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PubMed2001

Regulation of olfactory neurogenesis by amidated neuropeptides.

The existence of stem cells in the CNS raises issues concerning the ability of nervous tissues to regenerate in the adult mammal and provides new perspectives on the treatment of degenerative disease and traumatic injury of the nervous system. These cells have a relatively limited range of locations within the nervous system and include cells of the rostral migratory stream, hippocampus, retina, and olfactory epithelium. The olfactory epithelium has been studied as a model of adult neuronal regeneration, with neuronal precursor/basal cells serving as the olfactory "stem cells." The identification of factors that promote neuronal proliferation or regeneration within the olfactory epithelium can provide clues to the process of adult mammalian nervous system repair and treatment. Multiple factors have been examined that appear to influence the proliferation and subsequent maturation of basal cells. These factors include nerve growth factor, fibroblast growth factor-2, epidermal growth factor, and insulin/insulin-like growth factor-1. Recently, two amidated neuropeptides, neuropeptide Y (NPY) and pituitary adenylate cyclase-activating polypeptide (PACAP38), identified in the olfactory epithelium have been shown to promote dramatically neuronal proliferation. The effects of NPY and PACAP suggest that amidated neuropeptides may serve a broad developmental and regenerative role in the mammalian olfactory epithelium.

Amides↗
PubMed1980

Prodrugs as drug delivery systems IV: N-Mannich bases as potential novel prodrugs for amides, ureides, amines, and other NH-acidic compounds.

The hydrolysis kinetics of a series of N-Mannich bases of carboxamides, thioamides, and other NH-acidic compounds were studied to assess their suitability as prodrugs for various drugs. The pH-rate profiles for the compounds were determined at 37 degrees and were accounted for by assuming the spontaneous decomposition of both free and protonated Mannich bases. The reaction rate for the free base increased sharply with increasing steric effects of the amine component of the N-Mannich bases and also with increasing acidity of the amide component. N-Mannich bases may be potentially useful prodrugs for NH-acidic compounds such as various amides, and ureides and for amines.

Amides↗
PubMed1992

Ester and amide prodrugs of ibuprofen and naproxen: synthesis, anti-inflammatory activity, and gastrointestinal toxicity.

Ester and amide prodrugs of ibuprofen (1) and naproxen (16) were synthesized and evaluated for anti-inflammatory activity and gastrointestinal toxicity. The chemical structure of the prodrugs was varied in terms of lipophilicity and reactivity toward hydrolysis. Inhibition of acetic acid-induced writhing in mice indicated that prodrugs 7, 15, 19, and 20 exhibited significantly better activity (p less than 0.01) than the parent compounds. The average number of ulcers formed in the gastric mucosa following oral administration of 1 and 16 and prodrugs 5, 18, 21, and 22 was determined in rats. All prodrugs, except the glycine amide 21, were significantly less irritating to the gastric mucosa than either 1 or 16.

Amides↗
PubMed1994

Quantitative analyses of the structure-hydrophobicity relationship for N-acetyl di- and tripeptide amides.

The partition coefficient (P) of neutral species and the apparent partition ratio (P') at pH 7 of the ionized form were measured with the 1-octanol/water system for a number of N-acetyl di- and tripeptide amides having un-ionizable and ionizable side chains. Their log values were studied in terms of free-energy-related substituent and substructural parameters using regression analysis to give correlation equations of high quality physicochemically as well as statistically. The intrinsic hydrophobicity of side-chain substituents and their steric effect on the relative solvation of the backbone CONH groups were significant in determining the log P values of the un-ionizable acetyl peptide amides. For the log P value of peptides with polar side-chain substituents, respective indicator variable terms were required to account for the sum of specific effects of substituents such as intramolecular hydrogen-bond formation and the "polar proximity factor" for augmentation of the hydrophobicity. For the log P'(pH 7) value of basic and acidic peptides, the ability of counterionic species to form ion-pairs, the change in the apparent hydrophobicity of ionizable groups from the intrinsic value for their nonionized forms, the effect of ion-pairing itself, and other effects were additionally considered. From the regression coefficients of the parameter terms in correlation equations an effective hydrophobicity index was defined for each side chain, and the application and its limitation were suggested.

Acetylation↗
PubMed2004

15N T2' relaxation times of bacteriorhodopsin transmembrane amide nitrogens.

15N T(2)' relaxation times of bacteriorhodopsin (BR) amide nitrogens were determined in the temperature range from 40 to -60 degrees C using a Hahn echo pulse sequence and proton decoupling during the echo and detection times. Using oriented membrane samples, with their bilayer normal parallel to the external magnetic field, the (15)N amide nitrogens belonging to the transmembrane helices could be selected for the analysis. The experiments were performed on purple membrane fragments (in which BR is organized in a 2D crystalline network) and on BR reconstituted into dimyristoylphosphatidylcholine at a 1:150 molar ratio (in which BR is in a freely diffusing monomeric state at 40 degrees C and in an aggregated state at 4 degrees C and below). The results are discussed in terms of helix dynamics, mosaic spread and resolution of the (15)N spectra for the various samples and experimental conditions.

Amides↗
PubMed2003

Amide proton transfer (APT) contrast for imaging of brain tumors.

In this work we demonstrate that specific MR image contrast can be produced in the water signal that reflects endogenous cellular protein and peptide content in intracranial rat 9L gliosarcomas. Although the concentration of these mobile proteins and peptides is only in the millimolar range, a detection sensitivity of several percent on the water signal (molar concentration) was achieved. This was accomplished with detection sensitivity enhancement by selective radiofrequency (RF) labeling of the amide protons, and by utilizing the effective transfer of this label to water via hydrogen exchange. Brain tumors were also assessed by conventional T(1)-weighted, T(2)-weighted, and diffusion-weighted imaging. Whereas these commonly-used approaches yielded heterogeneous images, the new amide proton transfer (APT) technique showed a single well-defined region of hyperintensity that was assigned to brain tumor tissue.

Amides↗
PubMed2005

Suppression of lipid artifacts in amide proton transfer imaging.

Amide proton transfer (APT) imaging is a type of chemical exchange saturation transfer imaging in which the amide protons of cellular proteins and peptides are saturated and detected via the water resonance. To study this effect, conventional magnetization transfer and direct saturation effects in the frequency-dependent water saturation spectrum (z-spectrum) need to be removed by asymmetry analysis with respect to the water frequency offset. When using echo planar imaging, it was found that unequal pericranial fat saturation at equidistant higher and lower frequencies with respect to water leads to a lipid artifact in APT asymmetry images. It is demonstrated that a chemical-shift-selective refocusing pulse in combination with crusher gradients can suppress this artifact and provide high-quality images.

Amides↗
PubMed2006

Amide proton transfer imaging of human brain tumors at 3T.

Amide proton transfer (APT) imaging is a technique in which the nuclear magnetization of water-exchangeable amide protons of endogenous mobile proteins and peptides in tissue is saturated, resulting in a signal intensity decrease of the free water. In this work, the first human APT data were acquired from 10 patients with brain tumors on a 3T whole-body clinical scanner and compared with T1- (T1w) and T2-weighted (T2w), fluid-attenuated inversion recovery (FLAIR), and diffusion images (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)). The APT-weighted images provided good contrast between tumor and edema. The effect of APT was enhanced by an approximate 4% change in the water signal intensity in tumor regions compared to edema and normal-appearing white matter (NAWM). These preliminary data from patients with brain tumors show that the APT is a unique contrast that can provide complementary information to standard clinical MRI measures.

Algorithms↗
PubMedDate not supplied

Quantitative determination of anti-fungal and insecticide amides in adult plants, plantlets and callus from Piper tuberculatum by reverse-phase high-performance liquid chromatography.

A rapid, sensitive and reliable reverse-phase HPLC method was used for the quantitative determination of the anti-fungal and insecticide amides, dihydropiplartine (1), piplartine (2), deltaalpha,beta-dihydropiperine (3) and pellitorine (4) in plants in natura, in plantlets in vitro and ex vitro, and in callus of Piper tuberculatum. Well-resolved peaks were obtained with good detection response and linearity in the range of 15.0-3000 microg/mL. The plants in natura contained compounds 1-4, the plantlets ex vitro and in vitro accumulated compounds 1-2 and 1-4, respectively, while only amide 4 was found in callus.

Amides↗
PubMed1993

Amide proton exchange rates of oxidized and reduced Saccharomyces cerevisiae iso-1-cytochrome c.

Proton NMR spectroscopy was used to determine the rate constant, kobs, for exchange of labile protons in both oxidized (Fe(III)) and reduced (Fe(II)) iso-1-cytochrome c. We find that slowly exchanging backbone amide protons tend to lack solvent-accessible surface area, possess backbone hydrogen bonds, and are present in regions of regular secondary structure as well as in omega-loops. Furthermore, there is no correlation between kobs and the distance from a backbone amide nitrogen to the nearest solvent-accessible atom. These observations are consistent with the local unfolding model. Comparisons of the free energy change for denaturation, delta Gd, at 298 K to the free energy change for local unfolding, delta Gop, at 298 K for the oxidized protein suggest that certain conformations possessing higher free energy than the denatured state are detected at equilibrium. Reduction of the protein results in a general increase in delta Gop. Comparisons of delta Gd to delta Gop for the reduced protein show that the most open states of the reduced protein possess more structure than its chemically denatured form. This persistent structure in high-energy conformations of the reduced form appears to involve the axially coordinated heme.

Amides↗
PubMed1996

The pH dependence of hydrogen-deuterium exchange in trp repressor: the exchange rate of amide protons in proteins reflects tertiary interactions, not only secondary structure.

The pH dependence of amide proton exchange rates have been measured for trp-repressor. One class of protons exchanges too fast to be measured in these experiments. Among the protons that have measurable hydrogen-deuterium exchange rates, two additional classes may be distinguished. The second class of protons are in elements of secondary structure that are mostly on the surface of the protein, and exchange linearly with increasing base concentration (log kex versus pH). The third class of amide protons is characterized by much higher protection against exchange at higher pH. These protons are located in the core of the protein, in helices B and C. The exchange rate in the core region does not increase linearly with pH, but rather goes through a minimum around pH 6. The mechanism of exchange for the slowly exchanging core protons is interpreted in terms of the two-process model of Hilton and Woodward (1979, Biochemistry 18:5834-5841), i.e., exchange through both a local mechanism that does not require unfolding of the protein, and a mechanism involving global unfolding of the protein. The increase in exchange rates at low pH is attributed to a partial unfolding of the repressor. It is concluded that the formation of secondary structure alone is insufficient to account for the high protection factors seen in the core of native proteins at higher pH, and that tertiary interactions are essential to stabilize the structure.

Amides↗
PubMed1998

Amide proton exchange measurements as a probe of the stability and dynamics of the N-terminal domain of the ribosomal protein L9: comparison with the intact protein.

Amide H/D exchange rates have been measured for the N-terminal domain of the ribosomal protein L9, residues 1-56. The rates were measured at pD 3.91, 5.03, and 5.37. At pD 5.37, 18 amides exchange slowly enough to give reliable rate measurements. At pD 3.91, seven additional residues could be followed. The exchange is shown to occur by the EX2 mechanism for all conditions studied. The rates for the N-terminal domain are very similar to those previously measured for the corresponding region in the full-length protein (Lillemoen J et al., 1997, J Mol Biol 268:482-493). In particular, the rates for the residues that we have shown to exchange via global unfolding in the N-terminal domain agree within the experimental error with the rates measured by Hoffman and coworkers, suggesting that the structure of the domain is preserved in isolation and that the stability of the isolated domain is comparable to the stability of this domain in intact L9.

Amides↗
PubMed2005

Mass spectrometric decompositions of copper complexes with esters and amides of nicotinic acid.

Mass spectrometric decompositions of complexes of nicotinic acid esters and amides with copper are discussed. Liquid secondary ion mass spectrometry (LSIMS) was used as an ionisation technique and metastable ion spectra were recorded by using B/E linked scans. The fragmentation pathways consist mainly of the loss of one ligand molecule and also the cleavage of amide or ester bonds. It may be possible, on the basis of cleaved neutral fragments, to determine the site of coordination in the gas phase. It was also found that the presence of a chlorine atom affects the fragmentation pathways of complexes.

Amides↗
PubMed2003

Amide bond cleavage in deprotonated tripeptides: a newly discovered pathway to "b2 ions.

The fragmentation reactions of the [M-H](-) ions of the tripeptides H-Gly-Leu-Sar-OH, H-Leu-Gly-Pro-OH and H-Gly-Leu-Gly-OH have been investigated in detail using energy-resolved mass spectrometry, isotopic labelling and MS(3) experiments. It is shown that the major route to the "b(2) ions involves loss of a neutral amine from the a(3) ([M-H-CO(2)](-)) ion rather than being formed directly by fragmentation of the [M-H](-) ion. When there is no C-terminal amidic hydrogen (Sar, Pro), loss of a neutral amine is the dominant primary fragmentation reaction of the a(3) ion. However, when there is a C-terminal amidic hydrogen (Gly), elimination of the N-terminal amino acid residue is the major fragmentation reaction of the a(3) ion and formation of the "b(2) ion is greatly reduced in importance. It is proposed that the "b(2) ions are deprotonated oxazolones.

Amides↗
PubMed1997

Reversible hydrolysis and synthesis of anandamide demonstrated by recombinant rat fatty-acid amide hydrolase.

Previously we suggested that one porcine brain enzyme (anandamide amidohydrolase) catalyzed both the hydrolysis of anandamide and its synthesis from arachidonic acid and ethanolamine (Ueda et al., J. Biol. Chem. 270, 23823-23827, 1995). In the present study we investigated the reversibility of the enzyme reactions by the use of recombinant fatty-acid amide hydrolase of rat liver, which appears to be catalytically identical to porcine anandamide amidohydrolase. The particulate fraction of the COS-7 cells, in which the rat enzyme was overexpressed, hydrolyzed anandamide with a specific activity of 132 nmol/min/mg protein at 37 degrees C, and the Km value for anandamide was 18 microM. The enzyme also synthesized anandamide at a rate of 177 nmol/min/mg protein, and the Km values for arachidonic acid and ethanolamine as substrates were as high as 190 microM and 36 mM, respectively. The control cells transfected with the insert-free vector showed neither the hydrolase activity nor the synthase activity. Thus, the hydrolase and synthase are attributed to the same enzyme protein coded by one gene. However, the enzyme may act as a hydrolase rather than a synthase under physiological conditions judging from its high Km values for substrates in the synthase reactions. In addition, primary amides of fatty acids such as arachidonamide and oleamide and fatty acid ester like methyl arachidonate were hydrolyzed at considerable rates, and their reverse reactions occurred even if at lower rates.

Amidohydrolases↗
PubMed1998

Arachidonoylserotonin and other novel inhibitors of fatty acid amide hydrolase.

Fatty acid amide hydrolase (FAAH) catalyzes the hydrolysis of bioactive fatty acid amides and esters such as the endogenous cannabinoid receptor ligands, anandamide (N-arachidonoyl-ethanolamine) and 2-arachidonoylglycerol, and the putative sleep inducing factor cis-9-octadecenoamide (oleamide). Most FAAH blockers developed to date also inhibit cytosolic phospholipase A2 (cPLA2) and/or bind to the CB1 cannabinoid receptor subtype. Here we report the finding of four novel FAAH inhibitors, two of which, malhamensilipin A and grenadadiene, were screened out of a series of thirty-two different algal natural products, and two others, arachidonoylethylene glycol (AEG) and arachidonoyl-serotonin (AA-5-HT) were selected out of five artificially functionalized polyunsaturated fatty acids. When using FAAH preparations from mouse neuroblastoma N18TG2 cells and [14C]anandamide as a substrate, the IC50s for these compounds ranged from 12.0 to 26 microM, the most active compound being AA-5-HT. This substance was also active on FAAH from rat basophilic leukaemia (RBL-2H3) cells (IC50 = 5.6 microM), and inhibited [14C]anandamide hydrolysis by both N18TG2 and RBL-2H3 intact cells without affecting [14C]anandamide uptake. While AEG behaved as a competitive inhibitor and was hydrolyzed to arachidonic acid (AA) by FAAH preparations, AA-5-HT was resistant to FAAH-catalyzed hydrolysis and behaved as a tight-binding, albeit non-covalent, mixed inhibitor. AA-5-HT did not interfere with cPLA2-mediated, ionomycin or antigen-induced release of [3H]AA from RBL-2H3 cells, nor with cPLA2 activity in cell-free experiments. Finally, AA-5-HT did not activate CB1 cannabinoid receptors since it acted as a very weak ligand in in vitro binding assays, and, at 10-15 mg/kg body weight, it was not active in the 'open field', 'hot plate' and rectal hypothermia tests carried out in mice. Conversely AEG behaved as a cannabimimetic substance in these tests as well as in the 'ring' immobility test where AA-5-HT was also active. AA-5-HT is the first FAAH inhibitor reported to date which is inactive both against cPLA2 and at CB1 receptors, whereas AEG represents a new type of cannabinoid receptor agonist.

Amidohydrolases↗
PubMed1999

Identification of two serine residues involved in catalysis by fatty acid amide hydrolase.

Fatty acid amide hydrolase is an integral membrane protein that hydrolyzes a novel and growing class of neuromodulatory fatty acid molecules, including anandamide, 2-arachidonyl glycerol, and oleamide. This activity is inhibited by serine and cysteine reactive agents, suggesting that the active site contains a serine or cysteine residue. Therefore serine and cysteine residues were mutated to alanine and the effects on activity were determined. Mutants were prepared using site-directed mutagenesis methods and expressed in COS-7 cells. Serine mutations S217A and S241A completely abolished enzymatic activity. Mutants S152A and C249A had no effect on activity, while S218A showed a slight decrease in activity. To confirm these results biochemically, the mutant enzymes were reacted with the irreversible inhibitor [(14)C]-diisopropyl fluorophosphate. All of the mutants except S217A and S241A were labeled. We therefore confirm that fatty acid amide hydrolase is a serine hydrolase and propose that both Ser-217 and Ser-241 are essential for enzyme activity.

Alanine↗
PubMed1998

Conserved chromosomal location and genomic structure of human and mouse fatty-acid amide hydrolase genes and evaluation of clasper as a candidate neurological mutation.

Fatty-acid amide hydrolase (FAAH) is a membrane-bound enzyme that degrades neuromodulatory fatty acid amides, such as oleamide and anandamide, and is expressed in the mammalian central nervous system. To evaluate FAAH genes as candidates for neurogenetic diseases in humans and mice, we have mapped the loci in both species and have determined their intron-exon structures. The human FAAH gene was mapped to region 1p34-p35, closely linked to D1S197 and D1S443, by using PCR analysis of somatic cell hybrid (SCH) and radiation hybrid mapping panels. Analysis of an SCH mapping panel and a mouse interspecific backcross panel has localized the Faah gene to the conserved syntenic region on mouse chromosome 4, close to the neurological mutation clasper. Faah gene rearrangements were excluded by Southern blot analysis of clasper DNA. No sequence abnormality was detected in PCR products containing the 15 exons and splice junctions of the mouse Faah gene. FAAH protein levels were normal in clasper mouse tissues as determined by enzyme activity assays and Western blotting.

Amidohydrolases↗