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Pesquisa : D08.811.277.656.350.100.511 [Categoria DeCS]
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[PMID]:28388690
[Au] Autor:Peña-Diaz P; Vancová M; Resl C; Field MC; Lukes J
[Ad] Endereço:Institute of Parasitology, Biology Centre, Czech Academy of Sciences, Ceské Budejovice (Budweis), Czech Republic.
[Ti] Título:A leucine aminopeptidase is involved in kinetoplast DNA segregation in Trypanosoma brucei.
[So] Source:PLoS Pathog;13(4):e1006310, 2017 Apr.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The kinetoplast (k), the uniquely packaged mitochondrial DNA of trypanosomatid protists is formed by a catenated network of minicircles and maxicircles that divide and segregate once each cell cycle. Although many proteins involved in kDNA replication and segregation are now known, several key steps in the replication mechanism remain uncharacterized at the molecular level, one of which is the nabelschnur or umbilicus, a prominent structure which in the mammalian parasite Trypanosoma brucei connects the daughter kDNA networks prior to their segregation. Here we characterize an M17 family leucyl aminopeptidase metalloprotease, termed TbLAP1, which specifically localizes to the kDNA disk and the nabelschur and represents the first described protein found in this structure. We show that TbLAP1 is required for correct segregation of kDNA, with knockdown resulting in delayed cytokinesis and ectopic expression leading to kDNA loss and decreased cell proliferation. We propose that TbLAP1 is required for efficient kDNA division and specifically participates in the separation of daughter kDNA networks.
[Mh] Termos MeSH primário: Replicação do DNA/fisiologia
DNA de Cinetoplasto/genética
DNA Mitocondrial/genética
Leucil Aminopeptidase/genética
Leucil Aminopeptidase/metabolismo
[Mh] Termos MeSH secundário: Animais
Ciclo Celular/fisiologia
DNA de Protozoário/genética
Mitocôndrias/metabolismo
Mitocôndrias/ultraestrutura
Proteínas de Protozoários/metabolismo
Trypanosoma brucei brucei/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Kinetoplast); 0 (DNA, Mitochondrial); 0 (DNA, Protozoan); 0 (Protozoan Proteins); EC 3.4.11.1 (Leucyl Aminopeptidase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170803
[Lr] Data última revisão:
170803
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170408
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006310


  2 / 3158 MEDLINE  
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[PMID]:28108559
[Au] Autor:Guan J; Yang SJ; Gonzalez F; Yin Y; Shastri N
[Ad] Endereço:Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, People's Republic of China; and.
[Ti] Título:Antigen Processing in the Endoplasmic Reticulum Is Monitored by Semi-Invariant αß TCRs Specific for a Conserved Peptide-Qa-1 MHC Class Ib Ligand.
[So] Source:J Immunol;198(5):2017-2027, 2017 Mar 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ag processing in the endoplasmic reticulum (ER) by the ER aminopeptidase associated with Ag processing (ERAAP) is central to presentation of a normal peptide-MHC class I (MHC I) repertoire. Alternations in ERAAP function cause dramatic changes in the MHC I-presented peptides, which elicit potent immune responses. An unusual subset of CD8 T cells monitor normal Ag processing by responding to a highly conserved FL9 peptide that is presented by Qa-1 , a nonclassical MHC Ib molecule (QFL) in ERAAP-deficient cells. To understand the structural basis for recognition of the conserved ligand, we analyzed the αß TCRs of QFL-specific T cells. Individual cells in normal wild-type and TCRß-transgenic mice were assessed for QFL-specific TCR α- and ß-chains. The QFL-specific cells expressed a predominant semi-invariant TCR generated by DNA rearrangement of TRAV9d-3-TRAJ21 α-chain and TRBV5-TRBD1-TRBJ2-7 ß-chain gene segments. Furthermore, the CDR3 regions of the α- as well as ß-chains were required for QFL ligand recognition. Thus, the αß TCRs used to recognize the peptide-Qa-1 ligand presented by ERAAP-deficient cells are semi-invariant and likely reflect a conserved mechanism for monitoring the fidelity of Ag processing in the ER.
[Mh] Termos MeSH primário: Apresentação do Antígeno
Linfócitos T CD8-Positivos/imunologia
Retículo Endoplasmático/metabolismo
Leucil Aminopeptidase/metabolismo
Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo
[Mh] Termos MeSH secundário: Animais
Antígenos/metabolismo
Células Cultivadas
Sequência Conservada
Variação Genética
Antígenos de Histocompatibilidade Classe I/metabolismo
Leucil Aminopeptidase/genética
Ativação Linfocitária
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Peptídeos/metabolismo
Receptores de Antígenos de Linfócitos T alfa-beta/genética
Análise de Célula Única
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens); 0 (Histocompatibility Antigens Class I); 0 (Peptides); 0 (Q surface antigens); 0 (Receptors, Antigen, T-Cell, alpha-beta); EC 3.4.11.1 (Leucyl Aminopeptidase); EC 3.4.11.1 (puromycin-insensitive leucyl-specific aminopeptidase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170122
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1600764


  3 / 3158 MEDLINE  
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[PMID]:28038565
[Au] Autor:Wolke C; Teumer A; Endlich K; Endlich N; Rettig R; Stracke S; Fiene B; Aymanns S; Felix SB; Hannemann A; Lendeckel U
[Ad] Endereço:1 Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald D-17475, Germany.
[Ti] Título:Serum protease activity in chronic kidney disease patients: The GANI_MED renal cohort.
[So] Source:Exp Biol Med (Maywood);242(5):554-563, 2017 Mar.
[Is] ISSN:1535-3699
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Serum or plasma proteases have been associated with various diseases including cancer, inflammation, or reno-cardiovascular diseases. We aimed to investigate whether the enzymatic activities of serum proteases are associated with the estimated glomerular filtration rate (eGFR) in patients with different stages of chronic kidney disease (CKD). Our study population comprised 268 participants of the "Greifswald Approach to Individualized Medicine" (GANI_MED) cohort. Enzymatic activity of aminopeptidase A, aminopeptidase B, alanyl (membrane) aminopeptidase, insulin-regulated aminopeptidase, puromycin-sensitive aminopeptidase, leucine aminopeptidase 3, prolyl-endopeptidase (PEP), dipeptidyl peptidase 4 (DPP4), angiotensin I-converting enzyme, and angiotensin I-converting enzyme 2 (ACE2) proteases was measured in serum. Linear regression of the respective protease was performed on kidney function adjusted for age and sex. Kidney function was modeled either by the continuous Modification of Diet in Renal Disease (MDRD)-based eGFR or dichotomized by eGFR < 15 mL/min/1.73 m or <45 mL/min/1.73 m , respectively. Results with a false discovery rate below 0.05 were deemed statistically significant. Among the 10 proteases investigated, only the activities of ACE2 and DPP4 were correlated with eGFR. Patients with lowest eGFR exhibited highest DPP4 and ACE2 activities. DPP4 and PEP were correlated with age, but all other serum protease activities showed no associations with age or sex. Our data indicate that ACE2 and DPP4 enzymatic activity are associated with the eGFR in patients with CKD. This finding distinguishes ACE2 and DPP4 from other serum peptidases analyzed and clearly indicates that further analyses are warranted to identify the precise role of these serum ectopeptidases in the pathogenesis of CKD and to fully elucidate underlying molecular mechanisms. Impact statement • Renal and cardiac diseases are very common and often occur concomitantly, resulting in increased morbidity and mortality. Understanding of molecular mechanisms linking both diseases is limited, available fragmentary data point to a role of the renin-angiotensin system (RAS) and, in particular, Ras-related peptidases. • Here, a comprehensive analysis of serum peptidase activities in patients with different stages of chronic kidney disease (CKD) is presented, with special emphasis given to RAS peptidases • The serum activities of the peptidases angiotensin I-converting enzyme 2 and dipeptidyl peptidase 4 were identified as closely associated with kidney function, specifically with the estimated glomerular filtration rate. The findings are discussed in the context of available data suggesting protective roles for both enzymes in reno-cardiac diseases. • The data add to our understanding of pathomechanisms underlying development and progression of CKD and indicate that both enzymes might represent potential pharmacological targets for the preservation of renal function.
[Mh] Termos MeSH primário: Peptídeo Hidrolases/sangue
Insuficiência Renal Crônica/enzimologia
[Mh] Termos MeSH secundário: Idoso
Aminopeptidases/sangue
Aminopeptidases/metabolismo
Antígenos CD13/sangue
Antígenos CD13/metabolismo
Creatinina/sangue
Cistinil Aminopeptidase/sangue
Cistinil Aminopeptidase/metabolismo
Dipeptidil Peptidase 4/sangue
Dipeptidil Peptidase 4/metabolismo
Feminino
Taxa de Filtração Glomerular
Glutamil Aminopeptidase/sangue
Glutamil Aminopeptidase/metabolismo
Seres Humanos
Leucil Aminopeptidase/sangue
Leucil Aminopeptidase/metabolismo
Masculino
Meia-Idade
Peptídeo Hidrolases/metabolismo
Peptidil Dipeptidase A/sangue
Peptidil Dipeptidase A/metabolismo
Insuficiência Renal Crônica/sangue
Serina Endopeptidases/sangue
Serina Endopeptidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
AYI8EX34EU (Creatinine); EC 3.4.- (Peptide Hydrolases); EC 3.4.11.- (Aminopeptidases); EC 3.4.11.1 (LAP3 protein, human); EC 3.4.11.1 (Leucyl Aminopeptidase); EC 3.4.11.14 (enkephalin degrading enzyme); EC 3.4.11.2 (CD13 Antigens); EC 3.4.11.3 (Cystinyl Aminopeptidase); EC 3.4.11.3 (leucyl-cystinyl aminopeptidase); EC 3.4.11.6 (aminopeptidase B); EC 3.4.11.7 (Glutamyl Aminopeptidase); EC 3.4.14.5 (DPP4 protein, human); EC 3.4.14.5 (Dipeptidyl Peptidase 4); EC 3.4.15.1 (Peptidyl-Dipeptidase A); EC 3.4.17.- (angiotensin converting enzyme 2); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.26 (prolyl oligopeptidase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170101
[St] Status:MEDLINE
[do] DOI:10.1177/1535370216684040


  4 / 3158 MEDLINE  
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[PMID]:27880961
[Au] Autor:Kim KM; Lim J; Lee JJ; Hurh BS; Lee I
[Ad] Endereço:Department of Bio and Fermentation Convergence Technology, BK21 PLUS Project, Kookmin University, Seoul 02707, Republic of Korea.
[Ti] Título:Characterization of Isolated from Meju, Korean Traditional Fermented Soybean Brick.
[So] Source:J Microbiol Biotechnol;27(2):251-261, 2017 Feb 28.
[Is] ISSN:1738-8872
[Cp] País de publicação:Korea (South)
[La] Idioma:eng
[Ab] Resumo:Initially, we screened 18 -like strains from spp. isolated from meju (Korean traditional fermented soybean brick) according to their morphological characteristics. Because members of section are often incorrectly identified because of their phylogenetic similarity, we re-identified these strains at the morphological and molecular genetic levels. Fourteen strains were finally identified as . The isolates produced protease and α-amylase with ranges of 2.66-10.64 and 21.53-106.73 unit/g-initial dry substrate (U/g-IDS), respectively, which were equivalent to those of the koji (starter mold) strains employed to produce Japanese soy sauce. Among the isolates and Japanese koji strains, strains SMF 127 and SMF 131 had the highest leucine aminopeptidase (LAP) activities at 6.00 and 6.06 U/g-IDS, respectively. LAP plays an important role in flavor development because of the production of low-molecular-weight peptides that affect the taste and decrease bitterness. SMF 127 and SMF 131 appeared to be non-aflatoxigenic because of a termination point mutation in and the lack of the polyketide synthase gene found in other strains. In addition, SMF 127 and SMF 131 were not cyclopiazonic acid (CPA) producers because of the deletion of , , and , which are involved in CPA biosynthesis. Therefore, strains such as SMF 127 and SMF 131, which have high protease and LAP activities and are free of safety issues, can be considered good starters for soybean fermentations, such as in the production of the Korean fermented soybean products meju, doenjang, and ganjang.
[Mh] Termos MeSH primário: Aspergillus/genética
Aspergillus/isolamento & purificação
Microbiologia de Alimentos
Alimentos de Soja/microbiologia
[Mh] Termos MeSH secundário: Aflatoxinas
Aspergillus/enzimologia
Aspergillus/metabolismo
Aspergillus flavus/genética
Proteínas de Ligação a DNA/genética
Fermentação
Proteínas Fúngicas/genética
Indóis/metabolismo
Leucil Aminopeptidase/biossíntese
Leucil Aminopeptidase/química
Peptídeo Hidrolases/biossíntese
Filogenia
Policetídeo Sintases/genética
Policetídeo Sintases/metabolismo
Fatores de Transcrição/genética
alfa-Amilases/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AFLR protein, Aspergillus); 0 (Aflatoxins); 0 (DNA-Binding Proteins); 0 (Fungal Proteins); 0 (Indoles); 0 (Transcription Factors); 79956-01-7 (Polyketide Synthases); EC 3.2.1.1 (alpha-Amylases); EC 3.4.- (Peptide Hydrolases); EC 3.4.11.1 (Leucyl Aminopeptidase); X9TLY4580Z (cyclopiazonic acid)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170328
[Lr] Data última revisão:
170328
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161124
[St] Status:MEDLINE
[do] DOI:10.4014/jmb.1610.10013


  5 / 3158 MEDLINE  
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[PMID]:27922739
[Au] Autor:Ziemska J; Solecka J
[Ad] Endereço:National Institute of Public Health ­ National Institute of Hygiene, Laboratory of Biologically Active Compounds, 24 Chocimska Str., 00-791 Warsaw, Poland
[Ti] Título:Tyrosine kinase, aurora kinase and leucine aminopeptidase as attractive drug targets in anticancer therapy - characterisation of their inhibitors.
[So] Source:Rocz Panstw Zakl Hig;67(4):329-342, 2016.
[Is] ISSN:0035-7715
[Cp] País de publicação:Poland
[La] Idioma:eng
[Ab] Resumo:Cancers are the leading cause of deaths all over the world. Available anticancer agents used in clinics exhibit low therapeutic index and usually high toxicity. Wide spreading drug resistance of cancer cells induce a demanding need to search for new drug targets. Currently, many on-going studies on novel compounds with potent anticancer activity, high selectivity as well as new modes of action are conducted. In this work, we describe in details three enzyme groups, which are at present of extensive interest to medical researchers and pharmaceutical companies. These include receptor tyrosine kinases (e.g. EGFR enzymes) and non-receptor tyrosine kinases (Src enzymes), type A, B and C Aurora kinases and aminopeptidases, especially leucine aminopeptidase. We discuss classification of these enzymes, biochemistry as well as their role in the cell cycle under normal conditions and during cancerogenesis. Further on, the work describes enzyme inhibitors that are under in vitro, preclinical, clinical studies as well as drugs available on the market. Both, chemical structures of discovered inhibitors and the role of chemical moieties in novel drug design are discussed. Described enzymes play essential role in cell cycle, especially in mitosis (Aurora kinases), cell differentiation, growth and apoptosis (tyrosine kinases) as well as G1/S transition (leucine aminopeptidase). In cancer cells, they are overexpressed and only their inhibition may stop tumor progression. This review presents the clinical outcomes of selected inhibitors and argues the safety of drug usage in human volunteers. Clinical studies of EGFR and Src kinase inhibitors in different tumors clearly show the need for molecular selection of patients (to those with mutations in genes coding EGFR and Src) to achieve positive clinical response. Current data indicates the great necessity for new anticancer treatment and actions to limit off-target activity.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Aurora Quinases
Inibidores Enzimáticos/uso terapêutico
Leucil Aminopeptidase
Neoplasias/tratamento farmacológico
Proteínas Tirosina Quinases
[Mh] Termos MeSH secundário: Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); EC 2.7.10.1 (Protein-Tyrosine Kinases); EC 2.7.11.1 (Aurora Kinases); EC 3.4.11.1 (Leucyl Aminopeptidase)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170313
[Lr] Data última revisão:
170313
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161207
[St] Status:MEDLINE


  6 / 3158 MEDLINE  
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[PMID]:27697836
[Au] Autor:Textor A; Schmidt K; Kloetzel PM; Weißbrich B; Perez C; Charo J; Anders K; Sidney J; Sette A; Schumacher TN; Keller C; Busch DH; Seifert U; Blankenstein T
[Ad] Endereço:Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
[Ti] Título:Preventing tumor escape by targeting a post-proteasomal trimming independent epitope.
[So] Source:J Exp Med;213(11):2333-2348, 2016 Oct 17.
[Is] ISSN:1540-9538
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adoptive T cell therapy (ATT) can achieve regression of large tumors in mice and humans; however, tumors frequently recur. High target peptide-major histocompatibility complex-I (pMHC) affinity and T cell receptor (TCR)-pMHC affinity are thought to be critical to preventing relapse. Here, we show that targeting two epitopes of the same antigen in the same cancer cells via monospecific T cells, which have similar pMHC and pMHC-TCR affinity, results in eradication of large, established tumors when targeting the apparently subdominant but not the dominant epitope. Only the escape but not the rejection epitope required postproteasomal trimming, which was regulated by IFN-γ, allowing IFN-γ-unresponsive cancer variants to evade. The data describe a novel immune escape mechanism and better define suitable target epitopes for ATT.
[Mh] Termos MeSH primário: Epitopos de Linfócito T/imunologia
Complexo de Endopeptidases do Proteassoma/metabolismo
Evasão Tumoral/imunologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Afinidade de Anticorpos
Antígenos/imunologia
Epitopos de Linfócito T/química
Antígenos de Histocompatibilidade Classe I/imunologia
Interferon gama/metabolismo
Leucil Aminopeptidase/metabolismo
Camundongos Endogâmicos C57BL
Neoplasias/imunologia
Neoplasias/patologia
Peptídeos/imunologia
Receptores de Antígenos de Linfócitos T/imunologia
Transdução de Sinais
Linfócitos T/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens); 0 (Epitopes, T-Lymphocyte); 0 (Histocompatibility Antigens Class I); 0 (Peptides); 0 (Receptors, Antigen, T-Cell); 82115-62-6 (Interferon-gamma); EC 3.4.11.1 (Leucyl Aminopeptidase); EC 3.4.11.1 (puromycin-insensitive leucyl-specific aminopeptidase); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161005
[St] Status:MEDLINE


  7 / 3158 MEDLINE  
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[PMID]:27653442
[Au] Autor:Mann G; Huo L; Adam S; Nardone B; Vendome J; Westwood NJ; Müller R; Koehnke J
[Ad] Endereço:School of Chemistry and Biomedical Sciences Research Centre, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
[Ti] Título:Structure and Substrate Recognition of the Bottromycin Maturation Enzyme BotP.
[So] Source:Chembiochem;17(23):2286-2292, 2016 Dec 02.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The bottromycins are a family of highly modified peptide natural products, which display potent antimicrobial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. Bottromycins have recently been shown to be ribosomally synthesized and post-translationally modified peptides (RiPPs). Unique amongst RiPPs, the precursor peptide BotA contains a C-terminal "follower" sequence, rather than the canonical N-terminal "leader" sequence. We report herein the structural and biochemical characterization of BotP, a leucyl-aminopeptidase-like enzyme from the bottromycin pathway. We demonstrate that BotP is responsible for the removal of the N-terminal methionine from the precursor peptide. Determining the crystal structures of both apo BotP and BotP in complex with Mn allowed us to model a BotP/substrate complex and to rationalize substrate recognition. Our data represent the first step towards targeted compound modification to unlock the full antibiotic potential of bottro- mycin.
[Mh] Termos MeSH primário: Leucil Aminopeptidase/metabolismo
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Modelos Moleculares
Conformação Molecular
Peptídeos Cíclicos/biossíntese
Peptídeos Cíclicos/química
Peptídeos Cíclicos/metabolismo
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Peptides, Cyclic); 1393-68-6 (bottromycin); EC 3.4.11.1 (Leucyl Aminopeptidase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160923
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201600406


  8 / 3158 MEDLINE  
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[PMID]:27470355
[Au] Autor:Rout S; Mahapatra RK
[Ad] Endereço:School of Biotechnology, KIIT University, Bhubaneswar 751024, Odisha, India.
[Ti] Título:In silico screening of novel inhibitors of M17 Leucine Amino Peptidase (LAP) of Plasmodium vivax as therapeutic candidate.
[So] Source:Biomed Pharmacother;82:192-201, 2016 Aug.
[Is] ISSN:1950-6007
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:M17 LAP (Leucine Amino Peptidase) plays an important role in the hydrolysis of amino acids essential for growth and development of Plasmodium vivax (Pv), the pathogen causing malaria. In this paper a homology model of PvLAP was generated using MODELLER v9.15. From different in-silico methods such as structure based, ligand based and de novo drug designing a total of 90 compounds were selected for docking studies. A final list of 10 compounds was prepared. The study reported the identification of 2-[(3-azaniumyl-2-hydroxy-4-phenylbutanoyl) amino]-4-methylpentanoate as the best inhibitor in terms of docking score and pharmacophoric features. The reliability of the binding mode of the inhibitor is confirmed by molecular dynamics (MD) simulation study with GROMACS software for a simulation time of 20ns in water environment. Finally, in silico ADMET analysis of the inhibitors using MedChem Designer v3 evaluated the drug likeness of the best hits to be considered for industrial pharmaceutical research.
[Mh] Termos MeSH primário: Antimaláricos/farmacologia
Simulação por Computador
Avaliação Pré-Clínica de Medicamentos
Leucil Aminopeptidase/antagonistas & inibidores
Plasmodium vivax/enzimologia
Inibidores de Proteases/farmacologia
Proteínas de Protozoários/antagonistas & inibidores
[Mh] Termos MeSH secundário: Sítios de Ligação
Domínio Catalítico
Bases de Dados de Compostos Químicos
Leucil Aminopeptidase/metabolismo
Ligantes
Simulação de Acoplamento Molecular
Plasmodium vivax/efeitos dos fármacos
Proteínas de Protozoários/metabolismo
Reprodutibilidade dos Testes
Análise de Sequência de Proteína
Homologia Estrutural de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimalarials); 0 (Ligands); 0 (Protease Inhibitors); 0 (Protozoan Proteins); EC 3.4.11.1 (Leucyl Aminopeptidase)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170131
[Lr] Data última revisão:
170131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160730
[St] Status:MEDLINE


  9 / 3158 MEDLINE  
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[PMID]:27449897
[Au] Autor:Chaudhary M; Singh V; Anvikar AR; Sahi S
[Ti] Título:Screening and In Vitro Evaluation of Potential Plasmodium falciparum Leucyl Aminopeptidase Inhibitors.
[So] Source:Curr Comput Aided Drug Des;12(4):282-293, 2016.
[Is] ISSN:1875-6697
[Cp] País de publicação:United Arab Emirates
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Plasmodium falciparum leucyl aminopeptidase (PfA-M17) regulates the intracellular pool of amino acids required for the growth and development of parasites. Thus, PfA-M17 is a promising target for anti-malarial drug development. METHOD: In the present study, structure-based drug design was used to identify novel PfA-M17 inhibitors, which were subsequently validated by in vitro PfA-M17 and human LAP3 enzyme inhibition assay. A library of 3,147,882 compounds was screened using receptor-based virtual screening against the active site of PfA-M17, and three levels of accuracy were used: high-throughput virtual screening, gridbased ligand docking with energetics (Glide standard precision) and Glide extra precision. RESULTS: Seventeen screened compounds were selected and tested in the rPfA-M17 enzyme inhibition assay. Of these nine compounds were found to be effective inhibitors. To test the target activity, all nine PfA-M17 inhibitors were tested against rhLAP3, the human homolog of PfA-M17. One compound (compound 2) was found to be moderately effective against PfA-M17 (Ki = 287 µM) with limited inhibitory activity against hLAP3 (Ki of 4,464 µM). Subsequently, induced fit docking and pharmacophore modelling were used to further understand more precise ligand-protein interactions in the protein-inhibitor complexes. CONCLUSION: Among the 9 effective PfA-M17 inhibitors, 5 compounds were found effective in the P. falciparum schizont maturation inhibition (SMI) assay. A good correlation (r =0.83) was observed between the rPfA-M17 enzyme inhibition concentration and SMI assay.
[Mh] Termos MeSH primário: Antimaláricos/farmacologia
Desenho de Drogas
Leucil Aminopeptidase/antagonistas & inibidores
Malária Falciparum/tratamento farmacológico
Plasmodium falciparum/efeitos dos fármacos
Inibidores de Proteases/farmacologia
Proteínas de Protozoários/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antimaláricos/química
Antimaláricos/metabolismo
Sítios de Ligação
Ensaios de Triagem em Larga Escala
Cinética
Leucil Aminopeptidase/química
Leucil Aminopeptidase/metabolismo
Ligantes
Malária Falciparum/parasitologia
Simulação de Acoplamento Molecular
Plasmodium falciparum/enzimologia
Inibidores de Proteases/química
Inibidores de Proteases/metabolismo
Ligação Proteica
Conformação Proteica
Proteínas de Protozoários/química
Proteínas de Protozoários/metabolismo
Bibliotecas de Moléculas Pequenas
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimalarials); 0 (Ligands); 0 (Protease Inhibitors); 0 (Protozoan Proteins); 0 (Small Molecule Libraries); EC 3.4.11.1 (Leucyl Aminopeptidase)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170221
[Lr] Data última revisão:
170221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160725
[St] Status:MEDLINE


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[PMID]:27371725
[Au] Autor:Nagarajan NA; de Verteuil DA; Sriranganadane D; Yahyaoui W; Thibault P; Perreault C; Shastri N
[Ad] Endereço:Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720; and nshastri@berkeley.edu niranjana.nagarajan@icloud.com.
[Ti] Título:ERAAP Shapes the Peptidome Associated with Classical and Nonclassical MHC Class I Molecules.
[So] Source:J Immunol;197(4):1035-43, 2016 Aug 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The peptide repertoire presented by classical as well as nonclassical MHC class I (MHC I) molecules is altered in the absence of the endoplasmic reticulum aminopeptidase associated with Ag processing (ERAAP). To characterize the extent of these changes, peptides from cells lacking ERAAP were eluted from the cell surface and analyzed by high-throughput mass spectrometry. We found that most peptides found in wild-type (WT) cells were retained in the absence of ERAAP. In contrast, a subset of "ERAAP-edited" peptides was lost in WT cells, and ERAAP-deficient cells presented a unique "unedited" repertoire. A substantial fraction of MHC-associated peptides from ERAAP-deficient cells contained N-terminal extensions and had a different molecular composition than did those from WT cells. We found that the number and immunogenicity of peptides associated with nonclassical MHC I was increased in the absence of ERAAP. Conversely, only peptides presented by classical MHC I were immunogenic in ERAAP-sufficient cells. Finally, MHC I peptides were also derived from different intracellular sources in ERAAP-deficient cells.
[Mh] Termos MeSH primário: Apresentação do Antígeno/imunologia
Autoimunidade/imunologia
Antígenos de Histocompatibilidade Classe I/imunologia
Leucil Aminopeptidase/imunologia
Fragmentos de Peptídeos/imunologia
[Mh] Termos MeSH secundário: Animais
Ensaios de Triagem em Larga Escala
Leucil Aminopeptidase/metabolismo
Ativação Linfocitária/imunologia
Espectrometria de Massas
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Linfócitos T/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Histocompatibility Antigens Class I); 0 (Peptide Fragments); EC 3.4.11.1 (Leucyl Aminopeptidase); EC 3.4.11.1 (puromycin-insensitive leucyl-specific aminopeptidase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171021
[Lr] Data última revisão:
171021
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160703
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1500654



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