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PubMed1997

A monoclonal antibody induces opening of a coiled coil. Global protection of amide protons from H/D exchange decreases by up to 1000-fold in antibody-bound triple-stranded coiled coil.

Antibody specificity is limited, and different antigens may cross-react to varying degrees with the same antibody. An example is monoclonal antibody 42PF elicited against a 29-residue random-coil peptide. 42PF cross-reacts with a triple-stranded coiled coil of related amino acid sequence, and there was circumstantial evidence for an antibody-induced opening of the coiled coil [Leder, L., Berger, C., Bornhauser, S., Wendt, H., Ackermann, F., Jelesarov, I. & Bosshard, H. R. (1995) Biochemistry 34, 16,509-16,518]. To reveal in a direct way that antibody 42PF induces the opening of the coiled coil, we have compared the rates of H/D exchange of amide protons in the free and in the antibody-bound coiled-coil peptide using electrospray-ionization mass spectrometry for the analysis of deuterium incorporation. Complete H/D exchange lasted several days in the tightly folded coiled-coil conformation while in the presence of antibody 42PF the overall exchange took only minutes, corresponding to a thousand-fold decrease of protection of the most slowly exchanging amide hydrogens of the folded coiled coil. This demonstrates that the antibody induced a considerable opening of the coiled coil.

Amides↗
PubMedDate not supplied

Identification of yeasts by hydrolysis of amides.

We analysed the hydrolysis of 23 amides by 500 yeast and yeast-like strains isolated from clinical specimens, identified to species level by conventional methods, in order to verify the validity of this method of species identification. The results show that 10 of these amides (acetamide, acrylamide, alaninamide, formamide, glycinamide, propionamide, urea, thioacetamide, thiourea and valeramide) are sufficient to differentiate seven genera and 19 species, with an occasional requirement for three additional tests: cycloheximide susceptibility, surface film formation on liquid medium and ascospore formation. The study of the amidase activity in yeasts and yeast-like fungi seems to be a promising method of identifying strains isolated from clinical samples.

Amides↗
PubMed1989

The role of cytochromes P-450 and N-acetyl transferase in the carcinogenicity of aromatic amines and amides.

1. Epidemiological studies have clearly identified the aromatic amines 2-naphthylamine, benzidine and 4-aminobiphenyl as human carcinogens. Many other compounds of this class are suspected to be human carcinogens. 2. At least 12 heterocyclic aromatic amines have been isolated from cooked food, nine of which have been shown to be carcinogenic in vivo. The significance of these compounds in the aetiology of human cancer is yet to be established. 3. Specific forms of cytochrome P-450 have been shown to be involved in the initial step in the activation (N-hydroxylation) of aromatic amines and amides. A possible polymorphism exists for the N-hydroxylation of 2-acetylaminofluorene in human liver microsomes. 4. N-Acetyltransferase is involved in the further activation of arylhydroxamic acids and N-hydroxyarylamines to reactive intermediates. Polymorphisms in the expression of this enzyme activity have been associated with certain types of human cancer. 5. Polymorphisms in both cytochrome P-450 and N-acetyltransferase expression may be critical determinants in the susceptibility of individuals to the toxicity and carcinogenicity of aromatic amines and amides.

Acetyltransferases↗
PubMed2004

The spatial and temporal pattern of fatty acid amide hydrolase expression in rat hippocampus during postnatal development.

GABAergic synaptic transmission is efficiently controlled by endogenous cannabinoids in cortical structures. Fatty acid amide hydrolase (FAAH) is one of the metabolizing enzymes of endocannabinoids in the brain. In this study we investigated the cellular and subcellular distribution of FAAH at various timepoints during the first postnatal weeks, when GABA is still depolarizing, and plays a crucial role in network events. FAAH immunoreactivity is strong in the CA3 region already at postnatal day 0 (P0), but in CA1 only after P8. During this period, FAAH levels in hilar mossy cells decrease and in granule cells slowly increase. Pyramidal cells express FAAH first in the soma and proximal dendrites, and gradually in more distal segments, reaching adult levels in the most distal dendrites only at P22. Transient expression of FAAH was found in a small number of stratum radiatum cells that may be interneurons and in ependymal cells at the border of the alveus and corpus callosum between P2 and P8. At the ultrastructural level, FAAH distribution at all ages was very similar to the adult pattern, i.e. it was largely associated with the membrane of cytoplasmic vesicles, mitochondria and endoplasmic reticulum. During postnatal development of the hippocampus, the spatio-temporal expression of FAAH correlates well with the general pattern of neuronal maturation, but not with the arrival of afferent pathways, which suggests that FAAH - and its major endocannabinoid substrate, anandamide - is unlikely to be involved in the presynaptic control of neurotransmission. Instead, FAAH may subserve general roles as the inactivating enzyme for many fatty acid amides, in addition to anandamide.

Age Factors↗
PubMed1968

The cholinergic properties of some amino-acid esters and amides.

1. Several amino-acid esters and amides have been prepared and their toxicological and pharmacological properties have been investigated. Some of the quaternary esters and amides were lethal to mice at doses below 1 mg/kg; this lethality was usually associated with high nicotinic activity. None of the compounds showed high muscarinic activity.2. The cause of death was asphyxia due to paralysis of the respiratory muscles, but at higher doses there was also failure of the medullary respiratory centre.3. Administration of sub-lethal doses of nicotine to mice was shown to protect the animals from subsequent lethal doses of nicotine. The amino-acid esters did not share this property, nor was there any cross-protection between nicotine and these esters.4. The possible nature of the nicotinic receptor is discussed with reference to these compounds and other known nicotinic agents. A tentative suggestion is made that nicotinic activity can result from a two-point interaction between the drug and the receptor.

Amides↗
PubMed1978

The half-lives of angiotensin II, angiotensin II-amide, angiotensin III, Sar1-Ala8-angiotensin II and renin in the circulatory system of the rat.

1. Methods are described for estimating the half-life of angiotensin analogues and renin in the rat, from the time course of the blood pressure changes they evoke. 2. The following half-life values were measured: angiotensin II, 16 +/- 1 sec; angiotensin III, 14 +/- 1 sec; angiotensin II-amide, 15 +/- 1 sec; Sar1-Ala8-angiotensin II, 6.4 +/- 0.6 min; renin, 3.0 +/- 0.4 min. The distribution volume of angiotensin was found to be 18 ml./kg body wt. 3. It is inferred that the Asp1 residue does not reduce the rate of angiotensin II catabolism, but that substitution of this residue by sarcosine may inhibit catabolism while substitution by asparagine has no effect. 4. Five experimental criteria were identified which indicate that these methods give reliable estimates of the half-life. It is suggested that these results are more accurate than most previous half-life estimates. 5 When tachyphylaxis to angiotensin II-amide occurs, the pressor activity of the plasma is not reduced.

Angiotensin Amide↗
PubMed2004

Amide N-glucuronidation of MaxiPost catalyzed by UDP-glucuronosyltransferase 2B7 in humans.

MaxiPost [(3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one), or BMS-204352)] is a potent and specific maxi-K channel opener for potential use to treat stroke. This article describes structural characterization of a major human N-glucuronide metabolite of BMS-204352 and identification of the enzyme responsible for the N-glucuronidation reaction. After intravenous administrations of [(14)C]BMS-204352 (10 mg, 50 microCi) to eight healthy human subjects, one major metabolite M representing an average of 17% of the radioactive dose was excreted in pooled urine collected over 0 to 336 h after dosing. A major biliary metabolite of dogs dosed with [(14)C]BMS-204352 (5 mg/kg), which represented about 33% of the dose, has the same retention time and the same tandem mass spectrometry fragmentation pattern as the human urinary metabolite M. Four hundred fifty micrograms of the metabolite was isolated from the dog bile and analyzed by NMR. Long-range (1)H-(13)C NMR experimentation indicated that the glucuronic acid moiety was at the nitrogen site. The N-glucuronide of BMS-204352 was stable up to 24 h at 37 degrees C in the incubations at different pH values (3.0, 7.4, and 9.0) and with glucuronidases from Escherichia coli and Helix pomatia. Of the seven human UDP-glucuronosyltransferases (UGT) isozymes (1A1, 1A3, 1A4, 1A6, 1A7, 1A10, and 2B7) tested, only UGT2B7 produced metabolite M. UGT2B7-catalyzed N-glucuronidation of BMS-204352 exhibited Michaelis-Menten kinetics with a K(m) of 14.2 microM and V(max) of 0.29 nmol/min. mg of protein. Collectively, these results suggest that amide N-glucuronidation, a major elimination pathway of MaxiPost, is catalyzed by UGT2B7 in humans. This N-glucuronide represents a fully characterized amide N-glucuronide, and glucuronidation at the nitrogen represents a newly identified conjugation reaction for UGT2B7.

Amides↗
PubMed2004

Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity.

Fatty acid amide hydrolase (FAAH) is the primary catabolic regulator of several bioactive lipid amides in vivo, including the endogenous cannabinoid anandamide and the sleep-inducing substance oleamide. Inhibitors of FAAH are considered a potential therapeutic approach for the treatment of several nervous system disorders, including pain, anxiety, and insomnia. However, for FAAH inhibitors to achieve clinical utility, they must not only display efficacy in vivo but also selectivity for this enzyme relative to the numerous other serine hydrolases present in mammalian proteomes. Here, we report a general strategy for evaluating the pharmacological activity and target specificity of FAAH inhibitors and its implementation to develop the first class of selective reversible inhibitors of this enzyme that are highly efficacious in vivo. Using a series of functional proteomics, analytical chemistry, and behavioral pharmacology assays, we have identified a class of alpha-keto-heterocycles that show unprecedented selectivity for FAAH relative to other mammalian hydrolases, and, when administered to rodents, raise central nervous system levels of anandamide and promote cannabinoid receptor 1-dependent analgesia in several assays of pain sensation. These studies provide further evidence that FAAH may represent an attractive therapeutic target and describe a general route by which inhibitors of this enzyme can be optimized to achieve exceptional potency, selectivity, and efficacy in vivo.

Amidohydrolases↗
PubMed2005

Fatty acid amide hydrolase (-/-) mice exhibit an increased sensitivity to the disruptive effects of anandamide or oleamide in a working memory water maze task.

Although recent evidence suggests that fatty acid amide hydrolase (FAAH) may represent a potential therapeutic target, few published studies have investigated FAAH or its fatty acid amide substrates (FAAs) in animal models of learning and memory. Therefore, our primary goal was to determine whether FAAH (-/-) mice, which possess elevated levels of anandamide and other FAAs, would display altered performance in four Morris water maze tasks: acquisition of a hidden fixed platform, reversal learning, working memory, and probe trials. FAAH (-/-) mice failed to exhibit deficits in any task; in fact, they initially acquired the working memory task more rapidly than FAAH (+/+) mice. The second goal of this study was to investigate whether the FAAH inhibitor OL-135 (1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane), anandamide, other FAAs, and methanandamide would affect working memory in both genotypes. FAAH (-/-), but not (+/+), mice displayed working memory impairments following exogenous administration of anandamide (ED(50) = 6 mg/kg) or oleamide (50 mg/kg). However, the central cannabinoid receptor (CB(1)) receptor antagonist SR141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl] only blocked the disruptive effects of anandamide. Methanandamide, which is not metabolized by FAAH, disrupted working memory performance in both genotypes (ED(50) = 10 mg/kg), suggesting that CB(1) receptor signaling is unaltered by FAAH deletion. In contrast, OL-135 and other FAAs failed to affect working memory in either genotype. These results suggest that FAAH deletion does not impair spatial learning but may enhance acquisition under certain conditions. More generally, FAAH may represent a novel therapeutic target that circumvents the undesirable cognitive side effects commonly associated with direct-acting cannabinoid agonists.

Amidohydrolases↗
PubMed2006

Oxyhomologation of the amide bond potentiates neuroprotective effects of the endolipid N-palmitoylethanolamine.

The endolipid N-palmitoylethanolamine (PEA) shows a pleiotropic pattern of bioactivities, whose mechanistic characterization is still unclear and whose pharmacological potential is substantially limited by rapid metabolization by the amido hydrolyzing enzymes fatty acid amide hydrolases and N-acylethanolamine-hydrolyzing acid amidase. To overcome this problem, we have synthesized a new series of PEA homologs and characterized their activity on two in vitro models of neurodegeneration (oxidative stress, excitotoxicity). PEA partially prevented tert-butylhydroperoxide (t-BOOH; 100 microM; 3 h)-induced cell death (maximal effect, 26.3 +/- 7.5% in comparison with t-BOOH-untreated cells at 30 microM), whereas it was ineffective against the L-glutamate (1 mM; 24 h)-induced excitotoxicity at all concentrations tested (0.01-30 microM). Oxyhomologation of the amide bond, although leading to an increased enzymatic stability, also potentiated neuroprotective activity, especially for N-palmitoyl-N-(2-hydroxyethyl)hydroxylamine (EC(50) = 2.1 microM). These effects were not mediated by cannabinoid/vanilloid-dependent mechanisms but rather linked to a decreased t-BOOH-induced lipoperoxidation and reactive oxygen species formation and L-glutamate-induced intracellular Ca(2+) overload. The presence of the hydroxamic group and the absence of either redox active or radical scavenger moieties suggest that the improved neuroprotection is the result of increased metal-chelating properties that boost the antioxidant activity of these compounds.

Amides↗
PubMed1996

Catalysis of amide proton exchange by the molecular chaperones GroEL and SecB.

Hydrogen-deuterium exchange of 39 amide protons of Bacillus amyloliquefaciens ribonuclease (barnase) was analyzed by two-dimensional nuclear magnetic resonance in the presence of micromolar concentrations of the molecular chaperones GroEL and SecB. Both chaperones bound to native barnase under physiological conditions and catalyzed exchange of deeply buried amide protons with solvent. Such exchange required complete unfolding of barnase, which occurred in the complex with the chaperones. Subsequent collapse of unfolded barnase to the exchange-protected folding intermediate was markedly slowed in the presence of GroEL or SecB. Thus, both chaperones have the potential to correct misfolding in proteins by annealing.

Adenosine Diphosphate↗
PubMed1995

Cleavage of an amide bond by a ribozyme.

A variant form of a group I ribozyme, optimized by in vitro evolution for its ability to catalyze magnesium-dependent phosphoester transfer reactions involving DNA substrates, also catalyzes the cleavage of an unactivated alkyl amide when that linkage is presented in the context of an oligodeoxynucleotide analog. Substrates containing an amide bond that joins either two DNA oligos, or a DNA oligo and a short peptide, are cleaved in a magnesium-dependent fashion to generate the expected products. The first-order rate constant, kcat, is 0.1 x 10(-5) min-1 to 1 x 10(-5) min-1 for the DNA-flanked substrates, which corresponds to a rate acceleration of more than 10(3) as compared with the uncatalyzed reaction.

Amides↗
PubMed2001

ClC-2 Cl- channels in human lung epithelia: activation by arachidonic acid, amidation, and acid-activated omeprazole.

ClC-2 Cl- channels represent a potential target for therapy in cystic fibrosis. Key questions regarding the feasibility of using ClC-2 as a therapeutic target are addressed in the present studies, including whether the channels are present in human lung epithelia and whether activators of the channel can be identified. Two new mechanisms of activation of human recombinant ClC-2 Cl- channels expressed in HEK-293 cells were identified: amidation with glycine methyl ester catalyzed by 1-ethyl-3(3-dimethylaminopropyl) carbodiimide (EDC) and treatment with acid-activated omeprazole. ClC-2 mRNA was detected by RT-PCR. Channel function was assessed by measuring Cl- currents by patch clamp in the presence of a cAMP-dependent protein kinase (PKA) inhibitor, myristoylated protein kinase inhibitor, to prevent PKA-activated Cl- currents. Calu-3, A549, and BEAS-2B cell lines derived from different human lung epithelia contained ClC-2 mRNA, and Cl- currents were increased by amidation, acid-activated omeprazole, and arachidonic acid. Similar results were obtained with buccal cells from healthy individuals and cystic fibrosis patients. The ClC-2 Cl- channel is thus a potential target for therapy in cystic fibrosis.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Experimental evidence for amide hydrolysis of indomethacin in rabbit skin.

Amide hydrolysis of indomethacin was investigated in rabbit skin using the isolated perfused rabbit ear model. Indomethacin was applied topically on the surface area of 4 rabbit ears using a 1% alcoholic solution (Elmetacin). Indomethacin and its hydrolytic product N-deschloro-benzoyl-indomethacin (DBI) were determined in the venous efflux. The concentrations of indomethacin and DBI increased during the first 160 min and remained constant thereafter, the concentrations amounting from 0.041 +/- 0.001 to 0.497 +/- 0.018 nmol/min/cm2 (indomethacin) and from 0.84 +/- 0.03 to 3.24 +/- 0.31 pmol/min/cm2 (DBI). Thus steady state was reached with both substances, indicating a formation of DBI in the range of 0.65-2.01%. Considering the low hydrolytic turnover rate, the limited efficacy of topically applied indomethacin in the treatment of skin diseases does not seem to be due to extensive metabolic inactivation via amide hydrolysis in this target organ.

Amides↗
PubMed1994

An active amide group in the molecule of drugs that induce pemphigus: a casual or causal relationship?

Traditionally, drugs that are capable of inducing pemphigus are divided into two main groups according to their chemical structure, in particular, the existence of a sulfhydryl group in their molecule. Thus, two groups are formed: (1) drugs containing a sulfhydryl radical (thiol drugs or SH drugs) and (2) nonthiol or other drugs. Much emphasis has been put on the role of the sulfhydryl group in the pathogenesis of drug-induced pemphigus. The effects of this group have been extensively studied, and a logical paradigm on the mode of its action has been created. However, no attempt has been made to search for other biochemical radicals which might have an influence on the activation/triggering of this disease. The aim of the present report is to draw attention to a chemical group common to the molecule of several drugs that have been associated with the induction of pemphigus. Careful analysis of the chemical structure of nonthiol drugs known to induce pemphigus revealed that several of them share an active amide group in their molecule. We believe that this group might be responsible for the induction of the disease; thus, a third group of drugs capable of triggering pemphigus can be formed, namely drugs containing an active amide group. Several drugs of this group are discussed.

Amides↗
PubMed2004

Differential regulation of cytosolic and peroxisomal bile acid amidation by PPAR alpha activation favors the formation of unconjugated bile acids.

In human liver, unconjugated bile acids can be formed by the action of bile acid-CoA thioesterases (BACTEs), whereas bile acid conjugation with taurine or glycine (amidation) is catalyzed by bile acid-CoA:amino acid N-acyltransferases (BACATs). Both pathways exist in peroxisomes and cytosol. Bile acid amidation facilitates biliary excretion, whereas the accumulation of unconjugated bile acids may become hepatotoxic. We hypothesized that the formation of unconjugated and conjugated bile acids from their common substrate bile acid-CoA thioesters by BACTE and BACAT is regulated via the peroxisome proliferator-activated receptor alpha (PPARalpha). Livers from wild-type and PPARalpha-null mice either untreated or treated with the PPARalpha activator WY-14,643 were analyzed for BACTE and BACAT expression. The total liver capacity of taurochenodeoxycholate and taurocholate formation was decreased in WY-14,643-treated wild-type mice by 60% and 40%, respectively, but not in PPARalpha-null mice. Suppression of the peroxisomal BACAT activity was responsible for the decrease in liver capacity, whereas cytosolic BACAT activity was essentially unchanged by the treatment. In both cytosol and peroxisomes, the BACTE activities and protein levels were upregulated 5- to 10-fold by the treatment. These effects caused by WY-14,643 treatment were abolished in PPARalpha-null mice. The results from this study suggest that an increased formation of unconjugated bile acids occurs during PPARalpha activation.

Acyltransferases↗
PubMed1986

Immunohistochemical evidence that growth hormone-releasing factor (GRF) neurons contain an amidated peptide derived from cleavage of the carboxyl-terminal end of the GRF precursor.

Antisera were raised against synthetic replicates of the carboxyl-terminal (C-terminal) fragment of the precursor to human GH-releasing factor (GRF) (pre-proGRF) whose structure was predicted from the complementary DNA cloned from a pancreatic tumor. These antisera were used along with antisera to human GRF itself to search for the presence of related molecules in the human hypothalamus, with an immunohistochemical approach. The antisera to pre-proGRF that recognize specifically the C-terminal amidated form of pre-proGRF stain GRF neurons in their cell bodies, fibers, and nerve endings that are in contact with portal capillaries of the median eminence. Antisera against the nonamidated form of the molecule did not give any staining in the hypothalamus. These results strongly suggest that human hypothalamic GRF derives from a precursor immunologically related (and probably identical) to the tumorous one and that this precursor is cleaved inside GRF cell bodies to give, in addition to the GRF-44-NH2 a second amidated peptide, the C-terminal pre-proGRF that is transported distally to nerve endings and most probably coreleased with GRF into portal capillaries.

Adult↗
PubMed1987

Structure of the precursor to an enzyme mediating COOH-terminal amidation in peptide biosynthesis.

Many bioactive peptides terminate with an amino acid alpha-amide at their COOH terminus. The enzyme responsible for this essential posttranslational modification is known as peptidyl-glycine alpha-amidating monooxygenase or PAM. We identified cDNAs encoding the enzyme by using antibodies to screen a bovine intermediate pituitary lambda gt11 expression library. Antibodies to a beta-galactosidase/PAM fusion protein removed PAM activity from bovine pituitary homogenates. The 108,207 dalton protein predicted by the complete cDNA is approximately twice the size of purified PAM. An NH2-terminal signal sequence and short propeptide precede the NH2 terminus of purified PAM. The sequences of several PAM cyanogen bromide peptides were localized in the NH2-terminal half of the predicted protein. The cDNA encodes an additional 430 amino acid intragranular domain followed by a putative membrane spanning domain and a hydrophilic cytoplasmic domain. The forms of PAM purified from bovine neurointermediate pituitary may be generated by endoproteolytic cleavage at a subset of the 10 pairs of basic amino acids in the precursor. High levels of PAM mRNA were found in bovine pituitary and cerebral cortex. In corticotropic tumor cells, levels of PAM mRNA and pro-ACTH/endorphin mRNA were regulated in parallel by glucocorticoids and CRF.

Amides↗