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PubMed2000

The amino acid sequence of pancreatic alpha-amylase from the ostrich, Struthio camelus.

The amino-acid sequence of alpha-amylase isolated from the pancreas of the ostrich, Struthio camelus was determined. The alpha-amylase (OPA) consisted of 497 amino acid residues with pyroglutamic acid at the N-terminus and no oligosaccharide. Amino acid identity between OPA and chicken, porcine and human pancreatic alpha-amylases individually, was found to be 88, 82 and 86%, respectively.

Amino Acid Sequence↗

PubMed1971

Enzymatic conversion of 5-oxo-L-proline (L-pyrrolidone carboxylate) to L-glutamate coupled with cleavage of adenosine triphosphate to adenosine diphosphate, a reaction in the -glutamyl cycle.

A new enzyme, 5-oxoprolinase, was found in rat kidney and in several other tissues; it catalyzes the conversion of 5-oxo-L-proline (L-5-oxo-pyrrolidine-2-carboxylic acid, L-2-pyrrolidone-5-carboxylic acid, L-pyroglutamic acid) to L-glutamic acid, with concomitant stoichiometric cleavage of ATP to ADP and orthophosphate. The reaction catalyzed by 5-oxoprolinase, in which 5-oxoproline formed from gamma-glutamyl amino acids by the action of gamma-glutamylcyclotransferase is converted to glutamate, appears to function in the gamma-glutamyl cycle. 5-Oxoprolinase requires Mg(++) (or Mn(++)) and K(+) (or NH(4) (+)) for activity. The equilibrium is markedly in favor of glutamate formation at pH 7.8.

Adenine Nucleotides↗

PubMed2000

Isolation and characterization of gomesin, an 18-residue cysteine-rich defense peptide from the spider Acanthoscurria gomesiana hemocytes with sequence similarities to horseshoe crab antimicrobial peptides of the tachyplesin family.

We have purified a small size antimicrobial peptide, named gomesin, from the hemocytes of the unchallenged tarantula spider Acanthoscurria gomesiana. Gomesin has a molecular mass of 2270.4 Da, with 18 amino acids, including a pyroglutamic acid as the N terminus, a C-terminal arginine alpha-amide, and four cysteine residues forming two disulfide bridges. This peptide shows marked sequence similarities to antimicrobial peptides from other arthropods such as tachyplesin and polyphemusin from horseshoe crabs and androctonin from scorpions. Interestingly, it also shows sequence similarities to protegrins, antimicrobial peptides from porcine leukocytes. Gomesin strongly affects bacterial growth, as well as the development of filamentous fungi and yeast. In addition, we showed that gomesin affects the viability of the parasite Leishmania amazonensis.

Amino Acid Sequence↗

PubMed1993

Eisenin (L-pyroGlu-L-Gln-L-Ala), a new biological response modifier.

Eisenin (L-pyroGlu-L-Gln-L-Ala), a tripeptide extracted from a brown marine alga (Eisenia bicyclis Setchell) showed the immunological activity to augment natural cytotoxicity of peripheral blood lymphocytes (PBLs) in humans. This activity could be seen when it was added directly to 51Cr release assay, and also when PBLs alone were incubated with this compound for 0.5-1 h before addition to the 51Cr release assay. The resulting augmented cytotoxicity can be attributed to natural killer cells because treatment of eisenin-stimulated PBLs with anti-Leu 11b monoclonal antibody (mAb) plus complement completely abolished the augmented cytotoxicity, and, moreover, deletion of Leu 19-positive cells with anti-Leu 19 mAb (mouse IgG1) and anti-mouse IgG-coated magnetic beads showed the same effect. Eisenin could not augment natural cytotoxicity of Sephadex G-10 column-eluted cells. Eisenin rendered K-562 target cells resistant to lysis by PBLs stimulated by eisenin. Both amino acids, L-pyroglutamic acid and L-alanine, as well as a mixture of the three component amino acids of eisenin could augment the natural cytotoxicity. Therefore, it is considered that the structure responsible for the augmentation of natural cytotoxicity by eisenin may be that of the amino acids.

Alanine↗

PubMed1993

Synthesis of charybdotoxin and of two N-terminal truncated analogues. Structural and functional characterisation.

Charybdotoxin and two N-terminal truncated peptides, corresponding to the 2-37 and 7-37 sequences, were obtained by stepwise solid-phase synthesis using N alpha-t-butyloxycarbonyl and benzyltype side-chain protection. While this strategy was generally useful, the S-acetamidomethyl protecting group used for the six cysteines was not completely stable under HF treatment and its subsequent removal by mercury(II) treatment was neither complete nor devoid of side reactions. The completely deprotected native and truncated sequences were folded efficiently in the presence of glutathione and were finally purified by high-pressure liquid chromatography with overall yields of 4.0-5.0%. Each protein was characterised chemically, structurally and functionally. 1H-NMR spectroscopy was used and a complete assignment of all the protons of the three synthetic proteins was achieved. NMR data show that synthetic charybdotoxin is indistinguishable from the natural protein. The two truncated proteins contain the same elements of secondary structure and a similar overall three-dimensional structure, in agreement with circular dichroic measurements. The shortest analogue, however, may have local structural perturbations and/or higher flexibility. Biological activity on dog epithelial Ca(2+)-activated K+ channels and on rat brain synaptosomal voltage-dependent K+ channels show that synthetic charybdotoxin was as potent as the natural toxin on both channels. For both channels, deletion of the first amino acid, 5-oxoproline (pyroglutamic acid) decreased only slightly the potency of the inhibitor, while deletion of the entire 1-6 segment reduced potency much more. We conclude that the N-terminal region of charybdotoxin plays a functional role in tuning the toxin's biological activity but is not essential for the folding and stability of the structure. The structure of the shortest analogue represents an interesting example of how a well organised and stable alpha/beta fold can be engineered with only 31 amino acid residues.

Amino Acid Sequence↗

PubMed2004

Efficacy of organic acids in hand cleansers for prevention of rhinovirus infections.

Direct hand-to-hand contact is an important mechanism of transmission of rhinovirus infection. The rhinoviruses are inactivated at a low pH. A survey of organic acids in vitro revealed that these compounds have antirhinoviral activity that persists for at least 3 h after application to the skin. In additional studies of salicylic acid (SA) and pyroglutamic acid (PGA), the hands of volunteers were contaminated with rhinovirus at defined times after application of the acid, and then volunteers attempted to inoculate the nasal mucosa with one hand and quantitative viral cultures were done on the other hand. In one study, 3.5% SA or 1% SA with 3.5% PGA was compared with controls 15 min after application to assess the efficacy of the inactivation of virus and prevention of infection. Virus was recovered from the hands of 28 out of 31 (90%) of the volunteers in the control group compared to 4 out of 27 (15%) and 0 out of 27 in the groups administered 3.5 and 1% SA, respectively (P < 0.05). Rhinovirus infection occurred in 10 out of 31 (32%) of the controls and 2 out of 27 (7%) of volunteers in both treatment groups (P < 0.05 compared with control). In a second study, the efficacy of 4% PGA was evaluated 15 min, 1 h, and 3 h after application. Significantly fewer volunteers had positive hand cultures at all time points compared with the control group, but the proportion that developed rhinovirus infection was not significantly reduced. These results suggest the feasibility of the prevention of rhinovirus transmission by hand treatments that are virucidal on contact and have activity that persists after application.

Acids↗

PubMed2001

Stability and CTL activity of N-terminal glutamic acid containing peptides.

Several cytotoxic T lymphocyte peptide-based vaccines against hepatitis B, human immunodeficiency virus and melanoma were recently studied in clinical trials. One interesting melanoma vaccine candidate alone or in combination with other tumor antigens, is the decapeptide ELA. This peptide is a Melan-A/MART-1 antigen immunodominant peptide analog, with an N-terminal glutamic acid. It has been reported that the amino group and gamma-carboxylic group of glutamic acids, as well as the amino group and gamma-carboxamide group of glutamines, condense easily to form pyroglutamic derivatives. To overcome this stability problem, several peptides of pharmaceutical interest have been developed with a pyroglutamic acid instead of N-terminal glutamine or glutamic acid, without loss of pharmacological properties. Unfortunately compared with ELA, the pyroglutamic acid derivative (PyrELA) and also the N-terminal acetyl-capped derivative (AcELA) failed to elicit cytotoxic T lymphocyte (CTL) activity. Despite the apparent minor modifications introduced in PyrELA and AcELA, these two derivatives probably have lower affinity than ELA for the specific class I major histocompatibility complex. Consequently, in order to conserve full activity of ELA, the formation of PyrELA must be avoided. Furthermore, this stability problem is worse in the case of clinical grade ELA, produced as an acetate salt, like most of the pharmaceutical grade peptides. We report here that the hydrochloride salt, shows higher stability than the acetate salt and may be suitable for use in man. Similar stability data were also obtained for MAGE-3, another N-terminal glutamic acid containing CTL peptide in clinical development, leading us to suggest that all N-terminal glutamic acid and probably glutamine-containing CTL peptide epitopes may be stabilized as hydrochloride salts.

Animals↗

PubMed2004

Stabilization of peptide guinea pig myelin basic protein 72-85 by N-terminal acetylation-implications for immunological studies.

Peptide gpMBP72-85, containing amino acids 72-85 of guinea pig myelin basic protein is commonly used to induce experimental autoimmune encephalomyelitis in Lewis rats. The N-terminal glutamine in this peptide can cyclize to pyroglutamic acid, leading to loss of the first MHC anchor for binding to MHC class II. Acetylation of the peptide N-terminus prevents pyroglutamic acid formation and ensures a constant quality. An increased MHC binding affinity after N-terminal acetylation was observed. This modification also enhanced T cell proliferation of a gpMBP reactive T cell clone. The encephalitogenicity of peptide gpMBP72-85 was unaffected by acetylation. It is concluded that acetylation improves the chemical stability of gpMBP72-85, and is not detrimental but rather favorable for its biochemical and immunological, in vitro, and in vivo behavior.

Acetylation↗

PubMed1994

Synthesis and high-performance liquid chromatographic purification of tritiated thyrotrophin-releasing hormone-like peptides.

A simple method is presented for the synthesis and RP-HPLC purification of tritium-labelled thyrotrophin-releasing hormone (TRH)-like tripeptides. These peptides differ from TRH (pGlu-His-Pro-amide) in that they possess a neutral or acidic residue in place of the histidine of TRH. The method involves the preparation of the appropriate dipeptide by a solid-phase peptide synthesis procedure using 9-fluorenylmethoxycarbonyl (Fmoc) protection. Very small amounts of tritiated glutamine are then converted into tritiated pyroglutamic acid, and coupling to the dipeptide is effected using a mixed anhydride derived from Fmoc-phenylalanine and the tritiated pyroglutamic acid. The required labelled product is then separated from unlabelled material by reversed-phase HPLC, as the hydrophobicity of the phenylalanine-containing product ensures that it is strongly retained. The availability of a series of tritium-labelled markers prepared by this method has permitted the unequivocal identification of certain naturally occurring TRH-like peptides.

Amino Acid Sequence↗

PubMed2006

Design, synthesis, and evaluation of a new generation of modular nucleophilic glycine equivalents for the efficient synthesis of sterically constrained alpha-amino acids.

A new generation of modular achiral glycine equivalents have been evaluated with respect to their synthetic utility for the production of tailor-made, sterically constrained alpha-amino acids, which proved to be the most efficient approach developed to date for the synthesis of symmetrical alpha,alpha-disubstituted-alpha-amino acids. Among the new series of achiral glycine equivalents, one was found to be a superior glycine derivative for the Michael additions with various (R)- or (S)-N-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones representing a general and practical synthesis of sterically constrained beta-substituted pyroglutamic acids. In particular, the application of these complexes allowed for the preparation of several beta-substituted pyroglutamic acids which include electron-releasing and sterically demanding substituents in the structure thus increasing the synthetic efficiency and expanding the generality of these Michael addition reactions.

Amino Acids↗

PubMed1984

An improved procedure, involving mass spectrometry, for N-terminal amino acid sequence determination of proteins which are N alpha-blocked.

A modification to a previously described procedure [Gray & del Valle (1970) Biochemistry 9, 2134-2137; Rose, Simona & Offord (1983) Biochem. J. 215, 261-272] for mass-spectral identification of the N-terminal regions of proteins is shown to be useful in cases where the N-terminus is blocked. Three proteins were studied: vesicular-stomatitis-virus N protein, Sendai-virus NP protein, and a rabbit immunoglobulin lambda-light chain. These proteins, found to be blocked at the N-terminus with either the acetyl group or a pyroglutamic acid residue, had all failed to yield to attempted Edman degradation, in one case even after attempted enzymic removal of the pyroglutamic acid residue. The N-terminal regions of all three proteins were sequenced by using the new procedure.

Amino Acid Sequence↗

PubMed2005

CFSUM1 and CFSUM2 in urine from patients with chronic fatigue syndrome are methodological artefacts.

McGregor et al. reported increased levels of an unidentified urinary compound (CFSUM1) in patients with chronic fatigue syndrome (CFS), with reduced excretion of another unidentified compound (CFSUM2), and suggested the possibility of chemical or metabolic 'markers' for CFS. The identity of CFSUM1 as reported was erroneous and the identities of these compounds have remained unknown until now. Urine samples were obtained from 30 patients with ME/CFS, 30 age- and sex-matched healthy controls, 20 control patients with depression and 22 control patients with rheumatoid arthritis. Samples were prepared using the published methods of McGregor et al. to produce heptafluorobutyryl-isobutyl derivatives of urinary metabolites. Alternative preparations utilised isopropyl, n-butyl and trifluoroacetyl derivatives. These were separated and identified using gas chromatography-mass spectrometry. CFSUM2 was identified as being partially derivatised [isobutyl ester-mono-heptafluorobutyryl (HFB)] serine. CFSUM1 was identified as partially derivatised pyroglutamic acid, being the isobutyl ester without formation of a HFB derivative. Both CFSUM1 and CFSUM2 are artefacts of the sample preparation procedure and previously reported quantitative abnormalities of CFSUM1 and CFSUM2 in urine from patients with ME/CFS are also artefactual. Pyroglutamic acid may be of primarily dietary origin. The methods used cannot provide reliable qualitative or quantitative data on urinary metabolites. No clinical or biochemical significance can be drawn between these compounds in ME/CFS or any other clinical conditions.

Adult↗

PubMed1987

Specificity study of kits for detection of group A streptococci directly from throat swabs.

A total of 78 Streptococcus strains, 15 Staphylococcus strains, and 2 Stomatococcus strains were used to test the specificity of 18 different antigen detection systems for group A streptococci and five products that detect a specific enzyme associated with group A streptococci. All streptococcal strains possessing the group A antigen were correctly identified with 31 different lots of reagents in the 18 antigen detection systems. The specificities of the 31 different lots of reagents ranged between 88.5 and 100%. A limited number of nonspecific reactions were observed with Enterococcus gallinarium, group C Streptococcus strain C23, and Staphylococcus aureus F49 and Cowan 1. The antigen detection kits that used enzymes as the extraction reagent gave slightly more specific results than did the kits that used chemical extraction reagents. The reagents in the five kits designed to detect the enzyme pyroglutamic acid arylamidase in Streptococcus pyogenes reacted positively with S. pyogenes (group A streptococcus); however, the reagents also reacted positively with all group D enterococcal streptococci and with about half of the staphylococcal strains treated. The nonspecificity of tests based on pyroglutamic acid arylamidase detection would seem to limit the usefulness of these kits with mixed cultures.

Agglutination Tests↗

PubMed2000

Sulfakinin neuropeptides in a crustacean. Isolation, identification andtissue localization in the tiger prawn Penaeus monodon.

The sulfakinin (SK) family of neuropeptides are characterized by a C-terminal octapeptide sequence that begins with two acidic residues (most commonly DD), and ends with YGHMRF-NH2, usually with the tyrosyl residue sulfated. So far, sulfakinins have only been identified in insects and the present study was initiated to investigate if the family is more widely distributed within the arthropods. Purification of an extract of the central nervous system of the giant tiger prawn Penaeus monodon has revealed three novel members of the sulfakinin peptide family. One of the peptides, Pem SKI, has the sequence <QFDEY(SO3H)GHMRF-NH2, where <Q denotes a pyroglutamic acid residue, and is for all criteria typical of insect sulfakinins, several of which also have an N-terminal pyroglutamic acid. Tyrosyl O-sulfation was verified by mass spectrometry. The two other peptides have a hitherto unknown L/M variation at position three from the C-terminus. One of these, Pem SKII, has a particularly glycine-rich N-terminus, AGGSGGVGGEYDDYGHLRF-NH2. The other, Pem SKIII, is a truncated form of Pem SKII, with the sequence VGGEYDDYGHLRF-NH2. Mass spectrometry of the latter two peptides indicated that only one of the two tyrosyl residues is sulfated. By analogy, it is suggested that the sulfation is located at the residue in position six from the C-terminus. A small amount of a nonsulfated variant of Pem SKII was also present in the extract. Immunocytochemical studies with sulfakinin antisera show a sparse neuronal distribution pattern, similar to that of insects. A prominent pair of large (approximately 25 micrometer) cells and 6-8 pairs of smaller (approximately 10 micrometer) cells are present in the protocerebrum. The larger cells have prominent neurites that give rise to varicosities in the centre of the brain. Their axons exit the brain via the circumoesophageal connectives and continue along the intersegmental connectives. Each of the thoracic and abdominal ganglia has sulfakinin-immunoreactive arborizations as a result of branching from the intersegmental nerves. This distribution pattern strongly suggests a role in neurotransmission or neuromodulation, although it remains to be elucidated what the exact role(s) is. However, on account of the conservation of peptide structure during the evolutionary period spanning the insect/crustacean lineage, especially between Pem SKI and insect sulfakinins, it may be assumed that the sulfakinins have a significant physiological role.

Amino Acid Sequence↗

PubMed1986

Synthesis of thyrotropin-releasing hormone analogues. 2. Tripeptides structurally greatly differing from TRH with high central nervous system activity.

A new series of thyrotropin-releasing hormone (TRH) analogues, obtained by further modifications of our most potent central nervous system (CNS) stimulating neutral tripeptides at both termini, were synthesized by the pentafluorophenyl ester method and tested for CNS and thyrotropin (TSH) releasing activity. Replacement of pyroglutamic acid by pyro-2-aminoadipic acid, 2-oxoimidazolidine-4-carboxylic acid or gamma-butyrolactone-gamma-carboxylic acid and that of proline by pipecolic acid, thiazolidine-4-carboxylic acid, or homoproline in [Leu2]- and [Nva2]TRH led to tripeptides structurally widely different from TRH. In spite of this fact, 7 of the 17 analogues (1, 2, 8-10, 16, and 17) have stronger anticataleptic effect than TRH, with negligible or no hormonal potency. The highest CNS activity was achieved when pyroglutamic acid was replaced by pyro-2-aminoadipic acid at the N-terminus [pAad-Leu-Pro-NH2, 1 (RGH 2202), and pAad-Nva-Pro-NH2,2]. A novel synthesis of L-2-aminoadipic acid suitable for large-scale preparation is also described.

Animals↗

PubMed2005

A high-throughput liquid chromatography/tandem mass spectrometry method for screening glutathione conjugates using exact mass neutral loss acquisition.

Chemically reactive metabolites may cause hepatotoxicity and as a result liver failure or other adverse side reactions. Therefore, this is a vital topic of interest because early reactive metabolite screening may prevent compound failure at a later stage. In order to address this issue, a screening assay has been developed to detect the formation of reactive metabolites by using glutathione as a trapping reagent, which will allow us to search for phase I metabolites and also glutathiones during in vitro metabolite screening using liquid chromatography/tandem mass spectrometry (LC/MS/MS) with exact mass. Glutathione conjugations when fragmented by the mass spectrometer give a common loss corresponding to the pyroglutamic acid moiety, which can be monitored. Until recently, this work has been carried out with triple quadrupole technology using nominal mass. The advantage of the hybrid quadrupole time-of-flight mass spectrometer is the selectivity and sensitivity that can be achieved. Exact neutral loss detection is achieved via sequential low- and high-energy MS acquisitions. After detection of the loss of the pyroglutamic acid moiety, using a window of +/-20 mDa on the high-energy scan, MS/MS is carried out on the parent mass of interest to confirm the common neutral loss.

Algorithms↗

PubMed1989

Nootropic drugs and brain cholinergic mechanisms.

1. This review has two aims: first, to marshal and discuss evidences demonstrating an interaction between nootropic drugs and brain cholinergic mechanisms; second, to define the relationship between the effects on cholinergic mechanisms and the cognitive process. 2. Direct or indirect evidences indicating an activation of cholinergic mechanisms exist for pyrrolidinone derivatives including piracetam, oxiracetam, aniracetam, pyroglutamic acid, tenilsetam and pramiracetam and for miscellaneous chemical structures such as vinpocetine, naloxone, ebiratide and phosphatidylserine. All these drugs prevent or revert scopolamine-induced disruption of several learning and memory paradigms in animal and man. 3. Some of the pyrrolidinone derivatives also prevent amnesia associated with inhibition of acetylcholine synthesis brought about by hemicholinium. Oxiracetam prevents the decrease in brain acetylcholine and amnesia caused by electroconvulsive shock. Oxiracetam, aniracetam and pyroglutamic acid prevent brain acetylcholine decrease and amnesia induced by scopolamine. Comparable bell-shaped dose-effect relationships result for both actions. Phosphatidylserine restores acetylcholine synthesis and conditioned responses in aging rats. 4. The mechanisms through which the action on cholinergic systems might take place, including stimulation of the high affinity choline uptake, are discussed. The information available are not yet sufficient to define at which steps of the cognitive process the action on cholinergic system plays a role and which are the influences of the changes in cholinergic function on other neurochemical mechanisms of learning and memory.

Acetylcholine↗

PubMed1987

Post-translational modifications of chloroperoxidase from Caldariomyces fumago.

The secreted form of the halogenating glycoenzyme, chloroperoxidase, is processed from a precursor containing a 21-residue-long, moderately hydrophobic signal sequence, at an atypical Gln-Glu peptide bond. Following cleavage, the N-terminal glutamic acid readily cyclizes into pyroglutamic acid. Chloroperoxidase contains two high-mannose N-glycosylation sites, identified as Asn12 and Asn213. Other modifications include deamidation of residues Asn13, Asn198, and Gln183 into the corresponding acids. Finally, structural arguments suggest that Cys87 may be the axial heme ligand in the active site of chloroperoxidase.

Amino Acid Sequence↗