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PubMed1993

Antitermination of amidase expression in Pseudomonas aeruginosa is controlled by a novel cytoplasmic amide-binding protein.

Amide-inducible expression of the aliphatic amidase system of Pseudomonas aeruginosa can be reconstituted in Escherichia coli with only the amidase structural gene amiE, the negative regulator amiC and the positive regulator amiR, a transcription antitermination factor. Complementation experiments in E. coli suggest that negative control of amidase expression by AmiC is mediated by a protein-protein interaction with AmiR. Purified AmiC binds acetamide with a KD of 3.7 microM in equilibrium dialysis studies, and therefore AmiC appears to be the sensory partner of the AmiC/AmiR pair of regulatory proteins, responding to the presence of amides. Sequence analysis techniques suggest that AmiC is a member of the structural family of periplasmic binding proteins, but has a distinct and novel cytoplasmic role.

Amidohydrolases↗
PubMed2003

Molecular mechanics (MM3) calculations on lithium amide compounds.

The MM3 force field has been extended to deal with the lithium amide molecules that are widely used as efficient catalysts for stereoselective asymmetric synthesis. The MM3 force field parameters have been determined on the basis of the ab initio MP2/6-31G* and/or DFT (B3LYP/6-31G*, B3-PW91/6-31G*) geometry optimization calculations. To evaluate the electronic interactions specific to the lithium amides derived from the diamine molecules properly, the Lewis bonding potential term for the interaction between the lithium atom and the nonbonded adjacent electronegative atom such as nitrogen was introduced into the MM3 force field. The bond dipoles were evaluated correctly from the electronic charges on the atoms calculated by fitting to the electrostatic potential at points selected. The MM3 results on the molecular structures, conformational energies, and vibrational spectra show good agreement with those from the quantum mechanical calculations.

Journal Article↗
PubMed2002

Peptidyl alpha-keto amide inhibitor of calpain blocks excitotoxic damage without affecting signal transduction events.

The cysteine protease calpain is activated by calcium and has a wide range of substrates. Calpain-mediated cellular damage is associated with many neuropathologies, and calpain also plays a role in signal transduction events that are essential for cell maintenance, including the activation of important kinases and transcription factors. In the present study, the hippocampal slice culture was used as a model of excitotoxicity to test whether the neuroprotection elicited by selective calpain inhibition is associated with changes in cell signaling. Peptidyl alpha-keto amide and alpha-keto acid inhibitors reduced both calpain-mediated cytoskeletal damage and the concomitant synaptic deterioration resulting from an N-methyl-D-aspartate exposure. The alpha-keto amide CX295 was protective when infused into slice cultures before or after the excitotoxic episode. The slices protected with CX295 exhibited normal activation levels of mitogen-activated protein kinase and the transcription factor nuclear factor-kappaB. Thus, selective inhibition of calpain provides neuroprotection without influencing critical signaling pathways.

Animals↗
PubMed1984

Isolation and identification of piperacillin amide as an impurity in piperacillin.

Piperacillin amide (IV) was successfully identified as the predominant impurity in commercial lots of piperacillin monohydrate (III). The impurity was isolated via a preparative liquid chromatographic scheme utilizing Florisil as the adsorbent and a mobile phase of water-acetonitrile (4:96, v/v). The isolated component had nearly the same reverse-phase HPLC properties as piperacillin and was chemically and thermally unstable. This labile impurity was spectroscopically identified by field desorption (FD), fast atom bombardment (FAB) with collision activation decomposition (CAD), and desorption chemical ionization (DCI) mass spectrometries , and NMR and IR spectrometries . Identity was confirmed on comparison of the chromatographic and spectrometric data of the impurity with an independently synthesized sample of piperacillin amide.

Chemical Phenomena↗
PubMed1989

Cytotoxic effects of methionine alkyl esters and amides in normal and neoplastic cell lines.

Homologous series of L-methionine alkyl ester hydrochlorides and tosylates were synthesized and evaluated for in vitro growth inhibitory activity in Meth A sarcoma. Cytotoxicity, as determined by [3H]thymidine incorporation, was found to be directly proportional to alkyl chain length and surface tension lowering activity. L-Methionine decyl and dodecyl ester hydrochlorides possessed optimum cytotoxic activity (IC50 = 29, 28 microM) which was not reversible by the addition of L-methionine. Surface tension of a 50 microM solution of the decyl and dodecyl ester hydrochlorides were 35.4 and 32.7 dyn/cm, respectively. The corresponding decyl and dodecyl ester tosylates and amide hydrochlorides were less active. The N-t-butoxycarbonyl analogues were essentially inactive, demonstrating the necessity of an unsubstituted and/or potentially cationic amino group. Methionine dependence characteristics and cytotoxicity were also determined for three human (IMR-90, LX-1, MCF7) and four additional murine (L1210, L5178Y, 3T3, SV-T2) cell lines. The human cell lines Meth A, LX-1, and SV-T2 were found to be methionine independent. The LX-1 tumor cell line and the SV-T2 transformed line exhibited two to four times more sensitivity to the cytotoxic and cytolytic properties of the decyl and dodecyl ester hydrochlorides than their normal counterparts. The dodecyl amide hydrochloride derivative demonstrated enhanced cytotoxic activity in vivo relative to the corresponding ester, possibly due to decreased metabolic hydrolysis.

Animals↗
PubMed1991

Structure-activity relationship studies with mosquito repellent amides.

A series of amide analogues of N,N-diethyl-m-toluamide (DEET) and N,N-diethylphenylacetamide (DEPA) were synthesized to study their mosquito repellency in relation to chemical structure and physical properties. None of these parameters (vapor pressure, lipophilicity, and molecular length) could be related to protection time. However, when the protection time of all five amides derived from the same carboxylic acid was expressed in terms of all three parameters together, excellent correlation was obtained.

Acetamides↗
PubMed2003

Androgen-independent expression of adrenomedullin and peptidylglycine alpha-amidating monooxygenase in human prostatic carcinoma.

Most of the locally advanced and metastatic prostate carcinomas (PCs) treated with antiandrogenic therapy eventually become refractory to this treatment. Locally produced factors may control prostate tumor biology after androgen withdrawal. Adrenomedullin (AM) is expressed in the prostate and could control cell growth in androgen-independent conditions. AM needs to be amidated by the enzyme peptidylglycine alpha-amidating monooxygenase (PAM) to become fully active. The objective of the present study was to analyze whether the expression of preproadrenomedullin (preproAM) and PAM in PC is regulated by androgens. For this purpose, human in vitro and in vivo PC models were grown in the presence or absence of androgens, and the expression of AM and PAM was examined by immunohistochemistry, Western blotting, RT-PCR, and Northern blotting. Furthermore, immunohistochemical analysis of AM in clinical specimens was performed to test if its expression is related to Gleason score and antiandrogenic therapy. In PC cell lines and xenografts, mRNA and protein AM levels were similar in the presence or absence of androgens. PAM expression seemed to be induced by androgen-withdrawal. Our results in clinical samples showed no relationship between AM expression and Gleason score or antiandrogenic treatment. In conclusion, our results demonstrate that preproAM and PAM expression in the human prostate is androgen-independent. In addition, we also report for the first time the expression of a novel PAM transcript in PC, which has not been previously described in other tissues.

Adolescent↗
PubMed1996

Redox-dependent dynamics of putidaredoxin characterized by amide proton exchange.

Multidimensional NMR methods were used to obtain 1H-15N correlations and 15N resonance assignments for amide and side-chain nitrogens of oxidized and reduced putidaredoxin (Pdx), the Fe2S2 ferredoxin, which acts as the physiological reductant of cytochrome P-450cam (CYP101). A model for the solution structure of oxidized Pdx has been determined recently using NMR methods (Pochapsky TC, Ye XM, Ratnaswamy G, Lyons TA, 1994, Biochemistry 33:6424-6432) and redox-dependent 1H NMR spectral features have been described (Pochapsky TC, Ratnaswamy G, Patera A, 1994, Biochemistry 33:6433-6441). 15N assignments were made with NOESY-(1H/15N) HMQC and TOCSY-(1H/15N) HSQC spectra obtained using samples of Pdx uniformly labeled with 15N. Local dynamics in both oxidation states of Pdx were then characterized by comparison of residue-specific amide proton exchange rates, which were measured by a combination of saturation transfer and H2O/D2O exchange methods at pH 6.4 and 7.4 (uncorrected for isotope effects). In general, where exchange rates for a given site exhibit significant oxidation-state dependence, the oxidized protein exchanges more rapidly than the reduced protein. The largest dependence of exchange rate upon oxidation state is found for residues near the metal center and in a region of compact structure that includes the loop-turn Val 74-Ser 82 and the C-terminal residues (Pro 102-Trp 106). The significance of these findings is discussed in light of the considerable dependence of the binding interaction between Pdx and CYP101 upon the oxidation state of Pdx.

Bacterial Proteins↗
PubMed1997

Human recombinant [C22A] FK506-binding protein amide hydrogen exchange rates from mass spectrometry match and extend those from NMR.

Hydrogen/deuterium exchange behavior of human recombinant [C22A] FK506 binding protein (C22A FKBP) has been determined by protein fragmentation, combined with electrospray Fourier transform ion cyclotron resonance mass spectrometry (MS). After a specified period of H/D exchange in solution, C22A FKBP was digested by pepsin under slow exchange conditions (pH 2.4, 0 degree C), and then subjected to on-line HPLC/MS for deuterium analysis of each proteolytic peptide. The hydrogen exchange rate of each individual amide hydrogen was then determined independently by heteronuclear two-dimensional NMR on 15N-enriched C22A FKBP. A maximum entropy method (MEM) algorithm makes it possible to derive the distributions of hydrogen exchange rate constants from the MS-determined deuterium exchange-in curves in either the holoprotein or its proteolytic segments. The MEM-derived rate constant distributions of C22A FKBP and different segments of C22A FKBP are compared to the rate constants determined by NMR for individual amide protons. The rate constant distributions determined by both methods are consistent and complementary, thereby validating protein fragmentation/mass spectrometry as a reliable measure of hydrogen exchange in proteins.

Amino Acid Sequence↗
PubMed2006

Effect of temperature on the acidolysis of N-acyl-N,alpha,alpha-trialkyl glycine amides as related to the nature of substituents.

The C-terminal amide bond of N-acyl-N,alpha,alpha-trialkyl glycine amides is labile to acid and this has been currently assigned to steric crowding within the amino acid residue. However, our previous work has shown that in the acidolysis of some of these compounds steric hindrance seems to play a less important role than what one would expect. Thus, the cleavage of two sets of such compounds bearing different degrees of crowding was investigated at five different temperatures in order to clarify the effect of structure on reactivity in terms of enthalpy and entropy of activation. The compounds exhibited an Arrhenius-type behaviour, and both enthalpies and entropies of activation were calculated by taking advantage of the transition state theory. In addition, the kinetic data were analysed in terms of isokinetic relationships in order to find evidence to support that the compounds react under the same mechanism. The changes in the reaction rate are governed by the changes in both the enthalpy and the entropy of activation, which are related to bond energy and steric hindrance, respectively. In general, the entropies of activation are very negative for all compounds investigated, which reflects large steric constrictions associated with the formation of the transition state. In addition, they are very sensitive to the structure of the substrates.

Glycine↗
PubMed2006

Identification of an unusual naturally occurring apolar fatty acid amide in mammalian brain and a method for its quantitative determination.

Fatty acid amides (FAAs), such as the N-acylamides, N-acylethanolamides, N-acyldopamines and N-acylamino acids, are now emerging as an important new class of lipid-signalling molecules. This paper provides evidence, based on high-performance liquid chromatography/electrospray ionisation mass spectrometry (HPLC/ESI-MS/MS), gas chromatography/mass spectrometry (GC/MS) and 1H-NMR, of the occurrence in mouse and bovine brain extracts of a compound characterised by a mass spectrum attributable to a FAA not previously described, namely, the isopropyl-amide of stearic acid (SIPA). A highly sensitive GC/MS method was developed for quantification of naturally occurring SIPA and, also, for purposes of comparison, that of palmitoylethanolamide (PEA), a structurally related compound commonly determined in animal tissues. The results obtained show that SIPA levels in mouse brain are 8-10-fold higher than those of PEA. Moreover, SIPA was found in human neuroblastoma cell (SHSY-5Y) extracts, at significantly higher levels following exposure of the cells to the mitochondrial inhibitor rotenone. All this evidence not only shows surprisingly that SIPA may be found naturally in mammalian biological extracts despite the unusual functional group (i.e. isopropylamide) implicated, but also raises many important questions concerning its biological origin.

Animals↗
PubMed2007

Fourier transform mass spectrometry to monitor hyaluronan-protein interactions: use of hydrogen/deuterium amide exchange.

The use of Fourier transform mass spectrometry (FTMS) to monitor noncovalent complex formation in the gas phase under native conditions between the Link module from human tumor necrosis factor stimulated gene-6 (Link_TSG6) and hyaluronan (HA) oligosaccharides is reported. In particular, a titration experiment with increasing concentrations of octasaccharide (HA(8)) to protein produced a noncovalent complex with 1:1 stoichiometry when the oligosaccharide was in molar excess. However, in the presence of a molar excess of tetrasaccharide (HA(4)) nearly all proteins and oligosaccharides were observed in their unbound charge states. These results are consistent with solution-phase properties for this interaction in which HA(8), but not HA(4), supports high affinity Link_TSG6 binding. Hydrogen/deuterium amide exchange mass spectrometry (H/D-EX MS) was also utilized to investigate the level of global deuterium incorporation, over time, for Link_TSG6 in both the absence and presence of HA(8). After dilution into quenching conditions, deuterium incorporation reached limiting asymptotic values of 37 and 26 deuterons for the free and bound protein at 240 and 480 min, respectively, indicating that the oligosaccharide interferes with amide exchange on binding. To detect sequence-specific deuterium incorporation, pepsin digestion of Link_TSG6 in both the absence and presence of HA(8) was performed. A level of deuterium incorporation of 10-30% was observed for peptides analyzed in free Link_TSG6. Interestingly, HA(8) blocked some sites of proteolysis in Link_TSG6 compared to the free protein. Molecular modeling indicated that amino acids proximal to the ligand correlated with regions of the protein that were resistant to enzymatic digestion. Of the peptides that could be analyzed by H/D-EX MS in the presence of the ligand, a 30-60% reduction in deuterium incorporation, relative to the free protein, was observed, even for those sequences not directly involved in HA binding. These results support the utility of FTMS as a method for the characterization of protein-carbohydrate interactions.

Binding Sites↗
PubMed2002

Multi-stage tandem mass spectrometry of metal cationized leucine enkephalin and leucine enkephalin amide.

We have examined the multi-stage collision induced dissociation (CID) of metal cationized leucine enkephalin, leucine enkephalin amide, and the N-acetylated versions of the peptides using ion trap mass spectrometry. In accord with earlier studies, the most prominent species observed during the multi-stage CID of alkali metal cationized leucine enkephalin are the [b(n) + 17 + Cat]+ ions. At higher CID stages (i.e. >MS(4)), however, dissociation of the [b2 + 17 + Cat]+ ion, a cationized dipeptide, results in the production of [a(n) -1 + Cat]+ species. The multi-stage CID of Ag+ cationized leucine enkephalin can be initiated with either the [b(n) -1 + Ag]+ or [b(n) + 17 + Ag]+ ions produced at the MS/MS stage. For the former, sequential CID stages cause, in general, the loss of CO, and then the loss of the imine of the C-terminal amino acid, to reveal the amino acid sequence. Similar to the alkali cationized species, CID of [b2 -1 + Ag]+ produces prominent [a(n) -1 + Ag]+ ions. The multi-stage CID of argentinated peptides is reminiscent of fragmentation observed for protonated peptides, in that a series of (b(n)) and (a(n)) type ions are generated in sequential CID stages. The Ag+ cation is similar to the alkali metals, however, in that the [b(n) + 17 + Ag]+ product is produced at the MS/MS and MS3 stages, and that sequential CID stages cause the elimination of amino acid residues primarily from the C-terminus. We found that N-acetylation of the peptide significantly influenced the fragmentation pathways observed, in particular by promoting the formation of more easily interpreted (in the context of unambiguous sequence determination) dissociation spectra from the [b2 + 17 + Li]+, [b2 + 17 + Na]+ and [b2 -1 + Ag]+ precursor ions. Our results suggest, therefore, that N-acetylation may improve the efficacy of multi-stage CID experiments for C-terminal peptide sequencing in the gas phase. For leucine enkephalin amide, only the multi-stage CID of the argentinated peptide allowed the complete amino acid sequence to be determined from the C-terminal side.

Cations↗
PubMed2002

Poly(amide ester)s from 2,6-pyridinedicarboxylic acid and ethanolamine derivatives: identification of macrocycles by matrix-assisted laser desorption/ionization mass spectrometry.

The influence of the polycondensation pathway and aminoalcohol structure was investigated in the synthesis of poly(amide ester)s by polytransesterification from ethyl pyridine-2,6-dicarboxylate and 2-amino-2-methylpropan-1-ol or the corresponding bis(amide alcohol), or by polycondensation from the diacid dichloride. Both linear and cyclic structures were identified by steric exclusion chromatography (SEC) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). Transesterification led to cyclic oligomers (macrocycles) with 2-14 pyridine moities in the ring whereas polycondensation from the diacid dichloride gave low molecular weight polymers (Mn = 1800) and macrocycles.

Journal Article↗
PubMed1996

The different molar absorptivities of the secondary structure types in the amide I region: an attenuated total reflection infrared study on globular proteins.

Differences in molar absorptivity of the various secondary structures in the amide I region of infrared protein spectra would have a great impact on the interpretation of the data published thus far on protein films studied by attenuated total reflection infrared spectroscopy. In this work, representative values for amide I absorptivities are obtained for 15 different films of globular proteins spread from H2O solutions. The observed intensities are corrected for variations in film thickness and for contributions of hydration water, atmospheric water, and side chains. These absorptivities, together with the reported secondary structure of the proteins investigated, are used to deduce the molar absorptivities of the individual secondary structure types. It is found that the molar absorptivity of beta-strands is 1.4-1.6 times larger than that of alpha-helices, which in turn is 1.3-2.1 times larger than those found for beta-turns or random coiled structures. The implications of our findings for spectral analysis currently used in literature are discussed.

Deuterium↗
PubMed1993

Localization of the gene encoding peptidylglycine alpha-amidating monooxygenase (PAM) to human chromosome 5q14-5q21.

Peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) is a multifunctional protein containing two enzymes that act sequentially to catalyze the alpha-amidation of neuroendocrine peptides. Southern blot analysis of human placental DNA demonstrated that PAM is encoded by a single gene. The chromosomal localization of the PAM gene was established using in situ hybridization. A 2.2-kb human PAM cDNA hybridized to human metaphase chromosomes revealed a significant clustering of silver grains over chromosome 5 bands q14-q21. The gene encoding another enzyme important in the post-translational processing of neuroendocrine precursors, prohormone convertase 1 (PC1), is localized in the same region (5q15-q21).

Blotting, Southern↗
PubMed1996

Prevalence and turnover of peptidylglycine alpha-amidating monooxygenase mRNA in atrial cardiomyocytes.

Peptidylglycine alpha-amidating monooxygenase (PAM), the enzyme responsible for the alpha-amidation of neuroendocrine peptides, is more prevalent in the atrium of the heart than in pituitary or brain. RNase protection assays indicate that PAM transcripts account for approximately 0.5% of the mRNA in the neonatal atrium and 0.06% of the mRNA in the neonatal ventricle. In primary atrial cardiomyocyte cultures PAM mRNA turns over slowly, with a half-life of approximately 20 h. Levels of PAM mRNA in primary atrial cardiomyocytes are increased to 16.5% of control upon treatment with dexamethasone and decreased to 63% of control upon treatment with thyroid hormone.

Animals↗
PubMed1987

Segregation of FMRF amide-immunoreactive efferent fibers from NPY-immunoreactive amacrine cells in goldfish retina.

Immunocytochemical studies were conducted on goldfish to determine whether a retinal efferent fiber system, immunoreactive to the tetrapeptide Phe-Met-Arg-Phe-NH2 (FMRFamide), might contain instead a substance similar to one of the 36-amino acid pancreatic polypeptides, the C-terminus of which is similar to FMRFamide. Our results demonstrate the presence of two separate peptidergic systems, one containing FMRFamide-like, and the other pancreatic polypeptide-like peptides. Antisera to FMRF amide reveal the efferent fibers, whose axons exit the optic nerve and terminate in layer 1 of the inner plexiform layer, as previously described. Antisera to porcine neuropeptide Y, and to avian and bovine pancreatic polypeptides label a sparse population of putative amacrine cell bodies and a dense fiber plexus in layers 1, 3, and 5 of the inner plexiform layer. Based on intensity of staining, this amacrine cell peptide appears to be most similar to neuropeptide-Y. Radioimmunoassay and immunocytochemical staining of retinas in which the efferent fiber peptide was depleted by optic nerve crush confirm in large part the observation that the two peptide systems are distinct. However, there is some cross-recognition of the FMRF amide-like tissue antigen by pancreatic polypeptide antibodies. Double-label studies with antisera to tyrosine hydroxylase and neuropeptide-Y indicate that the pancreatic polypeptide antigen is not co-localized with catecholamines.

Animals↗