood amino acid concentration. However, the supplementation does not affect an acute physical performance.

Keywords: Keywords: Leucine; Amino acids; Training; Nutrition; Male athletes

Characterization of tryptophan high affinity transport system in pinealocytes of the rat. Day-night modulation by C. I. Gutiérrez; M. Urbina; F. Obregion; J. Glykys; L. Lima (pp. 95-105).

Tryptophan is required in the pineal gland for the formation of serotonin, precursor of melatonin biosynthesis. The level of this amino acid in the serum and in the pineal gland of the rat undergoes a circadian rhythm, and reduced plasma tryptophan concentration decreases secretion of melatonin in humans. Tryptophan is transported into the cells by the long chain neutral amine acid system T and by the aromatic amino acid system T. The high affinity component of [³H]tryptophan uptake was studied in pinealocytes of the rat. Inhibition was observed in the presence of phenylalanine or tyrosine, but not in the presence of neutral amino acids, alanine, glycine, serine, lysine or by 2-aminobicyclo[2,2,1]-heptane-2-carboxylic acid, a substrate specific for system L. The transport of tryptophan was temperature-dependent and trans-stimulated by phenylalanine and tyrosine, but was energy-, sodium-, chloride-, and pH-independent. In addition, the sulphydryl agent N-ethylmaleimide did not modify the high affinity transport of tryptophan in pinealocytes. The kinetic parameters were not significantly different at 12:00 as compared to 24:00 h. The treatment with the inhibitor of tryptophan hydroxylase, p-chlorophenylalanine, produced an increase in the maximal velocity of the uptake and a reduction in the affinity at 12:00, but not at 24:00 h, probably indicating that during the day, the formation of serotonin in the pineal gland is favoured by elevating the uptake of tryptophan, whereas at 24:00 h other mechanisms, such as induction of enzymes are taking place. High affinity tryptophan uptake in the rat pineal gland occurs through system T and is upregulated during the day when the availability of serotonin is reduced.

Keywords: Keywords: Amino acid transport; Day-night modifications; Pineal gland; Transport system T; Tryptophan transport

Syntheses of two neuromedin U (NMU) analogues and their comparative reducing food intake effect in rats by T. Abiko; Y. Takamura (pp. 107-110).

To examine the roles of aromatic rings Tyr residues at positions 1 and 6 and Phe residues at positions 16, 17 and 19 of rat neuromedin U-23 (NMU-23) (Tyr-Lys-Val-Asn-Glu-Tyr-Gln-Gly-Pro-Val-Ala-Pro-Ser-Gly-Phe-Phe-Leu-Phe-Arg-Pro-Arg-Asn-NH₂) for reducing food intake activity in male Wistar rats, two NMU-23 analogues, [Phe(4F)^16,17,19]NMU-23 and [Tyr(Me)^1,6]NMU-23, were synthesized by Fmoc strategy of manual solid-phase method. The synthetic NMU-23 showed reducing effect on food intake in rats. [Phe(4F)^16,17,19]NMU-23 exhibited higher reducing food intake effect than that of NMU-23. On the contrary, [Tyr(Me)^1,6]NMU-23 showed no reducing effect on food intake in rats than that of NMU-23.

Keywords: Keywords: Neuromedin U; Solid-phase method; reducing food intake; Neuromedin U analogue; Fmoc strategy; Aromatic ring substitution

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Amino Acids: The Forum for Amino Acid, Peptide and Protein Research (v.25, #1)