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PubMed1999

Use of lipase for regioselective one pot amidation and hydrolysis.

A study of the reactivity of esters with oxygenated linkers in lipase catalyzed transformations demonstrates that enhanced reactivity is observed in amidation reactions, but diminished reactivity is observed in hydrolyses using the same lipase. Two regioselective transformations (amidation and hydrolysis) can thus be achieved with diesters in the same pot using a single catalyst, effectively demonstrating lipase's versatility.

Amides↗
PubMed1999

Trifluoromethyl ketone inhibitors of fatty acid amide hydrolase: a probe of structural and conformational features contributing to inhibition.

The examination of a series of trifluoromethyl ketone inhibitors of Fatty Acid Amide Hydrolase (FAAH, oleamide hydrolase, anandamide amidohydrolase) is detailed in efforts that define structural and conformational properties that contribute to enzyme inhibition and substrate binding. The results imply an extended bound conformation, highlight a role for the presence, position, and stereochemistry of a delta cis double bond, and suggest little apparent role for C11-C18/C22 of the fatty acid amide substrates.

Amidohydrolases↗
PubMed1999

Synthesis of a transition state analogue for the hydrolysis of cocaine: assistance to phosphonylation of a 3beta-hydroxytropane by a neighbouring amide group.

A simple synthesis of phenylphosphonate monoester analogues of the transition state for hydrolysis of the benzoyl ester group in cocaine is provided by the reaction of 2beta-amido-3beta-tropanols with phenylphosphonyl dichloride. Steric hindrance to phosphonylation of the hydroxyl is overcome because the neighbouring 2beta-amido group participates in the reaction. The intramolecular assistance by the amide to formation of the phosphonate ester is influenced by the electronic environment of the amide group.

Amides↗
PubMed2000

Photosensitizers related to purpurin-18-N-alkylimides: a comparative in vivo tumoricidal ability of ester versus amide functionalities.

For a comparative study, 3-(alkyloxyethyl)-3-devinylpurpurin-18-N-hexylimides with ester and amide functionalities were investigated for tumor selectivity and in vivo photosensitizing efficacy. Compared to amide analogues, the related photosensitizers with ester functionalities were found to be more effective. Among these compounds the 3-devinyl-(3-hexyloxyethyl)-purpurin-18-N-hexylimide as methyl ester 12 showed excellent tumor uptake (tumor versus muscle ratio: 8:1), and produced 100% tumor cure on day 30 at a dose of 1.0 micromol/kg. The mice were treated with light (135 J/cm2, 705 nm) at 24 h post injection of the drug.

Amides↗
PubMed2002

Phenolic modification as an approach to improve the pharmacology of the 3-acyloxy-2-benzylpropyl homovanillic amides and thioureas, a promising class of vanilloid receptor agonists and analgesics.

In order to improve the analgesic activity and pharmacokinetics of thioureas 2 and 3, which we previously developed as potent vanilloid receptor (VR) agonists, we prepared and characterized phenolic modifications of them and of their amide surrogates (7, 8). The aminoethyl analogue of the amide template 13 was a potent analgesic with an EC50=0.96 microg/kg in the AA-induced writhing test and with better in vivo stability than the parent phenol.

Amides↗
PubMed2003

Synthesis of amide compounds of ferulic acid, and their stimulatory effects on insulin secretion in vitro.

We prepared amide compounds which were derived from ferulic acid using various amines, and investigated their stimulatory effects on insulin secretion using rat pancreatic RIN-5F cells. Most of these compounds exhibited significant promotion of the insulin-release at a concentration of 10 microM and in particular, the amides having n-butyl, n-pentyl, pyrrolidine, and piperidine groups showed high activity.

Amides↗
PubMed1999

Non-conventional hydrolase chemistry: amide and carbamate bond formation catalyzed by lipases.

Biocatalysis in nonaqueous media is becoming increasingly important in organic synthesis. Lipases are the most used enzymes, especially in transesterification reactions. However, in the last years the amidation reaction catalyzed by lipases has also been shown to be a useful tool for the organic chemists. In this review, we discuss the possibilities of the enzymatic aminolysis and ammonolysis reactions for the preparation of different amides and for the resolution of esters, amines and aminoalcohols. The enzymatic alkoxycarbonylation of amines opens a new way for the synthesis of chiral carbamates.

Alcohols↗
PubMed2002

Tandem mass spectrum of a growth hormone secretagogue: amide bond cleavage and resultant gas-phase rearrangement.

Compound 1 [N-[1(R)-[(1,2-dihydro-1-methylsulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide](MW 528) is an orally-active growth hormone secretagogue (GHS). As part of a continual effort to analyze the ESI/MS and MSn data of novel drugs, the ESI/MS and MS/MS data of protonated 1 (m/z 529) are analyzed and reported here. The analyses reveal that under low-energy collision-induced dissociation (CID) in an ion trap or a quadrupole collision cell, protonated 1 undergoes a gas-phase rearrangement to form protonated 3 (m/z 357) which competes with the y- and b-type product ions during the amide bond cleavages of protonated 1. It is proposed that when the b-type ion is formed by cleavage of the piperidine amide bond, piperidine (a neutral species) and the b-ion (a cation) form an ion-neutral complex. In this complex, piperidine functions as a nucleophile to attack the benzylic carbon of the b-ion, and the protonated ether group in the b-ion acts as a leaving group, which results in the migration of the benzylic group to the piperidine amine to form protonated 3. Protonated 2 (an analog of 1) was studied under the same experimental conditions. The results show that protonated 2 undergoes a similar rearrangement to form protonated 3. While this rearrangement is a relatively minor fragmentation process for protonated 1, it is a predominant process for protonated 2. This phenomenon is explained in terms of the proposed ion-neutral-complex mechanism.

Amides↗
PubMed1998

Amide protection in an early folding intermediate of cytochrome c.

BACKGROUND: For many proteins, compact states appear long before the rate-limiting step in the formation of the native structure. A key issue is whether the initial collapse of the chain is driven by random or more specific hydrophobic interactions. RESULTS: Hydrogen-exchange labeling coupled with NMR was used to monitor the formation of stable hydrogen-bonded and solvent-excluded structure in horse cytochrome c (cyt c). Protection was measured using a hydrogen exchange/folding competition protocol at variable pH and short competition time (2 ms). Protection factors of threefold to eightfold were observed in all three alpha helices of cyt c, whereas other regions showed no significant protection. This suggests that the compact states that are present contain segments of marginally stable hydrogen-bonded structure. When the intermediate(s) are destabilized, only amide protons from Cys14, Ala15 and His18 show significant protection, indicating a region of persistent residual structure near the covalently bound heme group in the unfolded protein. Fluorescence-detected stopped-flow studies showed that the maximum protection factor in the early intermediate is consistent with its unfolding equilibrium constant. CONCLUSIONS: Together with previous fluorescence and CD results, the observed pattern of amide protection is consistent with the early formation of an alpha-helical core domain in an ensemble of compact states, indicating that efficient folding is facilitated by stepwise acquisition of native structural elements. These specific early interactions are established on the sub-millisecond time scale, prior to the rate-limiting step for folding.

Amides↗
PubMed2003

Vibrational characterization of the tertiary amide and thioamide group.

Force field calculations and vibrational spectra of (CH(3))(2)NCOCON(CH(3))(2) (TMO), (CH(3))(2)NCOCSN(CH(3))(2) (TMMTO) and (CH(3))(2)NCSCSN(CH(3))(2) (TMDTO) are discussed. The amide and thioamide fundamentals and those of other simple tertiary amides are compared. A characteristic pattern in infrared and Raman is proposed.

Amides↗
PubMed1995

Peptide models of helical hydrophobic transmembrane segments of membrane proteins. 2. Differential scanning calorimetric and FTIR spectroscopic studies of the interaction of Ac-K2-(LA)12-K2-amide with phosphatidylcholine bilayers.

The interactions of the hydrophobic helical transmembrane peptide Ac-K2-(LA)12-K2-amide [(LA)12] with a series of n-saturated diacylphosphatidylcholines (N:0 PC) were studied by high-sensitivity differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy. The incorporation of (LA)12 into these lipid bilayers results in a broadening of the chain-melting phase transitions of the lipids and progressive decreases in the characteristic temperatures and enthalpies of their gel/liquid-crystalline phase transitions. At low peptide/lipid ratios, the DSC thermograms exhibited by mixtures of (LA)12 with the short chain PCs (13:0 and 14:0) and with very long chain PCs (21:0 and 22:0) appear to be a summation of sharp and broad components, the former diminishing in intensity with increases in peptide concentration. This behavior can be approximated by that of a macroscopic mixture of peptide-poor and peptide-rich lipid domains, the relative proportions of which change with changes in peptide concentration. For peptide mixtures with the medium-chain PCs, the hydrocarbon chain-melting phase transition endotherms are not clearly resolvable into similar sharp and broad components. Instead, at all finite peptide concentrations the DSC heating thermograms appear as broad and highly asymmetric endotherms, the transition temperatures of which decrease significantly with increases in peptide concentration. For mixtures of (LA)12 with each of the lipids studied, the total hydrocarbon chain-melting transition enthalpy decreases with increasing peptide concentration but does not vanish at high peptide/lipid ratios. The FTIR spectra of (LA)12 in these PC bilayers indicate that the peptide retains a predominantly alpha-helical conformation in both the gel and liquid-crystalline phases of the short to medium chain PCs studied (N < 18). However, when incorporated into bilayers composed of the longer chain PCs (N > or = 18), (LA)12 undergoes a reversible conformational change at the gel/liquid-crystalline phase transition of the mixture. In the liquid-crystalline phase, the amide I regions of the FTIR spectra of these mixtures are indicative of a predominantly alpha-helical peptide conformation. However, upon freezing of the lipid hydrocarbon chains, populations and/or domains of (LA)12 giving rise to a sharp conformationally unassigned band near 1665 cm-1 are formed.(ABSTRACT TRUNCATED AT 400 WORDS)

Alanine↗
PubMed1992

Use of liquid hydrocarbon and amide transfer data to estimate contributions to thermodynamic functions of protein folding from the removal of nonpolar and polar surface from water.

This extension of the liquid hydrocarbon model seeks to quantify the thermodynamic contributions to protein stability from the removal of nonpolar and polar surface from water. Thermodynamic data for the transfer of hydrocarbons and organic amides from water to the pure liquid phase are analyzed to obtain contributions to the thermodynamics of folding from the reduction in water-accessible surface area. Although the removal of nonpolar surface makes the dominant contribution to the standard heat capacity change of folding (delta C0fold), here we show that inclusion of the contribution from removal of polar surface allows a quantitative prediction of delta C0fold within the uncertainty of the calorimetrically determined value. Moreover, analysis of the contribution of polar surface area to the enthalpy of transfer of liquid amides provides a means of estimating the contributions from changes in nonpolar and polar surface area as well as other factors to the enthalpy of folding (delta H0fold). In addition to estimates of delta H0fold, this extension of the liquid hydrocarbon model provides a thermodynamic explanation for the observation [Privalov, P. L., & Khechinashvili, N. N. (1974) J. Mol. Biol. 86, 665-684] that the specific enthalpy of folding (cal g-1) of a number of globular proteins converges to a common value at approximately 383 K. Because amounts of nonpolar and polar surface area buried by these proteins upon folding are found to be linear functions of molar mass, estimates of both delta C0fold and delta H0fold may be obtained given only the molar mass of the protein of interest.(ABSTRACT TRUNCATED AT 250 WORDS)

Amides↗
PubMed2000

Vibriobactin biosynthesis in Vibrio cholerae: VibH is an amide synthase homologous to nonribosomal peptide synthetase condensation domains.

The Vibrio cholerae siderophore vibriobactin is biosynthesized from three molecules of 2,3-dihydroxybenzoate (DHB), two molecules of L-threonine, and one of norspermidine. Of the four genes positively implicated in vibriobactin biosynthesis, we have here expressed, purified, and assayed the products of three: vibE, vibB, and vibH. All three are homologous to nonribosomal peptide synthetase (NRPS) domains: VibE is a 2,3-dihydroxybenzoate-adenosyl monophosphate ligase, VibB is a bifunctional isochorismate lyase-aryl carrier protein (ArCP), and VibH is a novel amide synthase that represents a free-standing condensation (C) domain. VibE and VibB are homologous to EntE and EntB from Escherichia coli enterobactin synthetase; VibE activates DHB as the acyl adenylate and then transfers it to the free thiol of the phosphopantetheine arm of VibB's ArCP domain. VibH then condenses this DHB thioester (the donor) with the small molecule norspermidine (the acceptor), forming N(1)-(2, 3-dihydroxybenzoyl)norspermidine (DHB-NSPD) with a k(cat) of 600 min(-1) and a K(m) for acyl-VibB of 0.88 microM and for norspermidine of 1.5 mM. Exclusive monoacylation of a primary amine of norspermidine was observed. VibH also tolerates DHB-acylated EntB and 1,7-diaminoheptane, octylamine, and hexylamine as substrates, albeit at lowered catalytic efficiencies. DHB-NSPD possesses one of three acylations required for mature vibriobactin, and its formation confirms VibH's role in vibriobactin biosynthesis. VibH is a unique NRPS condensation domain that acts upon an upstream carrier-protein-bound donor and a downstream amine, turning over a soluble amide product, in contrast to an archetypal NRPS-embedded C domain that condenses two carrier protein thioesters.

Amide Synthases↗
PubMed1994

Hydrogen bonding in proteins as studied by amide hydrogen D/H fractionation factors: application to staphylococcal nuclease.

The D/H fractionation factor (sigma) is the extent to which a hydrogen at a particular site becomes enriched in 2H over 1H relative to the solvent. A growing body of experimental evidence suggest that there is a correlation between the value of the fractionation factor and hydrogen-bond strength, with a lower sigma value reflecting a stronger hydrogen bond. Fractionation factors of 60% of the individual backbone amide hydrogens in the staphylococcal nuclease V8 variant (H124L) have been measured for the enzyme in the presence and absence of bound ligands (the activating ion Ca2+ and the inhibitor thymidine 3',5'-bisphosphate). The method used employed two-dimensional 1H-15N nuclear magnetic resonance analysis of uniformly 15N-labeled protein in mixed H2O/D2O solvents. Fractionation factors of individual residues were found to range from 0.3 (T120) to 1.5 (L38). The sigma value of 0.3 for the NH of T120, which is the lowest fractionation factor reported for any system yet studied, suggests that the hydrogen bond between T120 HN and D77 O delta 1 is unusually strong. The results of previous site-directed mutagenesis experiments [Hinck, A. P. (1993) Ph.D. Thesis, University of Wisconsin-Madison, Madison, WI] support the notion that formation of this hydrogen bond is important to maintain the stability and conformation of the native state. The sigma value averaged over all residues was approximately 0.85 for both the unligated and ligated enzymes. Residues in alpha-helices displayed a slightly lower average sigma value (0.79), whereas residues with solvent-exposed amide hydrogens exhibited a slightly higher average figure (0.98).(ABSTRACT TRUNCATED AT 250 WORDS)

Amides↗
PubMed2001

Characterization and manipulation of the acyl chain selectivity of fatty acid amide hydrolase.

Fatty acid amide hydrolase (FAAH) is a mammalian integral membrane enzyme that catabolizes several neuromodulatory fatty acid amides, including the endogenous cannabinoid anandamide and the sleep-inducing lipid oleamide. FAAH belongs to a large group of hydrolytic enzymes termed the amidase signature (AS) family that is defined by a conserved, linear AS sequence of approximately 130 amino acids. Members of the AS family display strikingly different substrate selectivities, yet the primary structural regions responsible for defining substrate recognition in these enzymes remain unknown. In this study, a series of unbranched p-nitroanilide (pNA) substrates ranging from 6 to 20 carbons in length was used to probe the acyl chain binding specificity of FAAH, revealing that this enzyme exhibits a strong preference for acyl chains 9 carbons in length or longer. A fluorophosphonate inhibitor of FAAH containing a photoactivatable benzophenone group was synthesized and used to locate a region of the enzyme implicated in substrate binding. Protease digestion and mass spectrometry analysis of FAAH-inhibitor conjugates identified the major site of cross-linking as residues 487-493. Site-directed mutagenesis revealed that a single residue in this region, I491, strongly influenced substrate specificity of FAAH. For example, an I491A mutant displayed a greatly reduced binding affinity for medium-chain pNA substrates (7-12 carbons) but maintained nearly wild-type binding and catalytic constants for longer chain substrates (14-20 carbons). Mutation of I491 to aromatic or more polar residues generated enzymes with relative hydrolytic efficiencies for medium- versus long-chain pNAs that varied up to 90-fold. Collectively, these studies indicate that I491 participates in hydrophobic binding interactions with medium-chain FAAH substrates. Additionally, the significant changes in substrate selectivity achieved by single amino acid changes suggest that FAAH possesses a rather malleable substrate binding domain and may serve, along with other AS enzymes, as a template for the engineering of amidases with novel and/or tailored specificities.

Alanine↗
PubMed1985

Alkylation of amide linkages and cleavage of the C chain in the enzyme-activated-substrate inhibition of alpha-chymotrypsin with N-nitrosamides.

Active-site-directed N-nitrosamides inhibit alpha-chymotrypsin through an enzyme-activated-substrate mechanism. In this work, the activation results in the release--in the active site--of benzyl carbonium ions, which alkylate and inhibit the enzyme. The final ratio of benzyl groups to enzyme molecules is 1.0, but the alkyl groups are scattered over a number of sites. Reduction and alkylation of the inhibited enzyme generate peptides insoluble in most media. Guanidine hydrochloride at 6 M proved a good solvent, and its use as an eluant on G-75 Sephadex permitted separation of the peptides. In the case of 14C-labeled enzyme, such an approach has shown that all of the alkylation occurs on the C chain of the enzyme, the chain of which the active site is constructed. Chemical modification of the peptides with ethylenediamine and N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide rendered them soluble in dilute acid, permitting high-performance liquid chromatographic separation. Model studies have shown that the benzyl carbonium ions are highly reactive, alkylating amide linkages at both oxygen and nitrogen. Alkylation at oxygen produces imidate esters, which are labile centers. Hydrolysis of protein imidates results in a cleavage of the chain at that point, and separation of the peptides formed (followed by analysis) permits their identification. In our inhibition of alpha-chymotrypsin, a major site of O-alkylation has been identified as the carbonyl oxygen of Ser-214. Alkylation at the nitrogen atom of amide linkages generates stable labels; full hydrolysis with 6 N HC1 then leads to N-benzyl amino acids characteristic of those sites. Chromatography of this mixture and also 13C NMR spectroscopy of the intact inhibited enzyme have shown that three major N-alkylations have occurred. Tryptic digestion of the C chain of chymotrypsin, which contains all of the alkylation sites, provides evidence that the stable N sites are principally located between residue 216 and residue 230. These locations are consistent with predictions of alkylation sites based on inspection of a molecular model of chymotrypsin, with special reference to the aromatic binding pocket.

Alkylation↗
PubMed1986

Effects of denaturants on amide proton exchange rates: a test for structure in protein fragments and folding intermediates.

A method for detecting structure in marginally stable forms of a protein is described. The principle is to measure amide proton exchange rates in the absence and presence of varying concentrations of a denaturant. Unfolding of structure by the denaturant is reflected by an acceleration of amide proton exchange rates, after correction for the effects of the denaturant on the intrinsic rate of exchange. This exchange-rate test for structure makes no assumptions about the rate of exchange in the unfolded state. The effects of 0-8 M urea and 0-6 M guanidinium chloride (GdmCl) on acid- and base-catalyzed exchange from model compounds have been calibrated. GdmCl does not appear to be well-suited for use in the exchange-rate test; model compound studies show that the effects of GdmCl on intrinsic exchange rates are complicated. In contrast, the effects of urea are a more uniform function of denaturant concentration. Urea increases acid-catalyzed, and decreases base-catalyzed, rates in model compounds. The exchange-rate test is used here to study structure formation in the S-protein (residues 21-124 of ribonuclease A). In conditions where an equilibrium folding intermediate of S-protein (I3) is known to be populated (pH 1.7, 0 degree C), the exchange-rate test for structure is positive. At higher temperatures (greater than 32 degrees C) I3 is unfolded, but circular dichroism data suggest that residual structure remains [Labhardt, A. M. (1982) J. Mol. Biol. 157, 357-371].(ABSTRACT TRUNCATED AT 250 WORDS)

Amides↗