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  1 / 1222 MEDLINE  
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[PMID]:28744579
[Au] Autor:Uda K; Abe K; Dehara Y; Mizobata K; Edashige Y; Nishimura R; Radkov AD; Moe LA
[Ad] Endereço:Laboratory of Biochemistry, Faculty of Science and Technology, Kochi University, Kochi, 780-8520, Japan. k-uda@kochi-u.ac.jp.
[Ti] Título:Triple serine loop region regulates the aspartate racemase activity of the serine/aspartate racemase family.
[So] Source:Amino Acids;49(10):1743-1754, 2017 10.
[Is] ISSN:1438-2199
[Cp] País de publicação:Austria
[La] Idioma:eng
[Ab] Resumo:Recently, we cloned and characterized eleven serine and aspartate racemases (SerR and AspR, respectively) from animals. These SerRs and AspRs are not separated by their racemase functions and form a serine/aspartate racemase family cluster based on phylogenetic analysis. Moreover, we have proposed that the AspR-specific triple serine loop region at amino acid positions 150-152 may be responsible for the large AspR activity. In the present study, to test this hypothesis, we prepared and characterized fourteen mutants in this region of animal SerRs and AspRs. The large AspR activity in Acropora and Crassostrea AspR was reduced to <0.04% of wild-type after substitution of the triple serine loop region. Conversely, introducing the triple serine loop region into Acropora, Crassostrea, and Penaeus SerR drastically increased the AspR activity. Those mutants showed similar or higher substrate affinity for aspartate than serine and showed 11-683-fold higher k and 28-351-fold higher k /K values for aspartate than serine racemization. Furthermore, we introduced serine residues in all combinations at position 150-152 in mouse SerR. These mutants revealed that a change in the enzyme function from SerR to AspR can be caused by introduction of Ser151 and Ser152, and addition of the third serine residue at position 150 further enhances the enzyme specificity for aspartate due to a decrease in the serine racemase and serine dehydratase activity. Here, we provide convincing evidence that the AspR gene has evolved from the SerR gene by acquisition of the triple serine loop region.
[Mh] Termos MeSH primário: Isomerases de Aminoácido
Antozoários
Proteínas de Artrópodes
Crassostrea
Mutação de Sentido Incorreto
Penaeidae
Racemases e Epimerases
[Mh] Termos MeSH secundário: Isomerases de Aminoácido/química
Isomerases de Aminoácido/genética
Substituição de Aminoácidos
Animais
Antozoários/enzimologia
Antozoários/genética
Proteínas de Artrópodes/química
Proteínas de Artrópodes/genética
Crassostrea/enzimologia
Crassostrea/genética
Camundongos
Penaeidae/enzimologia
Penaeidae/genética
Estrutura Secundária de Proteína
Racemases e Epimerases/química
Racemases e Epimerases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Arthropod Proteins); EC 5.1.- (Racemases and Epimerases); EC 5.1.1.- (Amino Acid Isomerases); EC 5.1.1.13 (aspartate racemase); EC 5.1.1.16 (serine racemase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1007/s00726-017-2472-8


  2 / 1222 MEDLINE  
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[PMID]:29310027
[Au] Autor:Malapati P; Krishna VS; Nallangi R; Srilakshmi RR; Sriram D
[Ad] Endereço:Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawaharnagar, RangaReddy District, Hyderabad 500 078, India.
[Ti] Título:Identification and development of benzoxazole derivatives as novel bacterial glutamate racemase inhibitors.
[So] Source:Eur J Med Chem;145:23-34, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:In the present study, we attempted to develop novel class of Mycobacterium tuberculosis (Mtb) inhibitors by exploring the pharmaceutically underexploited enzyme targets which are majorly involved in cell wall biosynthesis of mycobacteria. For this purpose glutamate racemase was selected which racemizes d-glutamate from l-glutamate, a key step in peptidoglycan synthesis. Furthermore, enzyme is neither expressed nor its product, d-glutamate is produced in mammals, and hence inhibiting this enzyme will have no vulnerable effect in host organism. A library of our in-house compounds were screened against glutamate racemase using a biophysical technique; thermal shift assay and further by enzyme inhibition assay to identify Lead 1 molecule. Lead 1 optimization and expansion resulted in twenty four compounds. Among the synthesized compounds twelve compounds shown good enzyme inhibition than Lead 1 (IC 20.07 ±â€¯0.29 µM). Among all the compounds; compound 22 (IC 1.1 ±â€¯0.52 µM) showed potent non-competitive mode of inhibition in enzyme assay. Further showed good susceptibility (in replicating bacteria) of MIC 8.72 µM and bactericidal time dependant kill on dormant culture. It also exhibited significant activity in Mtb nutrient starvation model (2.5) and Mtb biofilm model (2.4) and in vivo M. marinum infected Zebra fish model studies (3.6) reduction at logarithmic scale.
[Mh] Termos MeSH primário: Isomerases de Aminoácido/antagonistas & inibidores
Antibacterianos/farmacologia
Benzoxazóis/farmacologia
Inibidores Enzimáticos/farmacologia
Mycobacterium/efeitos dos fármacos
[Mh] Termos MeSH secundário: Isomerases de Aminoácido/metabolismo
Animais
Antibacterianos/síntese química
Antibacterianos/química
Benzoxazóis/síntese química
Benzoxazóis/química
Biofilmes/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Cinética
Camundongos
Testes de Sensibilidade Microbiana
Simulação de Acoplamento Molecular
Estrutura Molecular
Mycobacterium/enzimologia
Células RAW 264.7
Relação Estrutura-Atividade
Peixe-Zebra
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Benzoxazoles); 0 (Enzyme Inhibitors); EC 5.1.1.- (Amino Acid Isomerases); EC 5.1.1.3 (glutamate racemase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180109
[St] Status:MEDLINE


  3 / 1222 MEDLINE  
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[PMID]:29199985
[Au] Autor:Mizobuchi T; Nonaka R; Yoshimura M; Abe K; Takahashi S; Kera Y; Goto M
[Ad] Endereço:Department of Biomolecular Science, Graduate School of Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
[Ti] Título:Crystal structure of a pyridoxal 5'-phosphate-dependent aspartate racemase derived from the bivalve mollusc Scapharca broughtonii.
[So] Source:Acta Crystallogr F Struct Biol Commun;73(Pt 12):651-656, 2017 Dec 01.
[Is] ISSN:2053-230X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aspartate racemase (AspR) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that is responsible for D-aspartate biosynthesis in vivo. To the best of our knowledge, this is the first study to report an X-ray crystal structure of a PLP-dependent AspR, which was resolved at 1.90 Šresolution. The AspR derived from the bivalve mollusc Scapharca broughtonii (SbAspR) is a type II PLP-dependent enzyme that is similar to serine racemase (SR) in that SbAspR catalyzes both racemization and dehydration. Structural comparison of SbAspR and SR shows a similar arrangement of the active-site residues and nucleotide-binding site, but a different orientation of the metal-binding site. Superposition of the structures of SbAspR and of rat SR bound to the inhibitor malonate reveals that Arg140 recognizes the ß-carboxyl group of the substrate aspartate in SbAspR. It is hypothesized that the aromatic proline interaction between the domains, which favours the closed form of SbAspR, influences the arrangement of Arg140 at the active site.
[Mh] Termos MeSH primário: Isomerases de Aminoácido/química
Scapharca/enzimologia
[Mh] Termos MeSH secundário: Isomerases de Aminoácido/genética
Isomerases de Aminoácido/metabolismo
Animais
Sítios de Ligação
Domínio Catalítico
Cristalografia por Raios X
Modelos Moleculares
Conformação Proteica
Fosfato de Piridoxal/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
5V5IOJ8338 (Pyridoxal Phosphate); EC 5.1.1.- (Amino Acid Isomerases); EC 5.1.1.13 (aspartate racemase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1107/S2053230X17015813


  4 / 1222 MEDLINE  
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[PMID]:29239770
[Au] Autor:Malapati P; Siva Krishna V; Nallangi R; Meda N; Reshma Srilakshmi R; Sriram D
[Ad] Endereço:Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, India.
[Ti] Título:Lead identification and optimization of bacterial glutamate racemase inhibitors.
[So] Source:Bioorg Med Chem;26(1):177-190, 2018 01 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mycobacterium tuberculosis glutamate racemase is an essential enzyme involved in peptidoglycan synthesis and conserved in most bacteria. Small molecule inhibitors were reported on other bacterial species whereas in M. tuberculosis it wasn't explored much. In this study we have screened in house compound library using fluorescence thermal shift assay and enzyme inhibition assay, form this (1-(3-(benzo[d]thiazol-2-yl)phenyl)-3-(p-tolyl)thiourea) was identified as lead compound with IC 19.47 ±â€¯0.81 µM. Further lead optimization by synthesis resulted in twenty-three compounds, of which Compound 25 has shown more efficacy compared to lead 1 showing non-competitive mode of inhibition with IC 1.32 ±â€¯0.43 µM. It also showed significant activity (represented in log reduction) in nutrient starved dormant M. tuberculosis model (2.1), M. tuberculosis biofilm assay (2.0) and in vivo M. marinum infected zebrafish model (3.5).
[Mh] Termos MeSH primário: Isomerases de Aminoácido/antagonistas & inibidores
Antituberculosos/farmacologia
Inibidores Enzimáticos/farmacologia
Mycobacterium tuberculosis/efeitos dos fármacos
[Mh] Termos MeSH secundário: Isomerases de Aminoácido/metabolismo
Animais
Antituberculosos/síntese química
Antituberculosos/química
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Camundongos
Testes de Sensibilidade Microbiana
Estrutura Molecular
Mycobacterium tuberculosis/enzimologia
Mycobacterium tuberculosis/crescimento & desenvolvimento
Células RAW 264.7
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Enzyme Inhibitors); EC 5.1.1.- (Amino Acid Isomerases); EC 5.1.1.3 (glutamate racemase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180106
[Lr] Data última revisão:
180106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171215
[St] Status:MEDLINE


  5 / 1222 MEDLINE  
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[PMID]:28344038
[Au] Autor:Awad R; Gans P; Reiser JB
[Ad] Endereço:Institut de Biologie Structurale (IBS), Univ. Grenoble Alpes, CEA, CNRS, 38044, Grenoble, France.
[Ti] Título:Structural insights into the substrate recognition and reaction specificity of the PLP-dependent fold-type I isoleucine 2-epimerase from Lactobacillus buchneri.
[So] Source:Biochimie;137:165-173, 2017 Jun.
[Is] ISSN:1638-6183
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The isoleucine 2-epimerase from Lactobacillus buchneri has been previously identified and characterized to catalyze the pyridoxal 5'-phosphate (PLP)-dependent racemization and epimerization of a broad spectrum of nonpolar amino acids from L- to D-form and vice versa, in particular isoleucine. In this study, crystal structures of both native and PLP-complex forms of this racemase are presented at 2.6 and 2.15 Å resolution, respectively. Both structures show that the protein belongs to the fold-type I subgroup of PLP-dependent enzymes and is very close to aminobutyrate aminotransferases family, as it has been suspected because of their sequence homology. The extensive structural comparison with fold-type I enzymes with known amino acid racemization activities, including the α-amino-ε-caprolactam racemase from Achromobacter obae and the cystathionine ß-lyase from Escherichia coli, allows us to identify the active site residues responsible for its nonpolar amino acid recognition and reactivity specificity. Our observations also suggest that the racemization reaction by the fold-type I racemases may generally occur thanks to a revised two-base mechanism. Lastly, both structures reveal details on the conformational changes provoked by PLP binding that suggest an induced fit of the active site "entrance door", necessary to accommodate PLP and substrate molecules.
[Mh] Termos MeSH primário: Isomerases de Aminoácido/química
Isomerases de Aminoácido/metabolismo
Isoleucina/metabolismo
Lactobacillus/enzimologia
Fosfato de Piridoxal/metabolismo
[Mh] Termos MeSH secundário: Isomerases de Aminoácido/genética
Sítios de Ligação
Catálise
Domínio Catalítico
Cristalografia por Raios X
Modelos Moleculares
Conformação Proteica
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
04Y7590D77 (Isoleucine); 5V5IOJ8338 (Pyridoxal Phosphate); EC 5.1.1.- (Amino Acid Isomerases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170328
[St] Status:MEDLINE


  6 / 1222 MEDLINE  
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[PMID]:27898711
[Au] Autor:Israyilova A; Buroni S; Forneris F; Scoffone VC; Shixaliyev NQ; Riccardi G; Chiarelli LR
[Ad] Endereço:Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Pavia, Italy.
[Ti] Título:Biochemical Characterization of Glutamate Racemase-A New Candidate Drug Target against Burkholderia cenocepacia Infections.
[So] Source:PLoS One;11(11):e0167350, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The greatest obstacle for the treatment of cystic fibrosis patients infected with the Burkholderia species is their intrinsic antibiotic resistance. For this reason, there is a need to develop new effective compounds. Glutamate racemase, an essential enzyme for the biosynthesis of the bacterial cell wall, is an excellent candidate target for the design of new antibacterial drugs. To this aim, we recombinantly produced and characterized glutamate racemase from Burkholderia cenocepacia J2315. From the screening of an in-house library of compounds, two Zn (II) and Mn (III) 1,3,5-triazapentadienate complexes were found to efficiently inhibit the glutamate racemase activity with IC50 values of 35.3 and 10.0 µM, respectively. Using multiple biochemical approaches, the metal complexes have been shown to affect the enzyme activity by binding to the enzyme-substrate complex and promoting the formation of an inhibited dimeric form of the enzyme. Our results corroborate the value of glutamate racemase as a good target for the development of novel inhibitors against Burkholderia.
[Mh] Termos MeSH primário: Isomerases de Aminoácido/antagonistas & inibidores
Isomerases de Aminoácido/metabolismo
Burkholderia cenocepacia/enzimologia
Complexos de Coordenação/farmacologia
Inibidores Enzimáticos/farmacologia
[Mh] Termos MeSH secundário: Antibacterianos/química
Antibacterianos/isolamento & purificação
Antibacterianos/farmacologia
Proteínas de Bactérias/antagonistas & inibidores
Proteínas de Bactérias/metabolismo
Infecções por Burkholderia/microbiologia
Burkholderia cenocepacia/efeitos dos fármacos
Burkholderia cenocepacia/isolamento & purificação
Complexos de Coordenação/química
Complexos de Coordenação/metabolismo
Sistemas de Liberação de Medicamentos
Ativação Enzimática/efeitos dos fármacos
Inibidores Enzimáticos/isolamento & purificação
Seres Humanos
Concentração Inibidora 50
Cinética
Manganês/química
Testes de Sensibilidade Microbiana
Ligação Proteica
Estabilidade Proteica
Zinco/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Coordination Complexes); 0 (Enzyme Inhibitors); 42Z2K6ZL8P (Manganese); EC 5.1.1.- (Amino Acid Isomerases); EC 5.1.1.3 (glutamate racemase); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170623
[Lr] Data última revisão:
170623
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161130
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0167350


  7 / 1222 MEDLINE  
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[PMID]:27893760
[Au] Autor:Wang J; Huang Y; Li K; Chen Y; Vanegas D; McLamore ES; Shen Y
[Ad] Endereço:College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China.
[Ti] Título:Leaf Extract from Lithocarpus polystachyus Rehd. Promote Glycogen Synthesis in T2DM Mice.
[So] Source:PLoS One;11(11):e0166557, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The purpose of this study was to investigate the effects of leaf extract from Lithocarpus polystachyus Rehd. on type II diabetes mellitus (T2DM) and the active ingredients of this effect. In addition, this study determined, for the first time, the underlying molecular and pharmacological mechanisms of the extracts on hyperglycemia using long-term double high diet-fed and streptozotocin (STZ) induced type II diabetic mice. In the present study, leaf extract, phloridzin and trilobatin were assessed in vivo (gavage) and in vitro (non-invasive micro-test technique, NMT) in experimental T2DM mice. The biochemical parameters were measured including blood glucose and blood lipid level, liver biochemical indexes, and hepatic glycogen. The relative expression of glycometabolism-related genes was detected. The effect of leaf extracts on physiological glucose flux in liver tissue from control and T2DM mice was also investigated. Body weight of experimental T2DM mice increased significantly after the first week, but stabilized over the subsequent three weeks; body weight of all other groups did not change during the four weeks' study. After four weeks, all treatment groups decreased blood glucose, and treatment with leaf extract had numerous positive effects: a) promoted in glucose uptake in liver, b) increased synthesis of liver glycogen, c) reduced oxidative stress, d) up-regulation of glucokinase (GK), glucose transporter 2 (GLUT2), insulin receptor (IR) and insulin receptor substrate (IRS) expression in liver, e) down-regulation of glucose-6-phosphatase (G-6-P) expression, and f) ameliorated blood lipid levels. Both treatment with trilobatin or phloridzin accelerated liver glycogen synthesis, decreased oxidative stress and increased expression of GK. IRS and phosphoenolpyruvate carboxykinase (PEPCK) were both up-regulated after treatment with trilobatin. Expression of GLUT2, PEPCK and G-6-P were also increased in liver tissue after treatment with phloridzin. Our data indicate that leaf extract from L. polystachyus Rehd. has a preferable hypoglycemic effects than trilobatin or phloridzin alone. Leaf extract significantly increased glucose uptake and hepatic glycogen synthesis while also inducing a decline of hepatic gluconeogenesis and oxidative stress in T2DM mice. From this study, we draw conclusions that L. polystachyus promoted glycogen synthesis in T2DM mice, and that the active compounds were not only the trilobatin or phloridzin.
[Mh] Termos MeSH primário: Diabetes Mellitus Experimental/tratamento farmacológico
Fagaceae/química
Glicogênio/metabolismo
Extratos Vegetais/uso terapêutico
[Mh] Termos MeSH secundário: Isomerases de Aminoácido/análise
Animais
Glicemia/análise
Peso Corporal/efeitos dos fármacos
Células Cultivadas
Diabetes Mellitus Experimental/induzido quimicamente
Regulação para Baixo/efeitos dos fármacos
Fagaceae/metabolismo
Teste de Tolerância a Glucose
Glutationa/análise
Hipoglicemiantes/química
Hipoglicemiantes/farmacologia
Insulina/metabolismo
Fígado/citologia
Fígado/efeitos dos fármacos
Fígado/metabolismo
Masculino
Malondialdeído/análise
Camundongos
Extratos Vegetais/química
Extratos Vegetais/farmacologia
Folhas de Planta/química
Folhas de Planta/metabolismo
Estreptozocina/toxicidade
Superóxido Dismutase/análise
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Hypoglycemic Agents); 0 (Insulin); 0 (Plant Extracts); 4Y8F71G49Q (Malondialdehyde); 5W494URQ81 (Streptozocin); 9005-79-2 (Glycogen); EC 1.15.1.1 (Superoxide Dismutase); EC 5.1.1.- (Amino Acid Isomerases); EC 5.1.1.3 (glutamate racemase); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170627
[Lr] Data última revisão:
170627
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161129
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0166557


  8 / 1222 MEDLINE  
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[PMID]:27480853
[Au] Autor:Prosser GA; Rodenburg A; Khoury H; de Chiara C; Howell S; Snijders AP; de Carvalho LP
[Ad] Endereço:Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, London, United Kingdom Luiz.Carvalho@crick.ac.uk gareth.prosser@nih.gov.
[Ti] Título:Glutamate Racemase Is the Primary Target of ß-Chloro-d-Alanine in Mycobacterium tuberculosis.
[So] Source:Antimicrob Agents Chemother;60(10):6091-9, 2016 Oct.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The increasing global prevalence of drug resistance among many leading human pathogens necessitates both the development of antibiotics with novel mechanisms of action and a better understanding of the physiological activities of preexisting clinically effective drugs. Inhibition of peptidoglycan (PG) biosynthesis and cross-linking has traditionally enjoyed immense success as an antibiotic target in multiple bacterial pathogens, except in Mycobacterium tuberculosis, where it has so far been underexploited. d-Cycloserine, a clinically approved antituberculosis therapeutic, inhibits enzymes within the d-alanine subbranch of the PG-biosynthetic pathway and has been a focus in our laboratory for understanding peptidoglycan biosynthesis inhibition and for drug development in studies of M. tuberculosis During our studies on alternative inhibitors of the d-alanine pathway, we discovered that the canonical alanine racemase (Alr) inhibitor ß-chloro-d-alanine (BCDA) is a very poor inhibitor of recombinant M. tuberculosis Alr, despite having potent antituberculosis activity. Through a combination of enzymology, microbiology, metabolomics, and proteomics, we show here that BCDA does not inhibit the d-alanine pathway in intact cells, consistent with its poor in vitro activity, and that it is instead a mechanism-based inactivator of glutamate racemase (MurI), an upstream enzyme in the same early stage of PG biosynthesis. This is the first report to our knowledge of inhibition of MurI in M. tuberculosis and thus provides a valuable tool for studying this essential and enigmatic enzyme and a starting point for future MurI-targeted antibacterial development.
[Mh] Termos MeSH primário: Isomerases de Aminoácido/química
Antituberculosos/farmacologia
Proteínas de Bactérias/química
Inibidores Enzimáticos/farmacologia
Mycobacterium tuberculosis/efeitos dos fármacos
beta-Alanina/análogos & derivados
[Mh] Termos MeSH secundário: Isomerases de Aminoácido/antagonistas & inibidores
Isomerases de Aminoácido/genética
Isomerases de Aminoácido/metabolismo
Sequência de Aminoácidos
Antituberculosos/química
Proteínas de Bactérias/antagonistas & inibidores
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Domínio Catalítico
Clonagem Molecular
Inibidores Enzimáticos/química
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Cinética
Testes de Sensibilidade Microbiana
Mycobacterium tuberculosis/enzimologia
Mycobacterium tuberculosis/genética
Mycobacterium tuberculosis/crescimento & desenvolvimento
Peptidoglicano/biossíntese
Ligação Proteica
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Especificidade por Substrato
beta-Alanina/química
beta-Alanina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Bacterial Proteins); 0 (Enzyme Inhibitors); 0 (Peptidoglycan); 0 (Recombinant Proteins); 11P2JDE17B (beta-Alanine); 3981-36-0 (3-chloroalanine); EC 5.1.1.- (Amino Acid Isomerases); EC 5.1.1.3 (glutamate racemase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160803
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.01249-16


  9 / 1222 MEDLINE  
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[PMID]:27444433
[Au] Autor:Femmer C; Bechtold M; Roberts TM; Panke S
[Ad] Endereço:ETH Zurich, Department of Biosystems Science and Engineering, Mattenstrasse 26, 4058, Basel, Switzerland.
[Ti] Título:Exploiting racemases.
[So] Source:Appl Microbiol Biotechnol;100(17):7423-36, 2016 Sep.
[Is] ISSN:1432-0614
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Chiral resolutions of racemic mixtures are limited to a theoretical yield of 50 %. This yield can be doubled by integration of a step-wise or continuous racemization of the non-desired enantiomer. Many of the different routes along which the racemization step can be conducted require harsh treatments and are therefore often incompatible with the highly functionalized state of many compounds relevant for the life science industries. Employing enzymatic catalysis for racemization can therefore be highly beneficial. Racemases allow racemization in one reaction step. Most representatives from this group are found in the domain of amino acid or amino acid derivative racemization, with few other examples, notably the racemization of mandelic acid. Corresponding to the importance of enantiospecific conversion of amino acid precursor racemates for the production of enantiopure amino acids, the most important biotechnological use for racemases is the racemization of such precursors. However, alternative uses, in particular for mandelate and amino acid racemases, are emerging. Here, we summarize the natural roles of racemases and their occurrence, the applications, and the biochemistry and engineering of this promising class of biocatalysts.
[Mh] Termos MeSH primário: Isomerases de Aminoácido/metabolismo
Aminoácidos/metabolismo
Bactérias/enzimologia
Bactérias/metabolismo
Biocatálise
[Mh] Termos MeSH secundário: Biotecnologia
Ácidos Mandélicos/metabolismo
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Amino Acids); 0 (Mandelic Acids); EC 5.1.1.- (Amino Acid Isomerases); NH496X0UJX (mandelic acid)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170227
[Lr] Data última revisão:
170227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160723
[St] Status:MEDLINE
[do] DOI:10.1007/s00253-016-7729-8


  10 / 1222 MEDLINE  
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[PMID]:27438592
[Au] Autor:Washio T; Kato S; Oikawa T
[Ad] Endereço:Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35 Yamate-Cho, Suita, Osaka-Fu, 564-8680, Japan.
[Ti] Título:Molecular cloning and enzymological characterization of pyridoxal 5'-phosphate independent aspartate racemase from hyperthermophilic archaeon Thermococcus litoralis DSM 5473.
[So] Source:Extremophiles;20(5):711-21, 2016 Sep.
[Is] ISSN:1433-4909
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:We succeeded in expressing the aspartate racemase homolog gene from Thermococcus litoralis DSM 5473 in Escherichia coli Rosetta (DE3) and found that the gene encodes aspartate racemase. The aspartate racemase gene consisted of 687 bp and encoded 228 amino acid residues. The purified enzyme showed aspartate racemase activity with a specific activity of 1590 U/mg. The enzyme was a homodimer with a molecular mass of 56 kDa and did not require pyridoxal 5'-phosphate as a coenzyme. The enzyme showed aspartate racemase activity even at 95 °C, and the activation energy of the enzyme was calculated to be 51.8 kJ/mol. The enzyme was highly thermostable, and approximately 50 % of its initial activity remained even after incubation at 90 °C for 11 h. The enzyme showed a maximum activity at a pH of 7.5 and was stable between pH 6.0 and 7.0. The enzyme acted on L-cysteic acid and L-cysteine sulfinic acid in addition to D- and L-aspartic acids, and was strongly inhibited by iodoacetic acid. The site-directed mutagenesis of the enzyme showed that the essential cysteine residues were conserved as Cys83 and Cys194. D-Forms of aspartic acid, serine, alanine, and valine were contained in T. litoralis DSM 5473 cells.
[Mh] Termos MeSH primário: Isomerases de Aminoácido/metabolismo
Proteínas Arqueais/metabolismo
Temperatura Alta
Fosfato de Piridoxal/metabolismo
Thermococcus/enzimologia
[Mh] Termos MeSH secundário: Isomerases de Aminoácido/química
Isomerases de Aminoácido/genética
Substituição de Aminoácidos
Proteínas Arqueais/química
Proteínas Arqueais/genética
Sequência Conservada
Estabilidade Enzimática
Concentração de Íons de Hidrogênio
Especificidade por Substrato
Thermococcus/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Archaeal Proteins); 5V5IOJ8338 (Pyridoxal Phosphate); EC 5.1.1.- (Amino Acid Isomerases); EC 5.1.1.13 (aspartate racemase)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM; S
[Da] Data de entrada para processamento:160721
[St] Status:MEDLINE
[do] DOI:10.1007/s00792-016-0860-8



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