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Novel Practical Synthesis of D-Cycloserine Tetrahedron Letters

Novel practical synthesis of d-cycloserine; Pages ..

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Doripenem is an ultra-broad-spectrum injectable antibiotic

The DcsG protein catalyzes the synthesis of -CS from -OUS, and the reaction includes covalent bond formation and hydrolysis of the urea moiety. At present, it is uncertain whether the urea moiety is hydrolyzed before or after the formation of the covalent N-C bond. However, since nucleophilic attack on the carbonyl carbon by the N-δ atom of -OUS is not favored, the urea moiety of -OUS may be hydrolyzed before the formation of the covalent N-C bond. Although DcsG also catalyzes the synthesis of -CS from β-aminooxy--alanine, the kcat/Km value for this compound was 1 order of magnitude lower than that with -OUS (). The carbamoyl group attached in -OUS may be an important factor for DcsG to catalyze the reaction effectively. Specifically, the Km for β-aminooxy--alanine was estimated to be much higher than that for -OUS, suggesting that the affinity of DcsG toward β-aminooxy--alanine is lower than that toward -OUS. The side chain of β-aminooxy--alanine is expected to exhibit a positive charge under physiological pH conditions, whereas the side chain of -OUS is uncharged. The low Km for -OUS indicates that DcsG would preferentially bind to the -amino acid having a neutral charge at the side chain. In addition, it indicates that the carbamoyl group may form hydrophilic interactions with the atoms in DcsG.

It is a beta-lactam and belongs to the subgroup of carbapenems

Our research group is interested in investigating the processing-structure-property relationships for various soft materials both of biological and synthetic origin towards different applications ranging from biomedical to energy storage to water purification to structural composites. The emphasis is identifying and synthesizing suitable materials systems, developing novel synthesis/processing/fabrication strategies for these materials, characterizing these materials using a combination of established and new experimental tools, and studying the engineering aspects needed to facilitate the transition from scientific discovery to practical implementation. The systems of present interest are polysaccharide networks, self-assembled gels, shear-thickening fluids, pulmonary mucus, thin-film nanocomposites, biofilms.

10.1056/NEJMoa0907635 - New England Journal of Medicine

21/01/2010 · Original Article

We have recently cloned a DNA fragment containing a gene cluster that is responsible for the biosynthesis of an antituberculosis antibiotic, -cycloserine. The gene cluster is composed of 10 open reading frames, designated dcsA to dcsJ. Judging from the sequence similarity between each putative gene product and known proteins, DcsC, which displays high homology to diaminopimelate epimerase, may catalyze the racemization of O-ureidoserine. DcsD is similar to O-acetylserine sulfhydrylase, which generates -cysteine using O-acetyl--serine with sulfide, and therefore, DcsD may be a synthase to generate O-ureido--serine using O-acetyl--serine and hydroxyurea. DcsG, which exhibits similarity to a family of enzymes with an ATP-grasp fold, may be an ATP-dependent synthetase converting O-ureido--serine into -cycloserine. In the present study, to characterize the enzymatic functions of DcsC, DcsD, and DcsG, each protein was overexpressed in Escherichia coli and purified to near homogeneity. The biochemical function of each of the reactions catalyzed by these three proteins was verified by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and, in some cases, mass spectrometry. The results from this study demonstrate that by using a mixture of the three purified enzymes and the two commercially available substrates O-acetyl--serine and hydroxyurea, synthesis of -cycloserine was successfully attained. These in vitro studies yield the conclusion that DcsD and DcsG are necessary for the syntheses of O-ureido--serine and -cycloserine, respectively. DcsD was also able to catalyze the synthesis of -cysteine when sulfide was added instead of hydroxyurea. Furthermore, the present study shows that DcsG can also form other cyclic -amino acid analogs, such as -homocysteine thiolactone.

The antituberculosis antibiotic -cycloserine (-CS) is produced by several Streptomyces species (). -CS, which is a cyclic analog of -alanine, prevents the catalytic activities of both alanine racemase (, ) and -alanyl–-alanine ligase (, ), which are necessary for the biosynthesis of the bacterial cell wall; that is, the antibiotic functions as an inhibitor of bacterial cell wall biosynthesis. -CS is clinically used as a second line of defense against Mycobacterium tuberculosis, especially when the bacterium is resistant to other antituberculosis antibiotics (, ). Furthermore, since -CS was recently shown to be a partial agonist for the N-methyl--aspartate receptor, the drug may be useful for the treatment of various psychological dysfunctions (–).

Israel Lowy, M.D., Ph.D., Deborah C

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The DcsG protein catalyzes the synthesis of -CS from -OUS, and the reaction includes covalent bond formation and hydrolysis of the urea moiety. At present, it is uncertain whether the urea moiety is hydrolyzed before or after the formation of the covalent N-C bond. However, since nucleophilic attack on the carbonyl carbon by the N-δ atom of -OUS is not favored, the urea moiety of -OUS may be hydrolyzed before the formation of the covalent N-C bond. Although DcsG also catalyzes the synthesis of -CS from β-aminooxy--alanine, the kcat/Km value for this compound was 1 order of magnitude lower than that with -OUS (). The carbamoyl group attached in -OUS may be an important factor for DcsG to catalyze the reaction effectively. Specifically, the Km for β-aminooxy--alanine was estimated to be much higher than that for -OUS, suggesting that the affinity of DcsG toward β-aminooxy--alanine is lower than that toward -OUS. The side chain of β-aminooxy--alanine is expected to exhibit a positive charge under physiological pH conditions, whereas the side chain of -OUS is uncharged. The low Km for -OUS indicates that DcsG would preferentially bind to the -amino acid having a neutral charge at the side chain. In addition, it indicates that the carbamoyl group may form hydrophilic interactions with the atoms in DcsG.

Our present study shows that DcsD uses -OAS, but not -serine, as the first substrate. Furthermore, we found that DcsD catalyzes the synthesis of various β-substituted -alanine derivatives, including -OUS. The kcat/Km value of DcsD for -cysteine synthesis is the highest, 80-fold higher than that for -OUS synthesis (). The DcsD protein exhibits lower activities for the synthesis of S-sulfo--cysteine and cystathionine than for -OUS synthesis. These results are in agreement with the fact that the amino acid sequence of DcsD is more homologous to that of O-acetylserine sulfhydrylase A than to those of O-acetylserine sulfhydrylase B and cystathionine β-synthase. In fact, when a sequence homology search for DcsD was done against structurally defined proteins, in order of similarity, O-acetylserine sulfhydrylase A, O-acetylserine sulfhydrylase B, and cystathionine β-synthase were retrieved. For example, the amino acid sequence of DcsD has 48% identity with that of Mycobacterium tuberculosis O-acetylserine sulfhydrylase A, 43% identity with that of E. coliO-acetylserine sulfhydrylase B, and 38% identity with that of the catalytic domain of human cystathionine β-synthase.

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In the present study, we were able to determine the enzymatic functions of the DcsC, DcsD, and DcsG proteins, which are responsible for -CS biosynthesis. Another research group recently showed that DcsC is a cofactor-independent racemase utilizing OUS as the substrate (). Based on the experimental evidence presented in this study, we conclude that DscD and DscG are an O-ureido--serine synthase and a -cycloserine synthethase, respectively. Since the DcsG protein needs ATP as an energy source, it may be right to call it a synthetase.

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Our present study shows that DcsD uses -OAS, but not -serine, as the first substrate. Furthermore, we found that DcsD catalyzes the synthesis of various β-substituted -alanine derivatives, including -OUS. The kcat/Km value of DcsD for -cysteine synthesis is the highest, 80-fold higher than that for -OUS synthesis (). The DcsD protein exhibits lower activities for the synthesis of S-sulfo--cysteine and cystathionine than for -OUS synthesis. These results are in agreement with the fact that the amino acid sequence of DcsD is more homologous to that of O-acetylserine sulfhydrylase A than to those of O-acetylserine sulfhydrylase B and cystathionine β-synthase. In fact, when a sequence homology search for DcsD was done against structurally defined proteins, in order of similarity, O-acetylserine sulfhydrylase A, O-acetylserine sulfhydrylase B, and cystathionine β-synthase were retrieved. For example, the amino acid sequence of DcsD has 48% identity with that of Mycobacterium tuberculosis O-acetylserine sulfhydrylase A, 43% identity with that of E. coliO-acetylserine sulfhydrylase B, and 38% identity with that of the catalytic domain of human cystathionine β-synthase.

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The antituberculosis antibiotic -cycloserine (-CS) is produced by several Streptomyces species (). -CS, which is a cyclic analog of -alanine, prevents the catalytic activities of both alanine racemase (, ) and -alanyl–-alanine ligase (, ), which are necessary for the biosynthesis of the bacterial cell wall; that is, the antibiotic functions as an inhibitor of bacterial cell wall biosynthesis. -CS is clinically used as a second line of defense against Mycobacterium tuberculosis, especially when the bacterium is resistant to other antituberculosis antibiotics (, ). Furthermore, since -CS was recently shown to be a partial agonist for the N-methyl--aspartate receptor, the drug may be useful for the treatment of various psychological dysfunctions (–).

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