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PubMed1994

The synthesis and thymidylate synthase inhibitory activity of L-gamma-L-linked dipeptide and L-gamma-amide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583).

Sixteen gamma-linked dipeptide and four L-Glu-gamma-amide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) have been synthesized and evaluated as inhibitors of thymidylate synthase (TS). Z-blocked L-Glu-gamma-L-linked dipeptides and L-Glu-gamma-amides were prepared by condensing alpha-tert-butyl-N-(benzyloxycarbonyl)-L-glutamic acid with the appropriate tert-butyl-protected L-amino acid or amine. The Z group was removed by catalytic hydrogenolysis, and the resulting dipeptides or L-Glu-gamma-amides were condensed with the appropriate pteroic acid analogue trifluoroacetate salt using diethyl cyanophosphoridate as coupling reagent. Deprotection with trifluoroacetic acid in the final step gave the desired quinazoline gamma-linked dipeptides and L-Glu-gamma-amides as their trifluoroacetate salts. Nearly all the dipeptide analogues were potent inhibitors of TS, the best being ICI 198583-gamma-L-2-aminoadipate (IC50 = 2 nM). Several of these dipeptides were found to be susceptible to enzymatic hydrolysis in mice. The quinazoline monocarboxylate L-Glu-gamma-amides, lacking an alpha'-carboxyl group, are less active against TS and L1210 cell growth but are also not susceptible to enzymatic hydrolysis in mice.

2-Aminoadipic Acid↗

PubMed1983

Chloralanyl and propargylglycyl dipeptides. Suicide substrate containing antibacterials.

A set of dipeptides containing the amino acid residues beta-chloroalanine and propargylglycine, which are mechanism-based inactivators of purified microbial enzymes (alanine racemase and cystathionine gamma-synthase, respectively), have been synthesized, and their antibacterial properties in vitro have been evaluated. Dipeptides containing a single beta-chloro-L-alanyl residue (e.g., 3, 5, 9, and 10) or a single L-propargylglycyl residue (e.g., 12 and 15) are potent antibacterials. The in vitro antibiotic activity of beta-chloro-L-alanine and of L-propargylglycine is increased as much as 4000-fold by incorporation of these residues into a dipeptide. Compounds that contain only a single enzyme-inactivating amino acid together with a second L-alanyl residue (3, 5, 12, and 15) have a restricted range of activity: of the species tested, only Streptococcus agalactiae, Staphylococcus aureus, and Staphylococcus epidermidis are sensitive. However, peptides that contain two suicide-substrate residues [e.g., beta-Cl-LAla-beta-Cl-LAla (8) or LppGly-LppGly (18)] are broad-spectrum antibacterials; as many as 12 different species of the 16 surveyed are sensitive. Dipeptides that contain an amino-terminal L-methionyl (9) or an L-norvalyl (10) residue and a carboxy-terminal beta-chloro-L-alanyl unit are also effective against a large number of organisms; the spectra of activity are like those seen for 8 and 18. A "mixed" dipeptide [beta-Cl-LAla-LppGly, (21)] gives apparent synergism of antibiotic action of beta-chloro-L-alanine and of L-propargylglycine when these two residues are incorporated into a single structure. Peptides of the D,D configuration (4, 6, 13, 16, and 20) and ones of L,D stereochemistry (e.g., 7) are not antibacterials. Peptides containing one (11 and 14) and two (17) D,L-propargylglycyl residues are unresolved sets of diastereomers; the mixtures of compounds are between two- and fourfold less active than the correspondingly resolved L,L dipeptides (12, 15, and 18). These findings are consistent with a mechanism of action for these antibiotics involving stereoselective processing of the peptidyl unit in vivo.

Alanine↗

PubMed1996

Quinazoline antifolate thymidylate synthase inhibitors: gamma-linked L-D, D-D, and D-L dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583).

The syntheses of gamma-linked L-D, D-D, and D-L dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) are described. The general methodology for the synthesis of these molecules involved the preparation of the dipeptide derivatives employing solution phase peptide synthesis followed by condensation of the dipeptide free bases with the appropriate pteroic acid analogue via diethyl cyanophosphoridate (DEPC) activation. In the final step, tert-butyl esters were removed by trifluoroacetic acid (TFA) hydrolysis. Z-L-Glu-OBut-gamma-D-Ala-OBut, for example, was prepared from alpha-tert-butyl N-(benzyloxycarbonyl)-L-glutamate and tert-butyl D-alaninate via isobutyl-mixed anhydride coupling. The Z-group was removed by catalytic hydrogenolysis and the resulting dipeptide free base condensed with 2-desamino-2-methyl-N10-propargyl-5,8-dideazapteroic acid via DEPC coupling. Finally, tert-butyl esters were removed by TFA hydrolysis to give ICI 198583-gamma-D-Ala. The compounds were tested as inhibitors of thymidylate synthase and L1210 cell growth. Good enzyme and growth inhibitory activity were found with gamma-linked L-D dipeptides, the best examples being the Glu-gamma-D-Glu derivative 35 (Ki = 0.19 nM, L1210 IC50 = 0.20 +/- 0.017 microM) and the Glu-gamma-D-alpha-aminoadipate derivative 39 (Ki = 0.12 nM, L1210 IC50 = 0.13 +/- 0.063 microM). In addition, ICI 198583 L-gamma-D-linked dipeptides were resistant to enzymatic degradation in mice.

Animals↗

PubMed1999

A combinatorial approach to the identification of dipeptide aldehyde inhibitors of beta-amyloid production.

In an effort to rapidly identify potent inhibitors of Abeta production and to probe the amino acid sequence specificity of the protease(s) responsible for the production of this peptide, a large number of dipeptide aldehydes were combinatorially synthesized and manually evaluated for their inhibitory properties. The starting point for this study was the dipeptide aldehyde carbobenzoxyl-valinyl-phenylalanal previously shown to inhibit the production of Abeta in CHO cells stably transfected with the cDNA encoding betaAPP695. Pools of related dipeptide aldehydes were combinatorially synthesized, and the most active pool was deconvoluted, resulting in the identification of the most active inhibitor of this pool. Systematic optimization of this inhibitor resulted in a series of dipeptide aldehydes with enhanced potencies relative to carbobenzoxyl-valinyl-phenylalanal. The most active dipeptide aldehydes were those that possessed hydrophobic amino acids at both the P1 and P2 positions. The most potent compound identified in this study was 3, 5-dimethoxycinnamamide-isoleucinyl-leucinal with an IC(50) of 9.6 microM, approximately 10-fold more active than carbobenzoxyl-valinyl-phenylalanal. In immunoprecipitation experiments using antibodies directed toward either Abeta1-40 or Abeta1-42, 3,5-dimethoxycinnamamide-isoleucinyl-leucinal, like carbobenzoxyl-valinyl-phenylalanal, preferentially inhibited the shorter 1-40 form of Abeta, whereas the longer 1-42 form was not as strongly inhibited. These results suggest that dipeptide aldehydes related to carbobenzoxyl-valinyl-phenylalanal inhibit Abeta through similar mechanisms and demonstrate the utility of a combinatorial synthesis approach to rapidly identify potent inhibitors of Abeta production.

Aldehydes↗

PubMed1975

Depression of jejunal dipeptide transport by pyridoxine deficiency in the rat.

Three dipeptides (L-alanyl-L-alanine, beta-alanyl-L-histidine and L-prolylglycine), representative of distinctly different transport groups, and a dicarboxylic acid dipeptide (L-glutamyl-L-glutamic acid) showed a quantitatively equivalent decrease of absorption (mean difference, 12% disappearance 15 min-1 5 cm-1) from jejunal loops in vivo in pyridoxine deficient rats, compared with pyridoxine-repleted controls. Analysis of results for seven dipeptides, including three studied previously, indicated that pyridoxine deficiency caused a general or non-specific reduction in dipeptide transport, similar for all dipeptides. Decrease in dipeptide transport in vitamin deficiency ran parallel to, but was significantly less than, the decrease in amino acid transport, suggesting in theory involvement of pyridoxine in a common cellular efflux mechanism or, less likely, in the energetics of active transport.

Animals↗

PubMed1975

A study of relations between the absorption of amino acids, dipeptides, water and electrolytes in the normal human jejunum.

1. A double-lumen perfusion technique was used to study the effect of a wide range of concentrations of the dipeptide glycyl-L-alanine and its constituent amino acids on water and electrolyte absorption from iso-osmotic solutions in the upper jejunum of normal human subjects. 2. There was no significant absorption of water and electrolytes from sodium chloride solution (150 mmol/l) but the presence of the dipeptide or its constituent amino acids stimulated water and electrolyte absorption. 3. Water absorption reached a peak at increasing amino acid and dipeptide concentrations and then tailed off. Our data suggest that the tailing off is not solely due to the diminished sodium content of the solutions. 4. During perfusion of the dipeptide-sodium chloride and amino acid-sodium chloride solutions solute and water were absorbed as an iso-osmotic solution. Analysis of the results indicates that this could occur at high dipeptide concentrations only if the majority of the dipeptide enters the cell intact.

Adult↗

PubMed1977

Effect of nephrectomy and enterectomy on plasma clearance of intravenously administered dipeptides in rats.

1. Sham-operated and bilaterally nephrectomized rats were injected intravenously with glycyl-L-leucine, glycylglycine and glycylsarcosine, and the concentrations of these dipeptides in plasma and muscle, liver, renal cortex (in the sham-operated rats) and intestinal mucosa at various intervals were determined. 2. Initially the plasma concentrations of glycyl-leucine and glycylglycine were higher in nephrectomized than in control rats but later the concentrations were similar in both groups of rats. The disappearance of these two dipeptides from plasma was almost complete within 20 min, and their plasma half-lives were not changed remarkably by nephrectomy. In contrast, nephrectomy markedly impaired disappearance of glycylsarcosine from plasma and prolonged its half-life from 7-6 min to 52-0 min. 3. Glycyl-leucine and glycylglycine were not detected in tissues of control rats injected with these dipeptides, but glycylsarcosine was recovered from all four tissues examined. Nephrectomy resulted in greater accumulations of glycylsarcosine in tissues and the appearance of glycylglycine in the remaining three tissues and glycyl-leucine in muscle. 4. Enterectomy did not have a remarkable effect on plasma half-life of glycylglycine but it allowed recovery of this dipeptide from renal cortex, liver and muscle. 5. It is concluded that kidneys amd small intestine are involved in the disposition of circulating dipeptides, but in their absence other tissues may assume a greater role in this regard. However, renal clearance appears to be an important route for the disposition of dipeptides which are poorly hydrolysed by body tissues.

Animals↗

PubMed2000

Specificity of the wound-induced leucine aminopeptidase (LAP-A) of tomato activity on dipeptide and tripeptide substrates.

Wounding of tomato leaves results in the accumulation of an exoprotease called leucine aminopeptidase (LAP-A) that preferentially hydrolyzes amino acid-p-nitroanilide and -beta-naphthylamide substrates with N-terminal Leu, Met and Arg residues. To determine the substrate specificity of LAP-A on more natural substrates, the rates of hydrolysis of 60 dipeptide and seven tripeptide substrates were determined. For comparison, the specificities of the porcine and Escherichia coli LAPs were evaluated in parallel. Several marked differences in substrate specificities for the animal, plant and prokaryotic LAP enzymes were observed. Substrates with variable N-terminal (P1) residues (Xaa) were evaluated; these substrates had Leu or Gly in the penultimate (P1') position. The plant, animal, and prokaryotic LAPs hydrolyzed dipeptides with N-terminal nonpolar aliphatic (Leu, Val, Ile, and Ala), basic (Arg), and sulfur-containing (Met) residues rapidly, while P1 Asp or Gly were cleaved inefficiently from peptides. Significant differences in the cleavage of dipeptides with P1 aromatic residues (Phe, Tyr, and Trp) were noted. To systematically evaluate the impact of the P1' residue on cleavage of dipeptides, three series of dipeptides (Leu-Xaa, Gly-Xaa, and Arg-Xaa) were evaluated. The P1' residue strongly influenced hydrolysis of dipeptides and the magnitude of its effect was dependent on the P1 residue. P1' Pro, Asp, Lys and Gly slowed the hydrolysis rates of the tomato LAP-A, porcine LAP, and E. coli PepA markedly. Analysis six Arg-Gly-Xaa tripeptides showed that more diversity was tolerated in the P2' position. P2' Arg inhibited tripeptide cleavage by all three enzymes, while P2' Asp enhanced hydrolysis rates for the porcine and prokaryotic LAPs.

Animals↗

PubMed1986

Formation of N-nitrosoiminodialkanoic acids and their unsuitability as biological monitors for endogenous nitrosation of dipeptides.

Nitrosation of dipeptides which do not contain imino acids leads to rearrangement and the formation of N-nitrosoiminodialkanoic acids. The optimum conditions for the nitrosation of dipeptides in buffer solutions occur at pH 2.0 (0.8-3.2% yield) and are not significantly catalysed by thiocyanate. In vitro nitrosation in gastric juice resulted in a lower yield. It was demonstrated that under normal gastric conditions, a maximum yield of 0.1 mumol total N-nitrosoiminodialkanoic acids/0.1 mol dipeptide would occur, 0.1 mol representing a typical dietary intake of dipeptide. This corresponds to a total concentration of approximately 20 micrograms/l N-nitrosoiminodialkanoic acids over a 24 h period. However, this figure may be significantly altered due to the fluctuation of nitrosation catalysts and inhibitors in gastric juice. Further studies showed that N-nitrosoiminodialkanoic acids are quantitatively excreted in urine when fed by gavage to rats. However, co-administration of the precursor dipeptide and nitrite resulted in negligible in vivo formation. The presence of N-nitrosoiminodialkanoic acids in normal human urine was not detected. Thus it was concluded that the monitoring of N-nitrosoiminodialkanoic acids in human urine is not a suitable method for biological monitoring of the endogenous nitrosation of dipeptides.

Animals↗

PubMed1981

Conformational characteristics of the N-acetyl-N'-methylamides of the four (Lys, Tyr) dipeptides.

The conformational properties of the N-acetyl-N'-methylamides of the dipeptides lysyl-lysine, lysyl-tyrosine, tyrosyl-lysine, and tyrosyl-tyrosine were studied by means of conformational energy calculations, by n.m.r. measurements in deuterated dimethylsulfoxide, and by circular dichroism in water, methanol, dioxane-water, and trifluoroethanol. Since these four dipeptides occur occasionally as bends in proteins, it was of interest to see whether short-range interactions, acting within the terminally blocked dipeptides, are sufficient to stabilize bend conformations significantly over other conformations. It was found that the four dipeptides exist as ensembles of conformations in solution. Therefore, it appears that longer-range interactions, such as those present in proteins, are required if bend conformations of these dipeptide sequences are to exist as stable conformations. Three of the dipeptides behave rather similarly. Both the CD and the n.m.r. experiments and computations indicate that the fourth (Lys-Tyr) differs from the others. It has a preference for compact conformations that appear to be stabilized by strong favorable interactions, primarily hydrogen bonds, between the tyrosyl and the lysyl side chains. The computations suggest that the presence of these interactions, and hence the existence of preferred conformations, is strongly solvent-dependent, and that these interactions are weakened in aqueous solution.

Circular Dichroism↗

PubMed1991

Inhibition of the release of endothelium-derived relaxing factor in vitro and in vivo by dipeptides containing NG-nitro-L-arginine.

1. We have shown that dipeptides containing NG-nitro-L-arginine (NO2Arg) inhibit the biosynthesis of endothelium-derived relaxing factor (EDRF) in vitro and in vivo. 2. In anaesthetized rats, intravenous administration at 1-30 mg kg-1 of the methyl ester of NO2Arg, NO2-Arg-L-phenylalanine (NO2Arg-Phe), L-alanyl-NO2Arg (Ala-NO2Arg) or NO2Arg-L-arginine (NO2Arg-Arg) produced dose-related increases in mean arterial blood pressure (MABP) which were unaffected by D-arginine (D-Arg; 20 mg kg-1 min-1 for 15 min), but prevented by co-infusions of L-arginine (L-Arg; 20 mg kg-1 min-1 for 15 min) or by their parent dipeptides. 3. NO2Arg methyl ester, NO2Arg-Phe methyl ester or Ala-NO2Arg methyl ester (10 mg kg-1, i.v.) also inhibited the reduction in MABP caused by the endothelium-dependent vasodilator, acetylcholine (30 micrograms kg-1 min-1 for 3 min), but not those induced by glycerly trinitrate (20 micrograms kg-1 min-1 for 3 min) or iloprost (6 micrograms kg-1 min-1 for 3 min) which act directly on the vascular smooth muscle. 4. Moreover, NO2Arg methyl ester, NO2Arg-Phe methyl ester or NO2Arg-Arg methyl ester (100 microM) inhibited the acetylcholine-induced relaxation of rabbit aortic strips, and NO2Arg-Phe methyl ester (30 microM) blocked the stimulated (bradykinin, 30 pmol) release of EDRF from bovine aortic endothelial cells grown on microcarrier beads. 5. In endothelial cells grown in L-Arg-deficient medium, L-Arg-containing dipeptides such as L-Arg-LPhe, L-Ala-L-Arg or L-Arg-L-Arg increased both the basal and stimulated release of EDRF. Moreover, the L-Arg containing dipeptides, but not their NO2Arg analogues, were rapidly cleaved by these cells. 6. Thus, dipeptides containing NO2Arg can directly interfere with the biosynthesis of EDRF in vitro and in vivo. Moreover, the potentiation of EDRF release from endothelial cells deprived of L-Arg by dipeptides containing L-Arg suggests that such peptides may serve as an additional or alternative substrate for the biosynthesis of EDRF.

Amino Acid Sequence↗

PubMed1983

Sites of dipeptide hydrolysis in relation to sites of histidine and glucose active transport in hamster intestine.

The effects of dipeptides and amino acids on the active transport of L-histidine and D-glucose by sacs of everted small intestine of the hamster have been used to determine the sites of final hydrolysis of the dipeptides in relation to the sites of active transport of L-histidine and D-glucose. The results, plus earlier observations (Wiseman, 1977), show that (a) dipeptide active transport occurs at a superficial site, followed by progressively deeper sites for (b) final hydrolysis of glycyl-phenylalanine and phenylalanyl-glycine, then deeper (c) L-histidine active transport, then (d) final hydrolysis of alanyl-alanine, alanyl-leucine, glycyl-alanine, glycyl-proline, leucyl-alanine and leucyl-leucine, then (e) D-glucose active transport, then (f) final hydrolysis of alanyl-glycine, alanyl-valine, glycyl-glycine, prolyl-glycine, valyl-alanine and valyl-valine. The site of D-glucose active transport (2e) and all the sites superficial to it (2a-d) lie in the intestinal epithelial cell's brush-border. The location within the cell of site(s) 2f is not known; it may lie in the cytosol. All the dipeptides appeared to inhibit L-histidine active transport by the release of free amino acid and not by action of intact dipeptide, supporting the view that dipeptides and free amino acids do not share a common transport pathway in the epithelium of the small intestine.

Animals↗

PubMed1972

Dipeptide absorption in man.

A quantitative perfusion method has been used to study intestinal absorption of two dipeptides-glycyl-glycine and glycyl-l-alanine-in normal subjects. In each case, the constituent amino acids were absorbed faster when presented as dipeptides than as free amino acids, suggesting intact dipeptide transport. During absorption constituent amino acids were measured within the lumen and it is suggested that these represent amino acids which have diffused back to the lumen after absorption as dipeptide. Portal blood analyses during absorption of a third dipeptide, glycyl-l-lysine, have shown that this dipeptide, known to be transported intact from the intestinal lumen, is hydrolysed to its constitutent amino acids before it reaches portal venous blood.

Adult↗

PubMed1971

Intestinal transport of dipeptides in man: relative importance of hydrolysis and intact absorption.

A 30 cm segment of the duodenum, jejunum, or ileum of normal human volunteers was perfused, on separate occasions, with test solutions containing either glycylglycine, free glycine, glycylleucine, or equimolar amounts of free glycine and free leucine. Luminal fluid contained no hydrolytic activity against glycylglycine and minimal activity against glycylleucine. In each intestinal segment, amino acid absorption rates were significantly greater from the test solutions containing the same amount of amino acids in dipeptide than in free form(as high as 185% increase). Perfusion of each intestinal segment with a test solution containing the equimolar mixture of free glycine and free leucine always resulted in a greater leucine than glycine absorption rate. This preferential absorption of leucine, however, was either diminished (jejunum) or almost abolished (duodenum and ileum) when the glycylleucine solution instead of the equimolar mixture was presented to the intestinal mucosa. Among the three segments, the duodenum exhibited the least potential for the disappearance of dipeptides. The jejunal and ileal dipeptide disappearance rates were either similar for glycylleucine (94% vs. 92%) or slightly different for glycylglycine (92% vs. 79%). Despite lack of a remarkable difference in the disappearance rates, absorption rates of constituent amino acids were markedly greater in the jejunum than in the ileum. This reduced amino acid absorption was brought about by a greater accumulation of free amino acids in the lumen of the ileal segment (3 to 10-fold difference). Inhibition of free glycine absorption by leucine during the perfusion of the intestine with a test solution containing glycylglycine and leucine did not result in any greater concentration of free glycine in the lumen than when the glycylglycine test solution did not contain free leucine. Similarly, inhibition of free glycine and free leucine absorption by isoleucine was not accompanied by any remarkable alteration of absorption rates of the constituent amino acids of glycylleucine. The results of these studies suggest that: (a) dipeptide disappearance in the gut lumen is principally accomplished by intact absorption and not by hydrolysis; (b) intracellular hydrolysis of dipeptides is markedly greater in the ileum than in the jejunum, while dipeptide absorption rates are either similar or only slightly different in these two segments; (c) there is no appreciable hydrolysis of glycylglycine by the membrane-bound enzymes and only a small fraction of glycylleucine is hydrolyzed by these enzymes.

Adolescent↗

PubMedDate not supplied

Comparison of parenteral nutrition supplemented with L-glutamine or glutamine dipeptides.

Although glutamine is an important fuel used by the intestinal mucosa and other visceral organs, it is not present in any commercially available parenteral amino acid solution. To compare the effects of L-glutamine with glutamine dipeptides, we studied the effects of each in 8 dogs and 60 Wistar rats. In the dog study, three amino acid solutions were compared: standard commercial amino acid solution (control), alanine-glutamine dipeptide-enriched solution (glutamine 3.4%), and glycine-glutamine dipeptide-enriched solution (glutamine 3.6%). Arterial and venous samples were collected to compare the effects of the three solutions on skeletal muscle amino acid exchange. In the rat study, two studies were undertaken: group 1 rats underwent only central venous catheterization; group 2 rats underwent central venous catheterization and a 50% intestinal resection. Within each group, three different solutions were infused: standard amino acid solution (control), glutamine-enriched (1.5% glutamine) solution, or glutamine dipeptide-enriched (1% glutamine) solution. After 7 days of parenteral nutrition, samples of gut, blood, and muscle were collected for determination of mucosal thickness, villus area, serum amino acid profile, liver and renal function tests, and muscle composition. When glutamine or glutamine-dipeptide solutions were administered, the dogs showed increasing serum glutamine concentrations and enhanced glutamine uptake across the hind leg muscle. Similarly, both groups of rats demonstrated significant differences in serum glutamine levels, nitrogen balance, intestinal mucosa thickness, and villus area. We conclude that both glutamine and glutamine-dipeptide infusions increase serum glutamine concentrations and result in regional tissue effects. Both exerted similar metabolic effects with no apparent complications.

Amino Acids↗

PubMed2005

A concept of dietary dipeptides: a step to resolve the problem of amino acid availability in the early life of vertebrates.

The premise that a dietary dipeptide approach will improve the understanding of amino acid utilization in the fastest-growing vertebrate, the teleost fish, was tested by examining the muscle free amino acid (FAA) pool and enzyme activities, in concert with growth response, when dietary amino acids were provided in free, dipeptide or protein molecular forms. We present the first evidence in fish that, in response to a synthetic dipeptide diet, muscle FAA varies as a result of both growth rate and amino acid availability of specific peptides. We demonstrate significantly diminished muscle indispensable FAA (3-10-fold) in rainbow trout alevins fed a dipeptide-based diet compared with a protein-based diet. The dipeptide-based diet did not contain proline, resulting in 10-27-fold less muscle free proline and hydroxyproline in alevins. The response of alevins fed FAA-based or peptide-based diets can be indicative of collagen turnover (Hyp/Pro ratio) and showed significant differences between dietary treatments. Pyrroline-5-carboxylate (P5C) reductase activity was detected, suggesting that P5C may ameliorate proline deficiency, but synthesis from glutamate could not maintain free proline levels in muscle. This finding will provide an impetus to test whether proline is conditionally indispensable in young fish, as in mammals and birds. This study shows that amino acids given entirely as dipeptides can sustain fish growth, result in muscle FAA and enzyme responses in line with dietary levels and identify growth-limiting amino acids. The understanding of these factors necessitates a diet formulation that will improve the accuracy of determining amino acid requirements in the early life stages of vertebrates.

Amino Acids↗

PubMed2002

Response of forage fiber degradation by ruminal microorganisms to branched-chain volatile fatty acids, amino acids, and dipeptides.

This study evaluated the effect of branched-chain volatile fatty acids (VFA; isobutyric acid, isovaleric acid), amino acids (valine, leucine), and dipeptides (valine-valine, leucine-leucine) on neutral detergent fiber (NDF) degradation by rumen microorganisms in vitro. The CP (%) and in situ NDF degradation rate (%/h) for alfalfa, bermudagrass, and pangolagrass hays, and napiergrass silage were 17.2 and 7.5, 4.7 and 3.1, 8.3 and 5.3, and 9.6 and 3.4, respectively. In vitro NDF digestibility was the lowest for bermudagrass; alfalfa and napiergrass were the highest. When the incubation contained more ammonia initially, digestibilities increased, but relative differences among forages were unchanged. Adding branched-chain VFA (2 mM) to incubations increased digestibilities more than controls on 15 out of 16 occasions. The effectiveness varied with isoacids and forages used. Amino acid (2 mM) or dipeptide (1 mM) addition consistently increased digestibility over controls. Amino acids further increased digestibility over corresponding isoacids on 14 occasions. Improvement in digestibility over control by leucine appeared to be greater than that by valine. Digestibilities with dipeptides were always greater than those with isoacids, except for one case. Dipeptide addition further increased digestibility significantly over corresponding amino acids on only six occasions, while percent improvement in digestibility numerically by dipeptides occurred in 10 cases. Valine-valine seemed to exert different effect than leucine-leucine, depending on initial ammonia availability. The results indicate that dipeptides could be more effective than isoacids and amino acids in improving NDF digestion. Forages with high CP content or rapid NDF degradation rate appeared to respond to additives to smaller degrees.

Amino Acids↗

PubMed2000

Carnosine-related dipeptides in neurons and glia.

Carnosine-related dipeptides have been demonstrated to occur in the nervous tissue of many vertebrates, including humans. Although several hypotheses have been formulated, to date their precise physiological role in the nervous system remains unknown. This article will review the studies on the presence and distribution of these dipeptides in the nervous system of different classes of vertebrates. It will focus on the most recent data on their cellular localization and potential functions in mammals. The studies on localization of carnosine-related dipeptides show a complex pattern of expression that involves both neuronal and glial cell types. The glial localization, widely distributed throughout the whole brain and spinal cord, includes a subset of both mature astrocytes and oligodendrocytes, whereas the neuronal localization is restricted to a particular type of neurons (the olfactory receptor neurons), and to restricted populations of putative migrating neurons and neuroblasts. There is no definitive demonstration of the function of these dipeptides in the various cell types. However, a wide array of evidence suggests that carnosine-related dipeptides could act as natural protective agents. Moreover, recent studies have suggested that, as previously postulated for the olfactory receptor neurons, in mature functional glial cells as well, carnosine-related dipeptides could be implicated in a neuromodulatory functional mechanism.

Animals↗