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[PMID]:27544863
[Au] Autor:Navia-Paldanius D; Patel JZ; López Navarro M; Jakupovic H; Goffart S; Pasonen-Seppänen S; Nevalainen TJ; Jääskeläinen T; Laitinen T; Laitinen JT; Savinainen JR
[Ad] Endereço:School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O Box 1627, 70211 Kuopio, Finland. Electronic address: dina.navia-paldanius@uef.fi.
[Ti] Título:Chemoproteomic, biochemical and pharmacological approaches in the discovery of inhibitors targeting human α/ß-hydrolase domain containing 11 (ABHD11).
[So] Source:Eur J Pharm Sci;93:253-63, 2016 Oct 10.
[Is] ISSN:1879-0720
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:ABHD11 (α/ß-hydrolase domain containing 11) is a non-annotated enzyme belonging to the family of metabolic serine hydrolases (mSHs). Its natural substrates and products are unknown. Using competitive activity-based protein profiling (ABPP) to identify novel inhibitors of human (h)ABHD11, three compounds from our chemical library exhibited low nanomolar potency towards hABHD11. Competitive ABPP of various proteomes revealed fatty acid amide hydrolase (FAAH) as the sole off-target among the mSHs. Our fluorescent activity assays designed for natural lipase substrates revealed no activity of hABHD11 towards mono- or diacylglycerols. A broader profiling using para-nitrophenyl (pNP)-linked substrates indicated no amidase/protease, phosphatase, sulfatase, phospholipase C or phosphodiesterase activity. Instead, hABHD11 readily utilized para-nitrophenyl butyrate (pNPC4), indicating lipase/esterase-type activity that could be exploited in inhibitor discovery. Additionally, a homology model was created based on the crystal structure of bacterial esterase YbfF. In contrast to YbfF, which reportedly hydrolyze long-chain acyl-CoA, hABHD11 did not utilize oleoyl-CoA or arachidonoyl-CoA. In conclusion, the present study reports the discovery of potent hABHD11 inhibitors with good selectivity among mSHs. We developed substrate-based activity assays for hABHD11 that could be further exploited in inhibitor discovery and created the first homology-based hABHD11 model, offering initial insights into the active site of this poorly characterized enzyme.
[Mh] Termos MeSH primário: Serina Proteases/metabolismo
Inibidores de Serino Proteinase/farmacologia
[Mh] Termos MeSH secundário: Animais
Arilformamidase/genética
Encéfalo/metabolismo
Linhagem Celular Tumoral
Descoberta de Drogas
Feminino
Células HEK293
Seres Humanos
Camundongos Endogâmicos C57BL
Mitocôndrias/metabolismo
Modelos Moleculares
Proteômica
Serina Proteases/química
Serina Proteases/genética
Tioléster Hidrolases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Serine Proteinase Inhibitors); EC 3.1.2.- (LYPLA2 protein, human); EC 3.1.2.- (Thiolester Hydrolases); EC 3.4.- (ABHD11 protein, human); EC 3.4.- (Serine Proteases); EC 3.5.1.9 (Arylformamidase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170417
[Lr] Data última revisão:
170417
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160822
[St] Status:MEDLINE


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Williams, Paul
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[PMID]:26654915
[Au] Autor:Butt A; Halliday N; Williams P; Atkins HS; Bancroft GJ; Titball RW
[Ad] Endereço:Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK. Electronic address: a.t.butt@sheffield.ac.uk.
[Ti] Título:Burkholderia pseudomallei kynB plays a role in AQ production, biofilm formation, bacterial swarming and persistence.
[So] Source:Res Microbiol;167(3):159-67, 2016 Apr.
[Is] ISSN:1769-7123
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Kynurenine formamidase (KynB) forms part of the kynurenine pathway which metabolises tryptophan to anthranilate. This metabolite can be used for downstream production of 2-alkyl-4-quinolone (AQ) signalling molecules that control virulence in Pseudomonas aeruginosa. Here we investigate the role of kynB in the production of AQs and virulence-associated phenotypes of Burkholderia pseudomallei K96243, the causative agent of melioidosis. Deletion of kynB resulted in reduced AQ production, increased biofilm formation, decreased swarming and increased tolerance to ciprofloxacin. Addition of exogenous anthranilic acid restored the biofilm phenotype, but not the persister phenotype. This study suggests the kynurenine pathway is a critical source of anthranilate and signalling molecules that may regulate B. pseudomallei virulence.
[Mh] Termos MeSH primário: Arilformamidase/metabolismo
Biofilmes/crescimento & desenvolvimento
Burkholderia pseudomallei/enzimologia
Burkholderia pseudomallei/fisiologia
Locomoção
Quinolonas/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Burkholderia pseudomallei/genética
Deleção de Genes
Triptofano/metabolismo
Virulência
ortoaminobenzoatos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Quinolones); 0 (ortho-Aminobenzoates); 0YS975XI6W (anthranilic acid); 8DUH1N11BX (Tryptophan); EC 3.5.1.9 (Arylformamidase)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151215
[St] Status:MEDLINE


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[PMID]:24942958
[Au] Autor:Díaz-Sáez L; Srikannathasan V; Zoltner M; Hunter WN
[Ad] Endereço:*Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
[Ti] Título:Structures of bacterial kynurenine formamidase reveal a crowded binuclear zinc catalytic site primed to generate a potent nucleophile.
[So] Source:Biochem J;462(3):581-9, 2014 Sep 15.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Tryptophan is an important precursor for chemical entities that ultimately support the biosynthesis of key metabolites. The second stage of tryptophan catabolism is catalysed by kynurenine formamidase, an enzyme that is different between eukaryotes and prokaryotes. In the present study, we characterize the catalytic properties and present the crystal structures of three bacterial kynurenine formamidases. The structures reveal a new amidase protein fold, a highly organized and distinctive binuclear Zn2+ catalytic centre in a confined, hydrophobic and relatively rigid active site. The structure of a complex with 2-aminoacetophenone delineates aspects of molecular recognition extending to the observation that the substrate itself may be conformationally restricted to assist binding in the confined space of the active site and for subsequent processing. The cations occupy a crowded environment, and, unlike most Zn2+-dependent enzymes, there is little scope to increase co-ordination number during catalysis. We propose that the presence of a bridging water/hydroxide ligand in conjunction with the placement of an active site histidine supports a distinctive amidation mechanism.
[Mh] Termos MeSH primário: Arilformamidase/química
Zinco/metabolismo
[Mh] Termos MeSH secundário: Arilformamidase/metabolismo
Bacillus anthracis/enzimologia
Biocatálise
Burkholderia cenocepacia/enzimologia
Domínio Catalítico
Cristalografia por Raios X
Cinética
Conformação Proteica
Pseudomonas aeruginosa/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 3.5.1.9 (Arylformamidase); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1410
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140620
[St] Status:MEDLINE
[do] DOI:10.1042/BJ20140511


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[PMID]:23328119
[Au] Autor:Seifert J
[Ad] Endereço:PEPS, University of Hawaii, Honolulu, HI 96822, USA. josef@hawaii.edu
[Ti] Título:Structural requirements of organophosphorus insecticides (OPI) to inhibit chicken yolk sac membrane kynurenine formamidase related to OPI teratogenesis.
[So] Source:Environ Toxicol Pharmacol;35(2):200-6, 2013 Mar.
[Is] ISSN:1872-7077
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:This paper provides new information related to the mechanism of OPI (organophosphorus insecticides) teratogenesis. The COMFA (comparative molecular field analysis) and COMSIA (comparative molecular similarity indices analysis) suggest that the electrostatic and steric fields are the best predictors of OPI structural requirements to inhibit in ovo chicken embryo yolk sac membrane kynurenine formamidase, the proposed target for OPI teratogens. The dominant electrostatic interactions are localized at nitrogen-1, nitrogen-3, nitrogen of 2-amino substituent of the pyrimidinyl of pyrimidinyl phosphorothioates, and the oxygen of crotonamide carbonyl in crotonamide phosphates. Bulkiness of the substituents at carbon-2 and carbon-6 of the pyrimidinyls and/or N-substituents and carbon-3 substituents of crotonamides are the steric structural components that contribute to superiority of those OPI as in ovo inhibitors of kynurenine formamidase.
[Mh] Termos MeSH primário: Arilformamidase/antagonistas & inibidores
Inseticidas/química
Inseticidas/toxicidade
Compostos Organofosforados/química
Compostos Organofosforados/toxicidade
Relação Quantitativa Estrutura-Atividade
Teratogênios/toxicidade
Saco Vitelino/enzimologia
[Mh] Termos MeSH secundário: Animais
Embrião de Galinha
Inibidores Enzimáticos/química
Inibidores Enzimáticos/toxicidade
Leptofós/química
Leptofós/toxicidade
Modelos Moleculares
Paration/química
Paration/toxicidade
Eletricidade Estática
Teratogênios/química
Saco Vitelino/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Insecticides); 0 (Organophosphorus Compounds); 0 (Teratogens); 61G466064D (Parathion); C45E8FUG3Z (Leptophos); EC 3.5.1.9 (Arylformamidase)
[Em] Mês de entrada:1309
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130119
[St] Status:MEDLINE


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[PMID]:22690733
[Au] Autor:Han Q; Robinson H; Li J
[Ad] Endereço:Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, USA.
[Ti] Título:Biochemical identification and crystal structure of kynurenine formamidase from Drosophila melanogaster.
[So] Source:Biochem J;446(2):253-60, 2012 Sep 01.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:KFase (kynurenine formamidase), also known as arylformamidase and formylkynurenine formamidase, efficiently catalyses the hydrolysis of NFK (N-formyl-L-kynurenine) to kynurenine. KFase is the second enzyme in the kynurenine pathway of tryptophan metabolism. A number of intermediates formed in the kynurenine pathway are biologically active and implicated in an assortment of medical conditions, including cancer, schizophrenia and neurodegenerative diseases. Consequently, enzymes involved in the kynurenine pathway have been considered potential regulatory targets. In the present study, we report, for the first time, the biochemical characterization and crystal structures of Drosophila melanogaster KFase conjugated with an inhibitor, PMSF. The protein architecture of KFase reveals that it belongs to the α/ß hydrolase fold family. The PMSF-binding information of the solved conjugated crystal structure was used to obtain a KFase and NFK complex using molecular docking. The complex is useful for understanding the catalytic mechanism of KFase. The present study provides a molecular basis for future efforts in maintaining or regulating kynurenine metabolism through the molecular and biochemical regulation of KFase.
[Mh] Termos MeSH primário: Arilformamidase/química
Arilformamidase/metabolismo
Proteínas de Drosophila/química
Proteínas de Drosophila/metabolismo
Drosophila melanogaster/enzimologia
[Mh] Termos MeSH secundário: Animais
Arilformamidase/antagonistas & inibidores
Arilformamidase/genética
Biocatálise
Domínio Catalítico
Simulação por Computador
Cristalografia por Raios X
Proteínas de Drosophila/antagonistas & inibidores
Proteínas de Drosophila/genética
Drosophila melanogaster/metabolismo
Inibidores Enzimáticos/química
Inibidores Enzimáticos/metabolismo
Inibidores Enzimáticos/farmacologia
Interações Hidrofóbicas e Hidrofílicas
Inseticidas/química
Inseticidas/metabolismo
Inseticidas/farmacologia
Cinética
Cinurenina/análogos & derivados
Cinurenina/química
Cinurenina/metabolismo
Ligantes
Modelos Moleculares
Ligação Proteica
Conformação Proteica
Proteínas Recombinantes/antagonistas & inibidores
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Compostos de Tosil/química
Compostos de Tosil/metabolismo
Compostos de Tosil/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (Enzyme Inhibitors); 0 (Insecticides); 0 (Ligands); 0 (Recombinant Proteins); 0 (Tosyl Compounds); 1022-31-7 (N'-formylkynurenine); 343-65-7 (Kynurenine); 455-16-3 (4-toluenesulfonyl fluoride); EC 3.5.1.9 (Arylformamidase)
[Em] Mês de entrada:1210
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120614
[St] Status:MEDLINE
[do] DOI:10.1042/BJ20120416


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[PMID]:22234533
[Au] Autor:Zummo FP; Marineo S; Pace A; Civiletti F; Giardina A; Puglia AM
[Ad] Endereço:Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari, Università degli Studi di Palermo, Viale delle Scienze-Edificio 16, 90128 Palermo, Italy. fpzummo@gmail.com
[Ti] Título:Tryptophan catabolism via kynurenine production in Streptomyces coelicolor: identification of three genes coding for the enzymes of tryptophan to anthranilate pathway.
[So] Source:Appl Microbiol Biotechnol;94(3):719-28, 2012 May.
[Is] ISSN:1432-0614
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Most enzymes involved in tryptophan catabolism via kynurenine formation are highly conserved in Prokaryotes and Eukaryotes. In humans, alterations of this pathway have been related to different pathologies mainly involving the central nervous system. In Bacteria, tryptophan and some of its derivates are important antibiotic precursors. Tryptophan degradation via kynurenine formation involves two different pathways: the eukaryotic kynurenine pathway, also recently found in some bacteria, and the tryptophan-to-anthranilate pathway, which is widespread in microorganisms. The latter produces anthranilate using three enzymes also involved in the kynurenine pathway: tryptophan 2,3-dioxygenase (TDO), kynureninase (KYN), and kynurenine formamidase (KFA). In Streptomyces coelicolor, where it had not been demonstrated which genes code for these enzymes, tryptophan seems to be important for the calcium- dependent antibiotic (CDA) production. In this study, we describe three adjacent genes of S. coelicolor (SCO3644, SCO3645, and SCO3646), demonstrating their involvement in the tryptophan-to-anthranilate pathway: SCO3644 codes for a KFA, SCO3645 for a KYN and SCO3646 for a TDO. Therefore, these genes can be considered as homologous respectively to kynB, kynU, and kynA of other microorganisms and belong to a constitutive catabolic pathway in S. coelicolor, which expression increases during the stationary phase of a culture grown in the presence of tryptophan. Moreover, the S. coelicolor ΔkynU strain, in which SCO3645 gene is deleted, produces higher amounts of CDA compared to the wild-type strain. Overall, these results describe a pathway, which is used by S. coelicolor to catabolize tryptophan and that could be inactivated to increase antibiotic production.
[Mh] Termos MeSH primário: Arilformamidase/genética
Hidrolases/genética
Cinurenina/metabolismo
Redes e Vias Metabólicas/genética
Streptomyces coelicolor/genética
Triptofano Oxigenase/genética
Triptofano/metabolismo
[Mh] Termos MeSH secundário: Arilformamidase/metabolismo
Hidrolases/metabolismo
Streptomyces coelicolor/metabolismo
Triptofano Oxigenase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
343-65-7 (Kynurenine); 8DUH1N11BX (Tryptophan); EC 1.13.11.11 (Tryptophan Oxygenase); EC 3.- (Hydrolases); EC 3.5.1.9 (Arylformamidase); EC 3.7.1.3 (kynureninase)
[Em] Mês de entrada:1207
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120112
[St] Status:MEDLINE
[do] DOI:10.1007/s00253-011-3833-y


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[PMID]:20304989
[Au] Autor:Keller U; Lang M; Crnovcic I; Pfennig F; Schauwecker F
[Ad] Endereço:Institut für Chemie, Arbeitsgruppe Biochemie und Molekulare Biologie, Technische Universität Berlin, Franklinstrasse 29, D-10587 Berlin-Charlottenburg, Germany. ullrich.keller@tu-berlin.de
[Ti] Título:The actinomycin biosynthetic gene cluster of Streptomyces chrysomallus: a genetic hall of mirrors for synthesis of a molecule with mirror symmetry.
[So] Source:J Bacteriol;192(10):2583-95, 2010 May.
[Is] ISSN:1098-5530
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A gene cluster was identified which contains genes involved in the biosynthesis of actinomycin encompassing 50 kb of contiguous DNA on the chromosome of Streptomyces chrysomallus. It contains 28 genes with biosynthetic functions and is bordered on both sides by IS elements. Unprecedentedly, the cluster consists of two large inverted repeats of 11 and 13 genes, respectively, with four nonribosomal peptide synthetase genes in the middle. Nine genes in each repeat have counterparts in the other, in the same arrangement but in the opposite orientation, suggesting an inverse duplication of one of the arms during the evolution of the gene cluster. All of the genes appear to be organized into operons, each corresponding to a functional section of actinomycin biosynthesis, such as peptide assembly, regulation, resistance, and biosynthesis of the precursor of the actinomycin chromophore 4-methyl-3-hydroxyanthranilic acid (4-MHA). For 4-MHA synthesis, functional analysis revealed genes that encode pathway-specific isoforms of tryptophan dioxygenase, kynurenine formamidase, and hydroxykynureninase, which are distinct from the corresponding enzyme activities of cellular tryptophan catabolism in their regulation and in part in their substrate specificity. Phylogenetic analysis indicates that the pathway-specific tryptophan metabolism in Streptomyces most probably evolved divergently from the normal pathway of tryptophan catabolism to provide an extra or independent supply of building blocks for the synthesis of tryptophan-derived secondary metabolites.
[Mh] Termos MeSH primário: Proteínas de Bactérias/genética
Dactinomicina/biossíntese
Dactinomicina/química
Família Multigênica/genética
Isoformas de Proteínas/genética
Streptomyces/metabolismo
[Mh] Termos MeSH secundário: Arilformamidase/genética
Arilformamidase/metabolismo
Proteínas de Bactérias/metabolismo
Cromatografia em Camada Delgada
Dactinomicina/metabolismo
Hidrolases/genética
Hidrolases/metabolismo
Dados de Sequência Molecular
Estrutura Molecular
Mutação
Isoformas de Proteínas/metabolismo
Análise de Sequência de DNA
Estereoisomerismo
Streptomyces/genética
ortoaminobenzoatos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Protein Isoforms); 0 (ortho-Aminobenzoates); 1CC1JFE158 (Dactinomycin); 552-14-7 (4-methyl-3-hydroxyanthranilic acid); EC 3.- (Hydrolases); EC 3.5.1.9 (Arylformamidase); EC 3.7.1.- (3-hydroxykynureninase)
[Em] Mês de entrada:1005
[Cu] Atualização por classe:141204
[Lr] Data última revisão:
141204
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100323
[St] Status:MEDLINE
[do] DOI:10.1128/JB.01526-09


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[PMID]:18205391
[Au] Autor:Wogulis M; Chew ER; Donohoue PD; Wilson DK
[Ad] Endereço:Section of Molecular and Cellular Biology, University of California, Davis, California 95616, USA.
[Ti] Título:Identification of formyl kynurenine formamidase and kynurenine aminotransferase from Saccharomyces cerevisiae using crystallographic, bioinformatic and biochemical evidence.
[So] Source:Biochemistry;47(6):1608-21, 2008 Feb 12.
[Is] ISSN:0006-2960
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The essential enzymatic cofactor NAD+ can be synthesized in many eukaryotes, including Saccharomyces cerevisiae and mammals, using tryptophan as a starting material. Metabolites along the pathway or on branches have important biological functions. For example, kynurenic acid can act as an NMDA antagonist, thereby functioning as a neuroprotectant in a wide range of pathological states. N-Formyl kynurenine formamidase (FKF) catalyzes the second step of the NAD+ biosynthetic pathway by hydrolyzing N-formyl kynurenine to produce kynurenine and formate. The S. cerevisiae FKF had been reported to be a pyridoxal phosphate-dependent enzyme encoded by BNA3. We used combined crystallographic, bioinformatic and biochemical methods to demonstrate that Bna3p is not an FKF but rather is most likely the yeast kynurenine aminotransferase, which converts kynurenine to kynurenic acid. Additionally, we identify YDR428C, a yeast ORF coding for an alpha/beta hydrolase with no previously assigned function, as the FKF. We predicted its function based on our interpretation of prior structural genomics results and on its sequence homology to known FKFs. Biochemical, bioinformatics, genetic and in vivo metabolite data derived from LC-MS demonstrate that YDR428C, which we have designated BNA7, is the yeast FKF.
[Mh] Termos MeSH primário: Arilformamidase/metabolismo
Saccharomyces cerevisiae/enzimologia
Transaminases/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Arilformamidase/química
Cromatografia Líquida de Alta Pressão
Biologia Computacional
Cristalografia
Modelos Moleculares
Dados de Sequência Molecular
Conformação Proteica
Homologia de Sequência de Aminoácidos
Transaminases/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.6.1.- (Transaminases); EC 2.6.1.7 (kynurenine-oxoglutarate transaminase); EC 3.5.1.9 (Arylformamidase)
[Em] Mês de entrada:0804
[Cu] Atualização por classe:080205
[Lr] Data última revisão:
080205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:080122
[St] Status:MEDLINE
[do] DOI:10.1021/bi701172v


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[PMID]:15935693
[Au] Autor:Pabarcus MK; Casida JE
[Ad] Endereço:Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720-3112, USA.
[Ti] Título:Cloning, expression, and catalytic triad of recombinant arylformamidase.
[So] Source:Protein Expr Purif;44(1):39-44, 2005 Nov.
[Is] ISSN:1046-5928
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Arylformamidase (AFMID) is the second enzyme of the kynurenine pathway metabolizing tryptophan to nicotinic acid and nicotinamide adenine dinucleotide cofactors. Inhibition of AFMID by organophosphorus insecticides in developing chicken embryos is correlated with lowered NAD levels and severe teratogenesis. The cDNA sequence previously identified for mouse liver AFMID (AF399717) (MW 34229) was cloned and expressed in Escherichia coli. Residues identified as potential catalytic triad members (S162, D247, and H279) through sequence motif and homology modeling were mutated to alanine to probe their contributions to enzyme activity. The wild-type and mutant AFMIDs were expressed as amino terminal 6 x His-tagged recombinant proteins to facilitate purification. Three chromatography steps isolated highly purified proteins for enzyme activity comparisons. Expressed AFMID showed high activity, 42+/-1 micromol/min/mg protein, for its natural substrate, N-formyl-l-kynurenine. The same K(m) (0.18--0.19 mM) was observed for expressed and native cytosolic AFMID. The single mutants (S162A, D247A, and H279A) lost essentially all (>99%) activity. The predicted catalytic triad of S162, D247, and H279 is therefore confirmed by site-directed mutagenesis.
[Mh] Termos MeSH primário: Substituição de Aminoácidos/genética
Arilformamidase/genética
Clonagem Molecular
Expressão Gênica
Fígado/enzimologia
[Mh] Termos MeSH secundário: Animais
Arilformamidase/isolamento & purificação
Arilformamidase/metabolismo
Sítios de Ligação/genética
Clonagem Molecular/métodos
Escherichia coli/genética
Expressão Gênica/genética
Camundongos
Mutagênese Sítio-Dirigida/métodos
Mutação Puntual/genética
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/isolamento & purificação
Proteínas Recombinantes de Fusão/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (Recombinant Fusion Proteins); EC 3.5.1.9 (Arylformamidase)
[Em] Mês de entrada:0601
[Cu] Atualização por classe:071114
[Lr] Data última revisão:
071114
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:050607
[St] Status:MEDLINE


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[PMID]:15866519
[Au] Autor:Dobrovolsky VN; Bowyer JF; Pabarcus MK; Heflich RH; Williams LD; Doerge DR; Arvidsson B; Bergquist J; Casida JE
[Ad] Endereço:Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, 3900 NCTR Rd., HFT-120, Jefferson, AR 72079, USA. vdobrovolsky@nctr.fda.gov
[Ti] Título:Effect of arylformamidase (kynurenine formamidase) gene inactivation in mice on enzymatic activity, kynurenine pathway metabolites and phenotype.
[So] Source:Biochim Biophys Acta;1724(1-2):163-72, 2005 Jun 20.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The gene coding for arylformamidase (Afmid, also known as kynurenine formamidase) was inactivated in mice through the removal of a shared bidirectional promoter region regulating expression of the Afmid and thymidine kinase (Tk) genes. Afmid/Tk -deficient mice are known to develop sclerosis of glomeruli and to have an abnormal immune system. Afmid-catalyzed hydrolysis of N-formyl-kynurenine is a key step in tryptophan metabolism and biosynthesis of kynurenine-derived products including kynurenic acid, quinolinic acid, nicotinamide, NAD, and NADP. A disruption of these pathways is implicated in neurotoxicity and immunotoxicity. In wild-type (WT) mice, Afmid-specific activity (as measured by formyl-kynurenine hydrolysis) was 2-fold higher in the liver than in the kidney. Formyl-kynurenine hydrolysis was reduced by approximately 50% in mice heterozygous (HZ) for Afmid/Tk and almost completely eliminated in Afmid/Tk knockout (KO) mice. However, there was 13% residual formyl-kynurenine hydrolysis in the kidney of KO mice, suggesting the existence of a formamidase other than Afmid. Liver and kidney levels of nicotinamide plus NAD/NADP remained the same in WT, HZ and KO mice. Plasma concentrations of formyl-kynurenine, kynurenine, and kynurenic acid were elevated in KO mice (but not HZ mice) relative to WT mice, further suggesting that there must be enzymes other than Afmid (possibly in the kidney) capable of metabolizing formyl-kynurenine into kynurenine. Gradual kidney deterioration and subsequent failure in KO mice is consistent with high levels of tissue-specific Afmid expression in the kidney of WT but not KO mice. On this basis, the most significant function of the kynurenine pathway and Afmid in mice may be in eliminating toxic metabolites and to a lesser extent in providing intermediates for other processes.
[Mh] Termos MeSH primário: Arilformamidase/genética
Arilformamidase/metabolismo
Cinurenina/metabolismo
[Mh] Termos MeSH secundário: Animais
Arilformamidase/análise
Inativação Gênica
Rim/química
Rim/enzimologia
Cinurenina/sangue
Fígado/química
Fígado/enzimologia
Ativação Linfocitária/genética
Ativação Linfocitária/imunologia
Camundongos
Camundongos Knockout
Niacinamida/análise
Fenótipo
Insuficiência Renal/genética
Timidina Quinase/análise
Timidina Quinase/genética
Triptofano/sangue
Triptofano/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
25X51I8RD4 (Niacinamide); 343-65-7 (Kynurenine); 8DUH1N11BX (Tryptophan); EC 2.7.1.21 (Thymidine Kinase); EC 3.5.1.9 (Arylformamidase)
[Em] Mês de entrada:0509
[Cu] Atualização por classe:161126
[Lr] Data última revisão:
161126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:050504
[St] Status:MEDLINE



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