Histidine-containing Dipeptides Research Articles

Ability of amino acids, dipeptides, polyamines, and sulfhydryls to quench hexanal, a saturated aldehydic lipid oxidation product.

Hexanal is a common product arising from the oxidation of omega-6 fatty acids. Because aldehydic lipid oxidation products can react with food components, interactions between hexanal and sulfhydryl- and amine-containing compounds were determined. The polyamines, spermidine and spermine, and the sulfhydryl-containing compounds, glutathione and thioctic acid, decreased headspace hexanal concentrations < or =7.0%. Histidine was the only amino acid tested that was able to quench headspace hexanal. Histidine-containing dipeptides decreased headspace hexanal 3.0-8.5-fold more than histidine. Hexanal quenching by the hisitidine-containing dipeptides increased as the size of the aliphatic side group of the amino acid adjacent to histidine increased, with Leu-His having the greatest hexanal quenching activity. The ability of Leu-His to quench histidine increased with increasing pH. The ability of histidine-containing dipeptides to interact with hexanal suggests that it may be possible to design peptides to alter the concentration of saturated aldehydes in oxidizing lipids.

Zinc Complexes of Artificial Histidine-containing Dipeptides as Catalysts of Hydrolyses of p-Nitrophenyl Phosphates

Abstract Zinc complexes of histidine-containing peptide derived from N,N′-dihistidylethylenediamine L1 and im-bzl-N,N″-dihistidyldiethylenetriamine L2 were designed and examined as catalysts for hydrolyses of bis(p-nitrophenyl)phosphate (BNPP) and p-nitrophenyl phosphate (NPP). The zinc complex of L1 was inactive and another L2 complex hydrolyzed efficiently BNPP and NPP: their pseudo-first-order rate constants are 1.1 × 10−5 s−1 and 2.1 × 10−5 s−1, respectively.

Ability of Carnosine and Other Skeletal Muscle Components To Quench Unsaturated Aldehydic Lipid Oxidation Products

Breakdown of lipid peroxides results in the formation of aldehydic compounds which are toxic to biological systems and deleterious to food quality. To determine the potential of skeletal muscle compounds to protect biomolecules from lipid oxidation products, the ability of carnosine and various other related compounds to quench monounsaturated and polyunsaturated aldehydes was investigated. Carnosine, the most abundant dipeptide in skeletal muscle, is capable of quenching alpha,beta-monounsaturated aldehydes and 4-hydroxy-2-trans-nonenal (HNE) more effectively than its constituent amino acid. Carnosine (5 mM) reduced 44% of headspace trans-2-hexenal (0.5 mM) after 1 h incubation at 40 degrees C and pH 7.4. Other histidine-containing dipeptides and the amine compounds, spermine and spermidine, had similar or slightly lower quenching activity than carnosine. Glutathione and thioctic acid had superior quenching ability than carnosine, but their overall contribution to aldehyde quenching compared to carnosine is limited due to their lower concentration in skeletal muscle. The results suggest that carnosine could be important for decreasing the toxicity of lipid oxidation products in biological systems and for minimizing rancidity in muscle foods.

Design and biological activity of imidazole-containing peptidomimetics with a broad-spectrum antioxidant activity

Histidine-containing natural dipeptides, such as L-carnosine, were reported to be effective against different oxygenderived free radicals, and also lipoperoxyl radicals. However, L-carnosine appeared to be uneffective in vivo, due to the presence of ubiquitous specific or semi-specific hydrolytic enzymes. Therefore, a series of peptidomimetics were synthesized in order to confer resistance to enzymatic hydrolysis. Some structural modifications were also done in an attempt to improve the antioxidant power of the molecule, for example, in relation to binding of ferrous ions. The following methods were used for the evaluation of peptidomimetics: 0 It was shown that decarboxylation of L-carnosine results in an important improvement of the resistance towards hydrolytic enzymes. In vitro experiment have demonstrated, for a series of peptidomimetrics free radical scavenging and lipid hydroperoxide deactivating properties similar to or even better than the natural peptide (depending on the experimental design). In addition, the two peptidomimetics β-alanylhistamine and L-prolylhistamine proved to be far superior in inhibiting the lipid hydroperoxide-mediated cross-linking of a representative protein. Finally, β-alanylhistamine was able to protect skin enzymes from UV-induced degradations in vivo.

Histidine-containing dipeptides as endogenous regulators of the activity of sarcoplasmic reticulum Ca-release channels

It is shown that histidine-containing dipeptide carnosine ( β-alanyl- l-histidine), which is present in skeletal muscles in millimolar concentrations, decreases the rate of Ca 2+ accumulation by the heavy fraction of sarcoplasmic reticulum from rabbit skeletal muscles. This effect results from the ability of carnosine to induce a rapid Ca 2+ release from the heavy sarcoplasmic reticulum vesicles via activation of the ruthenium red-sensitive Ca-channels. The effect of carnosine is dose-dependent that indicates the presence of saturable site(s) for carnosine in the molecules of Ca-channels. The C 0.5 value for carnosine (the concentration that induces the half-maximal Ca 2+ release) is 8.7 mM. The 1 N-methylated derivative of carnosine, i.e., anserine, also induces a rapid Ca 2+ release with the half-maximal effect at 2.7 mM. Conversely, neither histidine nor β-alanine (both separately and in the mixture) cause Ca 2+ release. In addition, carnosine increases the sensitivity of Ca-channels to their well-known activators (caffeine, AMP, and Ca 2+) and decreases inhibitory effect of low concentrations of Mg 2+. It is concluded that carnosine as a component of skeletal muscles can be an endogenous regulator of the sarcoplasmic reticulum Ca-channel activity.

Effect of histidine-containing dipeptides on brain tyrosine hydroxylase

Histidine-containing dipeptides inhibit highly purified tyrosine hydroxylase. The degree of inhibition is dependent on the peptide structure and decreases according to the following sequence: carnosine>anserine>homocarnosine. This effect is not associated with the buffer and antioxidant properties of the dipeptide.

The distribution of carnosine and related dipeptides in rat and human tissues

Carnosine and anserine are present in high concentrations in most skeletal muscles. In addition, carnosine and homocarnosine have been detected in brain and cardiac muscle. Other tissues have been found to be devoid of these histidine-containing dipeptides. However, Flancbaum et al. reported that carnosine was present in every rodent and human tissue analyzed. These authors postulated that carnosine serves as a non-mast cell reservoir for histidine which becomes available for histamine synthesis during periods of physiological stress. We have analyzed many rat and human tissues using an immunohistochemical procedure. Carnosine and related dipeptides were detected in skeletal muscle, cardiac muscle and brain, but not in kidney, liver, lung or several other organs. These negative results seem valid since the immunoassay gave positive staining in the tissues generally known to contain carnosine.

Endogenous skeletal muscle antioxidants.

Skeletal muscle is susceptible to oxidative deterioration due to a combination of lipid oxidation catalysts and membrane lipid systems that are high in unsaturated fatty acids. To prevent or delay oxidation reactions, several endogenous antioxidant systems are found in muscle tissue. These include alpha-tocopherol, histidine-containing dipeptides, and antioxidant enzymes such as glutathione peroxidase, superoxide dismutase, and catalase. The contribution of alpha-tocopherol to the oxidative stability of skeletal muscle is largely influenced by diet. Dietary supplementation of tocopherol has been shown to increase muscle alpha-tocopherol concentrations and inhibit both lipid oxidation and color deterioration. Dietary selenium supplementation has also been shown to increase the oxidative stability of muscle presumably by increasing the activity of glutathione peroxidase. The oxidative stability of skeletal muscle is also influenced by the histidine-containing dipeptides, carnosine and anserine. Whereas carnosine and anserine are affected by diet less than alpha-tocopherol and glutathione peroxidase, their concentrations vary widely with species and muscle type. In pigs, beef, and turkey muscle, carnosine concentrations are greater than anserine, while the opposite is true in rabbit, salmon, and chicken muscle. Anserine and carnosine are found in greater concentrations in muscle high in white fibers, with chicken white muscle containing over fivefold more anserine and carnosine than red muscle. Anserine and carnosine are thought to inhibit lipid oxidation by a combination of free radical scavenging and metal chelation.

Complexes of copper(II) ion with histamine-containing dipeptides: formation constants and structure

The acid–base properties and copper(II) complexes of glycyl- and sarcosyl-histamine (histamine = imidazole-4-ethanamine) have been studied by pH-metric, spectrophotometric and EPR methods, and compared to those of analogous histidine-containing dipeptides on the one hand and of carcinine (β-alanylhistamine) on the other. At pH 4–9 the predominant species is the 3N-co-ordinated complex CuLH–1(charges omitted) together with minor quantities of CuLH and CuL. The pK for metal ion-promoted deprotonation of the peptidic nitrogen is exceptionally low (pK= 3.20 and 3.66, respectively). The bis complexes CuL2 and CuL2H–1 also form in the presence of ligand in excess. Around pH 9–11 the monomeric 3N-co-ordinated hydroxo-complex CuLH–1(OH) and a polynuclear 4N-co-ordinated species are in equilibrium. The latter is assumed to be tetrameric Cu4L4H–8, with the imidazole rings as bridging bidentate units through co-ordination to both N3 and N1-pyrrolic nitrogens. At high pH (≈ 11) a further deprotonation results in the production of the monomeric 3N-co-ordinated hydroxo-complex CuLH–2(OH) with a pendant deprotonated N1-pyrrolic nitrogen.

Transition-metal complexes of carcinine, a peptide-type derivative of histamine

The acid–base properties and copper(II), nickel(II) and cobalt(II) complexes of carcinine {3-amino-N-[2-(imidazol-4-yl)ethyl]propanamide} and of N-tert-butoxycarbonylcarcinine have been studied at 25 °C by pH-metric, spectrophotometric and, in part, 1H NMR and EPR methods, and compared to those of histidine-containing dipeptides. Complexes of the type M(HL), ML and ML2(charges omitted) are found in the cobalt(II) and nickel(II) systems, with the additional presence of ML2H–1 for the latter system. Copper(II) forms CuLn(n⩽ 4) complexes with N-tert-butoxycarbonylcarcinine molecules acting as monodentate ligands. The copper(II)–carcinine system in the range pH 3–9 shows the expected series of 1 : 1 complexes, more or less deprotonated depending on the pH, of type Cu(HL), CuL and CuLH–1, and, for an excess of ligand, the unusual 1 : 4 complex CuL4H2 involving four N(3) inidazole nitrogens equatorially co-ordinated. At higher pH (> 9) the monomeric CuLH–2 and polynuclear Cu4L4H–8 complexes are formed depending on the total concentration. The tetrameric species probably involves co-ordination of deprotonated N(1)-pyrrole nitrogens, with consequent formation of imidazolate bridges. The co-ordination ability of the peptide nitrogen in histidyl- and histamine-peptides is shown to depend on the size of the chelate rings formed and the existence of a neighbouring carboxyl group in the ligand.

The high intracellular ph buffering of hagfish ( Eptatretus cirrhatus) dental plate retractor muscle cannot be attributed to the known histidine-related compounds present in other vertebrates

1. 1. Intracellular pH buffering capacity of hagfish ( Eplatretus cirrhatus) dental plate retractor muscles is among the highest reported for any vertebrate muscle. 2. 2. Over 80% of the pH buffering capacity of hagfish retractor and myotome muscle is due to components other than proteins and phosphate. 3. 3. The muscles have less than 0.5 μmol/g wet weight of l-histidine, and lack l-l-methyl histidine, l-3-methyl histidine and the histidine-containing dipeptides anserine, carnosine and ophidine. 4. 4. Instead, they contain an unidentified low molecular weight acid-soluble compound to which the high pH buffering capacity can be attributed.

The histidine-containing dipeptides, carnosine and anserine: Distribution, properties and biological significance

The biological significance of histidine-containing dipeptides discovered within the composition of nitrogenous extracts of skeletal muscles at the beginning of this century is still open to question. The present investigation is concerned with the analysis of distribution and metabolism of these compounds with special reference to their effects on functional activity of membrane-linked enzymatic systems, stability of cellular membranes, muscle contractability, etc. The proposed hypothesis on stabilizing properties of carnosine and related substances on biological membranes is based on the ability of the dipeptides to interact with lipid peroxidation products and active oxygen species and to prevent membrane damage. This remarkable antioxidative effect of carnosine reflects the high therapeutic value of this compound as an anti-inflammatory drug and a prominent tool in wound healing.

Retrospectives and perspectives on the biological activity of histidine-containing dipeptides

1. 1. An evaluation of the biological function of histidine-containing dipeptides, is presented. 2. 2. These have been found to be potent pH-buffering compounds, strong antioxidants and membrane stabilizers. 3. 3. Analysis of the biological and biomedical properties of carnosine and other related dipeptides suggests their use as universal membrane repairing compounds.

Intracellular Buffering by Dipeptides at High and Low Temperature in the Blue Crab Callinectes Sapidus

ABSTRACT Intracellular buffering is provided mainly by bicarbonate, phosphates and proteins (see Burton, 1978). A part may also be played by free histidine and small peptides containing histidine. Although the free histidine content of most animal tissues is low, a variety have been found to possess substantial amounts of histidine-containing dipeptides, most commonly N-β-alanyl-L-histidine, either without substitutions (carnosine) or methylated at the 1-position (anserine) or at the 3-position (ophidine or balenine). At 25°C the pK of carnosine is 6·83 whereas that of anserine is 7·04, so the combination of appropriate pK and high concentration leads to significant intracellular buffer action.

Intracellular Buffering Capacity in Molluscan Muscle: Superfused Muscle versus Homogenates

In situ estimates of intracellular pH (pHi) in isolated bands of radula protractor muscles from the whelk Busycon canaliculatum were made using phosphorus nuclear magnetic resonance spectroscopy (31P-NMR). The 31P-NMR spectra contained distinct resonances for arginine phosphate and the α, β, and γ phosphates of ATP. In addition, initial spectra displayed a small inorganic phosphate (Pi) peak, which disappeared upon continued superfusion under aerobic conditions. Addition of 2 mM 2-deoxyglucose to the medium resulted in the generation of an additional resonance corresponding to 2-deoxyglucose-6-phosphate (2DGP). Using the chemical shift differences of both the Pi and 2DGP peaks relative to the internal reference arginine phosphate, the resting aerobic pH, was found to be 7.29 ± 0.07 SD (n = 3) and 7.32 ± 0.04 SD (n = 5), respectively. Intracellular buffering capacity (β) was estimated in situ using NH₄Cl prepulse and weak acid loading techniques. The β values were 30 ± 3.9 SD (n = 7) and 31 ± 3.8 SD (n = 7) μ mol·pH⁻¹·g intracellular water⁻¹, respectively. A third method, by titration of tissue homogenates, yielded a β value of 85.8 ± 17.5 SD (n = 8) μ mol·pH⁻¹·g intracellular water⁻¹. This large discrepancy can be partially explained by the rapid hydrolysis of arginine phosphate immediately after homogenization, generating free inorganic phosphate, an excellent buffer in the physiological pH range. The chemical nature of intracellular buffers in B. canaliculatum radula protractor muscle was examined through crude acid fractionation and subsequent amino acid analysis. The total histidine content in this muscle accounted for 72% of the in situ buffering capacity. Unlike some vertebrate systems where large amounts of histidine-containing dipeptides function as buffers, most of the histidine is associated with the protein fraction of the tissue.

Ergothioneine, Histidine, and Two Naturally Occurring Histidine Dipeptides as Radioprotectors against γ-Irradiation Inactivation of Bacteriophages T4 and P22

Bacteriophages P22, T4+, and T4os (osmotic shock-resistant mutant with altered capsids) were diluted in 0.85% NaCl and exposed to gamma irradiation (2.79 Gy/min) at room temperature (24 degrees C). T4+ was more sensitive to inactivation than was P22, and the T4os mutant was even more sensitive than T4+. Catalase exhibited a strong protective effect and superoxide dismutase a weaker protection, indicating that H2O2 or some product derived therefrom was predominant in causing inactivation of plaque formation. Low but significant (0.1-0.3 mM) reduced glutathione (GSH) enhanced phage inactivation, but a higher (1 mM) GSH concentration protected. A similar effect was found for the polyamine, spermidine. In contrast, 0.1 mM L-ergothioneine (2-thiol-L-histidine betaine) exhibited strong protection and 1 mM afforded essentially complete protection. L-Ergothioneine is present in millimolar concentrations in some fungi and is conserved up to millimolar concentrations in critical tissues when consumed by man. L-Histidine and two histidine-containing dipeptides, carnosine and anserine, protected at a concentration of 1 mM, a level at which they are present in striated muscles of various animals.

The level of natural antioxidant glutathione and histidine-containing dipeptides in skeletal muscles of developing chick embryos

1. 1. The levels of glutathione and histidine-containing dipeptides in skeletal muscles change in different ways during ontogenesis. 2. 2. The glutathione content in skeletal muscles increases between the 9th and 18th days of embryongenesis—from 0.5 to 2.0 μmol/g of tissue wet wt and then drops to zero in 3-week-old chickens. 3. 3. The level of histidine-containing dipeptides increases throughout the observation period beginning with their appearance on the 14th day in leg muscles and on the 15th day in breast muscles of chicken embryos up to the 21st postnatal day. 4. 4. There is a negative correlation between the antioxidative systems of glutathione and histidine-containing dipeptides in muscle tissue, i.e. dipeptide-rich tissues contain little or no glutathione and vice versa.

Antioxidative properties of histidine-containing dipeptides from skeletal muscles of vertebrates

1. 1. Ascorbate-dependent peroxidation of lipid components of biological membranes is inhibited by the natural histidine-containing dipeptides, carnosine and anserine, used at physiological concentrations. 2. 2. Carnosine and anserine exhibit an equal antioxidative activity, whereas the preventing effect of homocarnosine is manifested only at low concentrations of oxidized lipid material. 3. 3. The inhibiting effect of the dipeptides is enhanced either by the rise in the dipeptide concentration or by the decrease in the level of membrane components. 4. 4. Addition of the dipeptides results in a marked decrease in the level of primary molecular products of lipid peroxidation. 5. 5. In this case the optical spectrum of primary molecular products of polyunsaturated fatty acids changes significantly.

Simultaneous determination of histidine-containing dipeptides, histamine, methylhistamine and histidine by high-performance liquid chromatography

Simultaneous determination of histidine-containing dipeptides, histamine, methylhistamine and histidine by high-performance liquid chromatography

Presence and measurement of sample histidine in the ames test: Quantification and possible elimination of a source of false‐positive mutagenicity test results

Both histidine and dipeptides that can be converted to histidine can potentially interfere with the Ames test by increasing the number of spontaneous revertants. Such interference might be especially evident when urine and other biological samples are studied in this assay. We have developed a turbidimetric bioassay that utilizes a nonrevertible Salmonella typhimurium histidine auxotroph, NS1135. The assay is linear with histidine over at least a 300-fold range (0.015-5 micrograms/ml of L-histidine.HCl.H2O). Data indicate that several histidine-containing dipeptides can be utilized as efficiently as free histidine. Our data suggest that this assay may be used to measure biological samples accurately for their histidine content and thereby permit an adjustment for sample histidine during the setup of Ames assays, thus eliminating increased reversion caused by sample histidine.