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PubMed1993

Comparison of the dynamics of an engineered insulin monomer and dimer by acid-quenched amide proton exchange. Non-local stabilization of interchain hydrogen bonds by dimerization.

Dynamic differences between an engineered insulin monomer and dimer are investigated under physiological conditions by an adaptation of the method of acid-quenched amide proton exchange. Although exchange lifetimes of amide protons involved in intrachain hydrogen bonds are similar in the two analogs, dimerization specifically stabilizes two interchain hydrogen bonds (LeuB6-NH...O = C-CysA6 and CysA11-NH...O = C-GluB4) that are distant from the dimer interface. Such non-local stabilization demonstrates that fluctuations in the tertiary structure of the monomer are damped by dimerization. As the B6-A6 and A11-B4 hydrogen bonds are specific to the crystallographic T-state, their stabilization also indicates that the R-state (an allosteric feature of hexamer assembly) is not significantly populated in an isolated dimer. Our results are discussed in reference to recent hypotheses that crystal structures of insulin depict inactive conformers and that detachment of interchain contacts accompany receptor binding.

Amides↗
PubMed1997

The stability and dynamics of ribosomal protein L9: investigations of a molecular strut by amide proton exchange and circular dichroism.

Nuclear magnetic resonance and circular dichroism experiments were used to investigate the stability and dynamic aspects of ribosomal protein L9 from Bacillus stearothermophilus in solution. This unusually shaped protein, with its two widely spaced RNA-binding domains linked by a connecting helix, has been hypothesized to serve as a "molecular strut", most likely playing a role in ribosome assembly and/or maintaining the catalytically active conformation of ribosomal RNA. Protection factors for amide proton exchange were quantitatively measured in an extensive series of NMR experiments, providing probes of the stability and dynamics of localized regions of the protein. Results show that each of the two RNA-binding domains contains a highly stable core. The exposed central helix that connects the two domains is helical in solution, albeit not rigid, a result that is supported by amide proton protection factors, circular dichroism measurements, and carbon-13 and proton chemical shift index values. A conserved glycine and lysine-rich loop in the N-terminal domain is ordered and quite stable, a surprising result, since this loop had been presumed to be disordered in the original crystallographic analysis. Interestingly, the most dynamic parts of the protein are the regions that contain the likely RNA-binding residues in each of the two domains. The present results add further support to the notion that the L9 protein plays an architectural role within the ribosome, with the central helix serving as a molecular strut, or perhaps a spring, linking the two widely spaced RNA-binding domains.

Amides↗
PubMed1995

The effect of 17O on the relaxation of an amide proton within a hydrogen bond.

The relaxation rates of the multiple-quantum coherence for the amide hydrogen of Gly13 in ras p21.GDP were determined in the presence and absence of 17O labeling in the beta-phosphate of GDP. No significant difference could be observed between labeled and unlabeled samples, in spite of the fact that the hydrogen bond from the amide group of Gly13 to the beta-phosphate is shorter than is typical, based on its chemical shift. For macromolecules in which an oxygen atom is the acceptor of a hydrogen bond, dipolar coupling between 17O and hydrogen is unlikely to be observable, except for extremely short H-bonds.

Amides↗
PubMed1995

Measurement of intrinsic exchange rates of amide protons in a 15N-labeled peptide.

We have used a modified version of a previously proposed technique, MEXICO [Gemmecker et al. (1993) J. Am. Chem. Soc., 115, 11620], and improved data analysis procedures in order to measure rapid hydrogen exchange (HX) rates of amide protons in peptides labeled only with 15N. The requirement of 13C-/15N-labeled material has been circumvented by adjusting conditions so that NOE effects associated with amide protons can be neglected (i.e., omega 0 tau c approximately 1). The technique was applied to an unstructured 15N-labeled 12-residue peptide to measure intrinsic HX rates, which are the essential reference for examining protein and peptide structure and dynamics through deceleration of HX rates. The method provided accurate HX rates from 0.5 to 50 s-1 under the conditions used. The measured rates were in good agreement with those predicted using correction factors determined by Englander and co-workers [Bai et al. (1993) Proteins, 17, 75], with the largest deviations from the predicted rates found for residues close to the N-terminus. The exchange rates were found to exhibit significant sensitivity to the concentration of salt in the sample.

Amides↗
PubMed1996

Molecular dynamics simulations of peptides from BPTI: a closer look at amide-aromatic interactions.

Molecular dynamics (MD) simulations of short peptides in water were performed to establish whether it is possible to reproduce experimental data from chemical shift measurements by nuclear magnetic resonance spectroscopy. Three different tetrapeptides were studied. The first, YTGP (Tyr-Thr-Gly-Pro), shows an electrostatic interaction between the aromatic ring of Tyr and the backbone amide hydrogen atom of Gly. The second, YTAP (Tyr-Thr-Ala-Pro), cannot make such an interaction because of steric hindrance of the Ala side chain and hence does not show a well-defined conformation. The third, FTGP (Phe-Thr-Gly-Pro), is shown to alternate between two different conformations. It is demonstrated that small differences in chemical shift, corresponding to these slightly different conformations, can be quantitatively modeled in MD simulations when using the proper force-field parameters and water model Explicit inclusion of hydrogen atoms o the aromatic rings is essential for a proper description of electrostatic interactions, but the choice of the water model is equally important. We found that a combination of the SPC/E water model and a revised GROMOS87 force field gives close agreement with experiment, while the same and other force fields in combination with SPC or TIP3P water did not reproduce the NMR data at all. Simulations of a longer peptide from bovine pancreatic trypsin inhibitor, containing the YTGP sequence, did show the interaction between the aromatic ring and the amide hydrogen, but not as pronounced as the simulations of shorter periods.

Amides↗
PubMed1993

1H-NMR study on ganglioside amide protons: evidence that the deuterium exchange kinetics are affected by the preparation of samples.

The kinetics of H/2H chemical exchange of the amide proton has been suggested as one of the tools available for investigating hydrogenbond stabilizing interactions in gangliosides. The amide proton/deuterium (NH/2H) exchange rates in GM2 ganglioside were studied by 1H-NMR spectroscopy on 12 samples prepared following different procedures. In samples passed through a sodium salt Chelex-100 cation exchange resin column prior to being analysed the N-acetylneuraminic acid NH exchange occurred in less than 10 min and that of ceramide NH in 30 min. The N-acetylgalactosamine acetamido NH exchange was slower, the half-life of the signal ranging from 15 min to 3.5 h. Contact of the Chelex-treated GM2 samples with water, through a dialysis process, modified the NH/2H exchange rate values, the N-acetylgalactosamine acetamido NH exchange becoming faster than that of ceramide NH and similar to that of N-acetylneuraminic acid NH. Our results indicate that the deuterium/proton exchange rate strongly depends on sample preparation (ion content and minor contaminants present in water). The three-dimensional model involving the N-acetylgalactosamine acetamido NH and the N-acetylneuraminic acid carboxyl group hydrogen-bonding, which is supported by experimental evidence, cannot be confirmed by NH-exchange measurement.

Amides↗
PubMed1991

1H-NMR study of GM2 ganglioside: evidence that an interresidue amide-carboxyl hydrogen bond contributes to stabilization of a preferred conformation.

Several properties of the exchangeable amide protons of the ganglioside GM2 were studied in detail by 1H-NMR spectroscopy in fully deuterated dimethylsulfoxide [2H6]DMSO/2% H2O, and compared with data obtained for the simpler constituent glycosphingolipids GA2 and GM3. In addition to chemical shifts, 3J2,HN coupling constants, and temperature shift coefficients, the kinetics of NH/2H chemical exchange were examined by following the disappearance of the amide resonances in [2H6]DMSO/2% 2H2O. The results included observation of an increase in half-life of the N-acetylgalactosamine acetamido HN by more than an order of magnitude in GM2 compared to GA2, attributable to the presence of the additional N-acetylneuraminic acid residue. Additional one-dimensional dipolar cross relaxation experiments were also performed on nonexchangeable protons of GM2. The results of all of these experiments support a three-dimensional model for the terminal trisaccharide in which a hydrogen bond is formed between the N-acetylgalactosamine acetamido NH and the N-acetylneuraminic acid carboxyl group. The interaction is proposed to be of the pi-acceptor type, a possibility which has not yet been explored in the literature on carbohydrates. The proposed model is discussed in comparison with that of Sabesan et al. (1984, Can J Chem 62:1034-45), and the models of GM1 proposed more recently by Acquotti et al. (1990, J Am Chem Soc 112:7772-8) and Scarsdale et al. (1990, Biochemistry 29:9843-55).

Amides↗
PubMed1996

Discovery of a herbicidal lead using polymer-bound activated esters in generating a combinatorial library of amides and esters.

A combinatorial library containing mixtures of amides and esters was prepared through solid-phase chemistry. The advantages of using solid-phase chemistry over solution-phase chemistry to prepare this library are discussed. The library was screened through a high-throughput whole organism herbicidal assay upon which a mixture containing amides was found to have herbicidal activity. Deconvolution of the mixture provided N-(3-benzoylphenyl)-3-(1,1-dimethylethyl)-1-methyl)-1 H-pyrazole-5-carboxamide as a herbicidal lead with broadleaf and narrowleaf pre-emergence herbicidal activity as low as 100 g/ha on some weed species. This study represents the first report of an agrochemical discovered using a combinatorial approach.

Amides↗
PubMed1977

Linoleic acid amides: effect on cholesteremia and atherosclerosis.

Several of a series of linoleic acid amides have been reported to inhibit cholesterol-induced atherosclerosis in rabbits. The three amides which have been studied to the greatest extent are (in order of increasing activity) N-cyclohexyl linoleamide (AC23), N(alpha methylbenzyl) linoleamide (AC223), and N[aplha-phenyl-beta-(p-tolyl)ethyl] linoeamide (AC 485). We have found AC223 to inhibit cholesterol absorption in rats and to slightly inhibit exogenous but not endogenous cholesteremia in rabbits. In a fiber-free diet, AC223 reduces serum cholesterol and liver triglyceride levels. Rats were also fed a basal semipurified diet with and without AC223. Fecal excretion of labeled exogenous (as [ (14)C] cholesterol) or endogenous (as [14 C] mevalonolactone) steroid was 44 and 43% higher in drug treated groups. The mechanism of hypocholesteremic action of the linoleamides appears to involve inhibition of cholesterol absorption.

Amides↗
PubMed2005

Overexpression, purification and characterization of SimL, an amide synthetase involved in simocyclinone biosynthesis.

Simocyclinone D8 is a potent inhibitor of bacterial gyrase, produced by Streptomyces antibioticus Tu 6040. It contains an aminocoumarin moiety, similar to that of novobiocin, which is linked by an amide bond to a structurally complex acyl moiety, consisting of an aromatic angucycline polyketide nucleus, the deoxysugar olivose and a tetraene dicarboxylic acid. We have now investigated the enzyme SimL, responsible for the formation of the amide bond of simocyclinone. The gene was cloned, expressed in S. lividans T7, and the protein was purified to near homogeneity, and characterized. The 60 kDa protein catalyzed both the ATP-dependent activation of the acyl component as well as its transfer to the amino group of the aminocoumarin ring, with no requirement for a 4'-phosphopantetheinyl cofactor. Besides its natural substrate, simocyclinone C4, SimL also accepted a range of cinnamic and benzoic acid derivatives and several other, structurally very diverse acids. These findings make SimL a possible tool for the creation of new aminocoumarin antibiotics.

Adenosine Triphosphate↗
PubMed2004

Modeling carbon monoxide dehydrogenase/acetyl-CoA synthase (CODH/ACS): a trinuclear nickel complex employing deprotonated amides and bridging thiolates.

Carbon monoxide dehydrogenase/acetyl-CoA synthase (CODH/ACS) utilizes a unique Ni-M bimetallic site in the biosynthesis of acetyl-CoA, where a square-planar Ni ion is coordinated to two thiolates and two deprotonated amides in a Cys-Gly-Cys motif. The identity of M is currently a matter of debate, although both Cu and Ni have been proposed. In an effort to model ACS's unusual active site and to provide insight into the mechanism of acetyl-CoA formation and the role of each of the metals ions, we have prepared and structurally characterized a number of Ni(II)-peptide mimic complexes. The mononuclear complexes Ni(II) N, N'-bis(2-mercaptoethyl)oxamide (1), Ni(II) N, N'-ethylenebis(2-mercaptoacetamide) (2), and Ni(II) N, N'-ethylenebis(2-mercaptopropionamide) (3) model the Ni(Cys-Gly-Cys) site and can be used as synthons for additional multinuclear complexes. Reaction of 2 with MeI resulted in the alkylation of the sulfur atoms and the formation of Ni(II) N, N'-ethylenebis(2-methylmercaptoacetamide) (4), demonstrating the nucleophilicity of the terminal alkyl thiolates. Addition of Ni(OAc)(2).4H(2)O to3 resulted in the formation of a trinuclear species (5), while 2 crystallizes as an unusual paddlewheel complex (6) in the presence of nickel acetate. The difference in reactivity between the similar complexes 2 and 3 highlights the importance of ligand design when synthesizing models of ACS. Significantly,5 maintains the key features observed in the active site of ACS, namely a square-planar Ni coordinated to two deprotonated amides and two thiolates, where the thiolates bridge to a second metal, suggesting that 5 is a reasonable structural model for this unique enzyme.

Acetate-CoA Ligase↗
PubMed2003

Molecular modeling of diastereoisomeric aggregates of l/d ser/histamine amide with 5'-TpTpdC-3'.

Novel nonpeptide serine/histamine amides (1: l-Ser-Hism,2: d-Ser-Hism) with potent DNA cleavage activity were designed. Conformational analysis and docking study were carried out in an attempt to understand the DNA cleavage mechanism of the designed enantiomeric nonpeptides. First, the most stable conformers of the designed amides were obtained from the conformational analysis by random search. Next, the three-dimensional structures of l-Ser-Hism.5'-TpTpdC-3' and d-Ser-Hism.5'-TpTpdC-3' complexes were built using molecular docking techniques. The docked diastereoisomeric aggregates show that both l-Ser-Hism and d-Ser-Hism bind to two neighboring phosphates in the 5'-TpTpdC-3' backbone through H-bonds. This binding mode suggests a possible phosphodiester bond hydrolysis mechanism. In addition, the binding energies of two constructed complexes were also calculated with the Tripos force field. It indicates that the binding ability between l-Ser-Hism and 5'-TpTpdC-3' is stronger than that of d-Ser-Hism, suggesting a stronger DNA cleavage activity of l-Ser-Hism than that of d-Ser-Hism. The results agree with our experimental DNA cleavage assays. Supplementary material is available for this article if you access the article at http://dx.doi.org/10.1007/s00894-002-0114-9. A link in the frame on the left on that page takes you directly to the supplementary material. Figure Docking structures of1 and2 binding with oligonucleotide: l-Ser-Hism.5'-TpTpdC-3'(left), d-Ser-Hism.5'-TpTpdC-3'(right). Hydrogen bonds are shown in dotted lines. Only one strand of the oligonucleotide is shown for clarity

Amides↗
PubMed2006

An experimental and theoretical study of the enantioselective deprotonation of cyclohexene oxide with isopinocampheyl-based chiral lithium amides.

The mechanism of the enantioselective deprotonation of cyclohexene oxide with isopinocampheyl-based chiral lithium amide was studied by quantum chemical calculations. The transition states of eight molecules were fully optimized at the ab initio HF/3-21G and density functional B3LYP/3-21G levels with Gaussian 98. The activation energies were calculated at the B3LYP/6-31+G(3df,2p)//B3LYP/3-21G level. We found the theoretical evaluation to be consistent with the experimental data. At the best case, an enantiomeric excess of up to 95% for (R)-2-scyclohexen-1-ol was achieved with (-)-N, N-diisopinocampheyl lithium amide.

Amides↗
PubMed1986

Participation of liver aldehyde oxidase in reductive metabolism of hydroxamic acids to amides.

The liver enzyme responsible for the reduction of aromatic and heterocyclic hydroxamic acids to the corresponding amides was investigated with salicylhydroxamic acid, benzohydroxamic acid, anthranilhydroxamic acid, and nicotinohydroxamic acid. Rabbit liver cytosol exhibited significant reductase activities toward the hydroxamic acids under anaerobic conditions when supplemented with an electron donor of aldehyde oxidase. Similarly, rabbit liver aldehyde oxidase reduced these compounds to amides in the presence of its own electron donor, indicating that the reductase activities observed in the liver cytosol are due mainly to the cytosolic molybdoflavin enzyme. Furthermore, a significant reduction of salicylhydroxamic acid and nicotinohydroxamic acid was also observed, when an electron donor of aldehyde oxidase was added, with liver cytosols from hamsters, guinea pigs, rats, and mice. The cytosolic reductase activities toward salicylhydroxamic acid were markedly inhibited by menadione, an inhibitor of aldehyde oxidase.

Aldehyde Oxidase↗
PubMed1979

Individual assignments of amide proton resonances in the proton NMR spectrum of the basic pancreatic trypsin inhibitor.

Studies of proton-proton nuclear Overhauser effects were used to obtain individual assignments of 17 amide proton resonances in the 360 MHz proton nuclear magnetic resonance spectrum of the basic pancreatic trypsin inhibitor. First, optimizing the conditions for obtaining selective nuclear Overhauser effects in the presence of spin diffusion in macromolecules is discussed. Truncated driven nuclear Overhauser experiments were used to assing the amide proton resonances of the beta-sheet in the inhibitor. It is suggested that these techniques could serve quite generally to obtain individual resonance assignments in beta-sheet secondary structures of proteins. Combination of nuclear Overhauser studies with spin decoupling further resulted in individual assignments of the gamma-methyl resonances of the two isoleucines and numerous Calpha and Cbeta protons.

Amides↗
PubMed1983

4-methyleneglutamine synthetase: a new amide synthetase present in germinating peanuts.

Enzymatic activity which catalyzes the synthesis of 4-methyleneglutamine from 4-methyleneglutamic acid + ammonia was detected in and partially purified from cotyledons of peanut seeds germinated 5 to 7 days. This activity was separated from glutamine and asparagine synthetases by ammonium sulfate precipitation and DEAE-cellulose chromatography. The enzyme is distinct from these other amide synthetases in its substrate specificity, lack of amide/hydroxylamine exchange, and use of ammonium ion as amide donor together with formation of AMP from ATP. The activity is quite labile in solution, but is retained as a precipitate in ammonium sulfate or when frozen in 12.5% glycerol at -77 degrees C. This activity might be responsible for catalyzing the rapid synthesis of 4-methyleneglutamine which occurs in germinating peanuts.

Adenosine Triphosphate↗
PubMed1987

Proton nuclear magnetic resonance measurement of the amide hydrogen exchange rates of group A streptococcal polysaccharide in H2O.

The solvent exchange rates of the acetamido hydrogen of the 2-acetamido-2-deoxy-beta-D-glucopyranosyl unit of group A streptococcal polysaccharide dissolved in H2O have been measured and compared with the corresponding exchange rates in the solvated model compound 1-O-methyl-2-acetamido-2-deoxy-beta-D-glucopyranoside. Amide hydrogen exchange rates were measured at 25 degrees C over a wide pH range by a combination of two separate NMR techniques: the transfer of solvent saturation and the amide hydrogen saturation recovery NMR experiments. The data indicate that the acetamido hydrogen essentially exists in a solvated environment and that its contribution to the conformational stability of this polysaccharide through intramolecular hydrogen bonding is negligible.

Amides↗