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Pesquisa : D08.811.913.225.437 [Categoria DeCS]
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[PMID]:29248353
[Au] Autor:Matthiesen RA; Varney ML; Xu PC; Rier AS; Wiemer DF; Holstein SA
[Ad] Endereço:Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, United States.
[Ti] Título:α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors.
[So] Source:Bioorg Med Chem;26(2):376-385, 2018 01 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Disruption of protein geranylgeranylation via inhibition of geranylgeranyl diphosphate synthase (GGDPS) represents a novel therapeutic strategy for a variety of malignancies, especially those characterized by excessive protein secretion such as multiple myeloma. Our work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. Here we present the synthesis and biological evaluation of a new series of isoprenoid triazoles modified by incorporation of a methyl group at the α-carbon. These studies reveal that incorporation of an α-methyl substituent enhances the potency of these compounds as GGDPS inhibitors, and, in the case of the homogeranyl/homoneryl series, abrogates the effects of olefin stereochemistry on inhibitory activity. The incorporation of the methyl group allowed preparation of a POM-prodrug, which displayed a 10-fold increase in cellular activity compared to the corresponding salt. These studies form the basis for future preclinical studies investigating the anti-myeloma activity of these novel α-methyl triazole bisphosphonates.
[Mh] Termos MeSH primário: Difosfonatos/farmacologia
Inibidores Enzimáticos/farmacologia
Farnesiltranstransferase/antagonistas & inibidores
Terpenos/farmacologia
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Difosfonatos/síntese química
Difosfonatos/química
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Farnesiltranstransferase/metabolismo
Seres Humanos
Metilação
Estrutura Molecular
Relação Estrutura-Atividade
Terpenos/síntese química
Terpenos/química
Triazóis/síntese química
Triazóis/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Diphosphonates); 0 (Enzyme Inhibitors); 0 (Terpenes); 0 (Triazoles); EC 2.5.1.29 (Farnesyltranstransferase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


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[PMID]:29269486
[Au] Autor:Barghetti A; Sjögren L; Floris M; Paredes EB; Wenkel S; Brodersen P
[Ad] Endereço:Department of Biology, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
[Ti] Título:Heat-shock protein 40 is the key farnesylation target in meristem size control, abscisic acid signaling, and drought resistance.
[So] Source:Genes Dev;31(22):2282-2295, 2017 11 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protein farnesylation is central to molecular cell biology. In plants, protein farnesyl transferase mutants are pleiotropic and exhibit defective meristem organization, hypersensitivity to the hormone abscisic acid, and increased drought resistance. The precise functions of protein farnesylation in plants remain incompletely understood because few relevant farnesylated targets have been identified. Here, we show that defective farnesylation of a single factor-heat-shock protein 40 (HSP40), encoded by the and genes-is sufficient to confer ABA hypersensitivity, drought resistance, late flowering, and enlarged meristems, indicating that altered function of chaperone client proteins underlies most farnesyl transferase mutant phenotypes. We also show that expression of an abiotic stress-related microRNA (miRNA) regulon controlled by the transcription factor SPL7 requires HSP40 farnesylation. Expression of a truncated SPL7 form mimicking its activated proteolysis fragment of the membrane-bound SPL7 precursor partially restores accumulation of SPL7-dependent miRNAs in farnesyl transferase mutants. These results implicate the pathway directing SPL7 activation from its membrane-bound precursor as an important target of farnesylated HSP40, consistent with our demonstration that HSP40 farnesylation facilitates its membrane association. The results also suggest that altered gene regulation via select miRNAs contributes to abiotic stress-related phenotypes of farnesyl transferase mutants.
[Mh] Termos MeSH primário: Ácido Abscísico/fisiologia
Proteínas de Arabidopsis/metabolismo
Proteínas de Choque Térmico HSP40/metabolismo
Meristema/metabolismo
[Mh] Termos MeSH secundário: Arabidopsis/anatomia & histologia
Arabidopsis/genética
Arabidopsis/crescimento & desenvolvimento
Arabidopsis/metabolismo
Proteínas de Arabidopsis/genética
Membrana Celular/metabolismo
Proteínas de Ligação a DNA/metabolismo
Secas
Farnesiltranstransferase/genética
Proteínas de Choque Térmico HSP90/genética
Meristema/anatomia & histologia
MicroRNAs/metabolismo
Mutação
Prenilação
Transdução de Sinais
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Arabidopsis Proteins); 0 (DNA-Binding Proteins); 0 (ERA1 protein, Arabidopsis); 0 (HSP40 Heat-Shock Proteins); 0 (HSP90 Heat-Shock Proteins); 0 (MicroRNAs); 0 (SPL7 protein, Arabidopsis); 0 (Transcription Factors); 72S9A8J5GW (Abscisic Acid); EC 2.5.1.29 (Farnesyltranstransferase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180202
[Lr] Data última revisão:
180202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171223
[St] Status:MEDLINE
[do] DOI:10.1101/gad.301242.117


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[PMID]:29196256
[Au] Autor:Yang D; Fang Y; Xia P; Zhang X; Liang Z
[Ad] Endereço:Key Laboratory of Plant Secondary Metabolism and Regulation of Zhejiang Province, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
[Ti] Título:Diverse responses of tanshinone biosynthesis to biotic and abiotic elicitors in hairy root cultures of Salvia miltiorrhiza and Salvia castanea Diels f. tomentosa.
[So] Source:Gene;643:61-67, 2018 Feb 15.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Salvia miltiorrhiza (S. miltiorrhiza) and Salvia castanea Diels f. tomentosa (S. castanea) are both used for treatment of cardiovascular diseases. They have the same bioactive compound tanshinones, but whose contents are hugely different. This study illustrated diverse responses of tanshinone biosynthesis to yeast extract (YE) and Ag in hairy roots of the two species. YE enhanced both the growth and tanshinone biosynthesis of two hairy roots, and contributed more to tanshinone accumulation in S. castanea than that in S. miltiorrhiza. Genes encoding 1-deoxy-d-xylulose 5-phosphate synthase (DXS2), geranylgeranyl diphosphatesynthase (GGPPS1), copalyl diphosphate synthase (CPS1), and two cytochromes P450 (CYP76AH1 and CYP76AH3) were also more responsive to YE in S. castanea than those in S. miltiorrhiza. Accumulations of dihydrotanshinone I and tanshinone I, and most biosynthetic genes in S. miltiorrhiza were more responsive to Ag than those in S. castanea. Accumulations of dihydrotanshinone I and cryptotanshinone were more responsive to YE, while tanshinone IIA accumulation was more responsive to Ag in S. miltiorrhiza. However, accumulations of other four tanshinones and related genes in S. castanea were more responsive to YE than Ag . This study provides foundations for studying diverse specialized metabolism between the related species.
[Mh] Termos MeSH primário: Diterpenos Abietanos/biossíntese
Salvia miltiorrhiza/genética
Salvia miltiorrhiza/metabolismo
[Mh] Termos MeSH secundário: Alquil e Aril Transferases/genética
Alquil e Aril Transferases/metabolismo
Sistema Enzimático do Citocromo P-450/genética
Sistema Enzimático do Citocromo P-450/metabolismo
Farnesiltranstransferase/genética
Farnesiltranstransferase/metabolismo
Regulação da Expressão Gênica de Plantas/genética
Medicina Tradicional Chinesa
Proteínas de Plantas/genética
Proteínas de Plantas/metabolismo
Raízes de Plantas/metabolismo
Salvia/genética
Prata/metabolismo
Transferases/genética
Transferases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Diterpenes, Abietane); 0 (Plant Proteins); 03UUH3J385 (tanshinone); 3M4G523W1G (Silver); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 2.- (Transferases); EC 2.2.1.- (deoxyxylulose-5-phosphate synthase); EC 2.5.- (Alkyl and Aryl Transferases); EC 2.5.1.- (ent-kaurene synthetase A); EC 2.5.1.29 (Farnesyltranstransferase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180123
[Lr] Data última revisão:
180123
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171203
[St] Status:MEDLINE


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[PMID]:28666857
[Au] Autor:Cadelis MM; Bourguet-Kondracki ML; Dubois J; Kaiser M; Brunel JM; Barker D; Copp BR
[Ad] Endereço:School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: mcad006@aucklanduni.ac.nz.
[Ti] Título:Structure-activity relationship studies on thiaplidiaquinones A and B as novel inhibitors of Plasmodium falciparum and farnesyltransferase.
[So] Source:Bioorg Med Chem;25(16):4433-4443, 2017 Aug 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Marine meroterpenoids, thiaplidiaquinones A and B and their respective non-natural dioxothiazine regioisomers have been shown to inhibit mammalian and protozoal farnesyltransferase (FTase) with the regioisomers exhibiting activity in the nanomolar range. In order to explore the structure-activity relationship (SAR) of this class of marine natural products, analogues of thiaplidiaquinones A and B and their regioisomers were synthesised, with variation in the number of isoprene units present in their side chains to afford prenyl and farnesyl analogues. The previously reported geranyl series of compounds were found to be the most potent FTase inhibitors closely followed by the novel farnesyl series. The prenyl series exhibited the most potent anti-plasmodial activity but the series was also the most cytotoxic. Overall, the farnesyl series exhibited moderate anti-plasmodial activity with one analogue, 14 also exhibiting low cytotoxicity, identifying it as a scaffold worthy of further exploration.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Antimaláricos/farmacologia
Farnesiltranstransferase/antagonistas & inibidores
Plasmodium falciparum/efeitos dos fármacos
Staphylococcus/efeitos dos fármacos
Terpenos/farmacologia
[Mh] Termos MeSH secundário: Animais
Antibacterianos/síntese química
Antibacterianos/química
Antimaláricos/síntese química
Antimaláricos/química
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Farnesiltranstransferase/metabolismo
Testes de Sensibilidade Microbiana
Estrutura Molecular
Plasmodium falciparum/enzimologia
Ratos
Staphylococcus/classificação
Relação Estrutura-Atividade
Terpenos/síntese química
Terpenos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Antimalarials); 0 (Terpenes); 0 (thiaplidiaquinone A); 0 (thiaplidiaquinone B); EC 2.5.1.29 (Farnesyltranstransferase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170702
[St] Status:MEDLINE


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[PMID]:28666734
[Au] Autor:Tanaka A; Radwan MO; Hamasaki A; Ejima A; Obata E; Koga R; Tateishi H; Okamoto Y; Fujita M; Nakao M; Umezawa K; Tamanoi F; Otsuka M
[Ad] Endereço:Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
[Ti] Título:A novel inhibitor of farnesyltransferase with a zinc site recognition moiety and a farnesyl group.
[So] Source:Bioorg Med Chem Lett;27(16):3862-3866, 2017 08 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protein prenylation such as farnesylation and geranylgeranylation is associated with various diseases. Thus, many inhibitors of prenyltransferase have been developed. We report novel inhibitors of farnesyltransferase with a zinc-site recognition moiety and a farnesyl/dodecyl group. Molecular docking analysis showed that both parts of the inhibitor fit well into the catalytic domain of farnesyltransferase. The synthesized inhibitors showed activity against farnesyltransferase in vitro and inhibited proliferation of the pancreatic cell line AsPC-1. Among the compounds with farnesyl and dodecyl groups, the inhibitor with a farnesyl group was found to have stronger and more selective activity.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Farnesiltranstransferase/antagonistas & inibidores
Compostos Organometálicos/farmacologia
Zinco/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Farnesiltranstransferase/metabolismo
Seres Humanos
Simulação de Acoplamento Molecular
Estrutura Molecular
Compostos Organometálicos/síntese química
Compostos Organometálicos/química
Relação Estrutura-Atividade
Zinco/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Organometallic Compounds); EC 2.5.1.29 (Farnesyltranstransferase); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170702
[St] Status:MEDLINE


  6 / 1415 MEDLINE  
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[PMID]:28630045
[Au] Autor:Shimizu H; Toma-Fukai S; Saijo S; Shimizu N; Kontani K; Katada T; Shimizu T
[Ad] Endereço:From the Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
[Ti] Título:Structure-based analysis of the guanine nucleotide exchange factor SmgGDS reveals armadillo-repeat motifs and key regions for activity and GTPase binding.
[So] Source:J Biol Chem;292(32):13441-13448, 2017 Aug 11.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Small GTPases are molecular switches that have critical biological roles and are controlled by GTPase-activating proteins and guanine nucleotide exchange factors (GEFs). The smg GDP dissociation stimulator (SmgGDS) protein functions as a GEF for the RhoA and RhoC small GTPases. SmgGDS has various regulatory roles, including small GTPase trafficking and localization and as a molecular chaperone, and interacts with many small GTPases possessing polybasic regions. Two SmgGDS splice variants, SmgGDS-558 and SmgGDS-607, differ in GEF activity and binding affinity for RhoA depending on the lipidation state, but the reasons for these differences are unclear. Here we determined the crystal structure of SmgGDS-558, revealing a fold containing tandem copies of armadillo repeats not present in other GEFs. We also observed that SmgGDS harbors distinct positively and negatively charged regions, both of which play critical roles in binding to RhoA and GEF activity. This is the first report demonstrating a relationship between the molecular function and atomic structure of SmgGDS. Our findings indicate that the two SmgGDS isoforms differ in GTPase binding and GEF activity, depending on the lipidation state, thus providing useful information about the cellular functions of SmgGDS in cells.
[Mh] Termos MeSH primário: Fatores de Troca do Nucleotídeo Guanina/metabolismo
Modelos Moleculares
Prenilação de Proteína
Proteína rhoA de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Substituição de Aminoácidos
Sítios de Ligação
Farnesiltranstransferase/genética
Farnesiltranstransferase/metabolismo
Fatores de Troca do Nucleotídeo Guanina/química
Fatores de Troca do Nucleotídeo Guanina/genética
Seres Humanos
Cinética
Simulação de Acoplamento Molecular
Mutagênese Sítio-Dirigida
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Mutação Puntual
Isoformas de Proteínas/química
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Multimerização Proteica
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Sequências Repetitivas de Aminoácidos
Solubilidade
Ressonância de Plasmônio de Superfície
Proteína rhoA de Ligação ao GTP/química
Proteína rhoA de Ligação ao GTP/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Guanine Nucleotide Exchange Factors); 0 (Peptide Fragments); 0 (Protein Isoforms); 0 (RAP1GDS1 protein, human); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 124671-05-2 (RHOA protein, human); EC 2.5.1.29 (Farnesyltranstransferase); EC 3.6.5.2 (rhoA GTP-Binding Protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.792556


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[PMID]:28556912
[Au] Autor:Li W; Tu J; Liu X; Yang W
[Ad] Endereço:Wuhan Institute of Biological Products Co. Ltd, Wuhan, Hubei Province, China.
[Ti] Título:Farnesyltransferase inhibitor FTI-277 inhibits PD-L1 expression on septic spleen lymphocytes and promotes spleen lymphocyte activation.
[So] Source:Clin Exp Immunol;190(1):8-18, 2017 Oct.
[Is] ISSN:1365-2249
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Farnesyltransferase inhibitors have been tested in clinical trials for the treatment of tumours. In sepsis, the binding of programmed death 1 (PD-1) to programmed death ligand 1 (PD-L1) promotes lymphocyte apoptosis and decreases cytokine expression, thus affecting survival rates. The PD-1/PD-L1 pathway plays an important role in chronic viral infection, bacterial infection and sepsis. However, the precise immunosuppressive and anti-inflammatory functions of this pathway remain poorly understood. In our previous study, the induction of sepsis by caecal ligation and puncture (CLP) resulted in increased farnesyltransferase activity and farnesylated protein levels in the spleen relative to sham treatment. However, the effect of inhibition of farnesyltransferase activity on overall survival rates in patients with sepsis and the specific signalling pathway involved remain to be investigated. In this study, mice with CLP-induced sepsis were treated with farnesyltransferase inhibitor (FTI-277), and PD-L1 expression on septic spleen lymphocytes was examined. Flow cytometric analysis revealed that PD-L1 is expressed constitutively on lymphocytes and that PD-L1 protein expression was up-regulated strongly following CLP. FTI-277 down-regulated PD-L1 mRNA and protein expression on septic spleen lymphocytes in a dose-dependent manner. This effect was associated closely with nuclear factor kappa B (NF-κB). In addition, the significant damping effect of FTI-277 on the PD-L1 signal promoted interferon (IFN)-γ secretion, interleukin (IL)-2 production and splenocyte proliferation in response to anti-CD3 CD28 antibodies in mice. Furthermore, FTI-277 reduced spleen lymphocyte apoptosis in septic mice. Therefore, FTI-277 regulates spleen lymphocyte activity via the PD-L1 signalling pathway, with significant anti-inflammatory effects attributable to suppression of the NF-κB pathway. Farnesyltransferase represents a valuable therapeutic target for the treatment of sepsis.
[Mh] Termos MeSH primário: Ativação Linfocitária/efeitos dos fármacos
Linfócitos/imunologia
Metionina/análogos & derivados
Sepse/tratamento farmacológico
Baço/imunologia
[Mh] Termos MeSH secundário: Animais
Antígeno B7-H1/genética
Antígeno B7-H1/metabolismo
Ceco/cirurgia
Células Cultivadas
Modelos Animais de Doenças
Farnesiltranstransferase/antagonistas & inibidores
Seres Humanos
Masculino
Metionina/farmacologia
Metionina/uso terapêutico
Camundongos
Camundongos Endogâmicos C57BL
NF-kappa B/metabolismo
Receptor de Morte Celular Programada 1/metabolismo
Sepse/imunologia
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (FTI 277); 0 (NF-kappa B); 0 (Programmed Cell Death 1 Receptor); AE28F7PNPL (Methionine); EC 2.5.1.29 (Farnesyltranstransferase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170531
[St] Status:MEDLINE
[do] DOI:10.1111/cei.12995


  8 / 1415 MEDLINE  
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[PMID]:28419130
[Au] Autor:Ogata T; Nagatoshi Y; Yamagishi N; Yoshikawa N; Fujita Y
[Ad] Endereço:Biological Resources and Post-Harvest Division, Japan International Research Center for Agricultural Sciences (JIRCAS), Tsukuba, Ibaraki, Japan.
[Ti] Título:Virus-induced down-regulation of GmERA1A and GmERA1B genes enhances the stomatal response to abscisic acid and drought resistance in soybean.
[So] Source:PLoS One;12(4):e0175650, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Drought is a major threat to global soybean production. The limited transformation potential and polyploid nature of soybean have hindered functional analysis of soybean genes. Previous research has implicated farnesylation in the plant's response to abscisic acid (ABA) and drought tolerance. We therefore used virus-induced gene silencing (VIGS) to evaluate farnesyltransferase genes, GmERA1A and GmERA1B (Glycine max Enhanced Response to ABA1-A and -B), as potential targets for increasing drought resistance in soybean. Apple latent spherical virus (ALSV)-mediated GmERA1-down-regulated soybean leaves displayed an enhanced stomatal response to ABA and reduced water loss and wilting under dehydration conditions, suggesting that GmERA1A and GmERA1B negatively regulate ABA signaling in soybean guard cells. The findings provide evidence that the ALSV-VIGS system, which bypasses the need to generate transgenic plants, is a useful tool for analyzing gene function using only a single down-regulated leaf. Thus, the ALSV-VIGS system could constitute part of a next-generation molecular breeding pipeline to accelerate drought resistance breeding in soybean.
[Mh] Termos MeSH primário: Ácido Abscísico/farmacologia
Secas
Proteínas de Plantas/genética
Estômatos de Plantas/efeitos dos fármacos
Feijão de Soja/genética
[Mh] Termos MeSH secundário: Adaptação Fisiológica/genética
Sequência de Aminoácidos
Sequência de Bases
Regulação para Baixo/efeitos dos fármacos
Farnesiltranstransferase/genética
Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos
Regulação da Expressão Gênica de Plantas/efeitos dos fármacos
Inativação Gênica
Isoenzimas/genética
Malus/virologia
Reguladores de Crescimento de Planta/farmacologia
Folhas de Planta/enzimologia
Folhas de Planta/genética
Folhas de Planta/crescimento & desenvolvimento
Estômatos de Plantas/genética
Estômatos de Plantas/fisiologia
Vírus de Plantas/genética
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Homologia de Sequência de Aminoácidos
Homologia de Sequência do Ácido Nucleico
Feijão de Soja/enzimologia
Feijão de Soja/crescimento & desenvolvimento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Isoenzymes); 0 (Plant Growth Regulators); 0 (Plant Proteins); 72S9A8J5GW (Abscisic Acid); EC 2.5.1.29 (Farnesyltranstransferase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170522
[Lr] Data última revisão:
170522
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0175650


  9 / 1415 MEDLINE  
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[PMID]:28395021
[Au] Autor:Duluc L; Ahmetaj-Shala B; Mitchell J; Abdul-Salam VB; Mahomed AS; Aldabbous L; Oliver E; Iannone L; Dubois OD; Storck EM; Tate EW; Zhao L; Wilkins MR; Wojciak-Stothard B
[Ad] Endereço:Department of Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, W120NN London, UK.
[Ti] Título:Tipifarnib prevents development of hypoxia-induced pulmonary hypertension.
[So] Source:Cardiovasc Res;113(3):276-287, 2017 Mar 01.
[Is] ISSN:1755-3245
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Aims: RhoB plays a key role in the pathogenesis of hypoxia-induced pulmonary hypertension. Farnesylated RhoB promotes growth responses in cancer cells and we investigated whether inhibition of protein farnesylation will have a protective effect. Methods and results: The analysis of lung tissues from rodent models and pulmonary hypertensive patients showed increased levels of protein farnesylation. Oral farnesyltransferase inhibitor tipifarnib prevented development of hypoxia-induced pulmonary hypertension in mice. Tipifarnib reduced hypoxia-induced vascular cell proliferation, increased endothelium-dependent vasodilatation and reduced vasoconstriction of intrapulmonary arteries without affecting cell viability. Protective effects of tipifarnib were associated with inhibition of Ras and RhoB, actin depolymerization and increased eNOS expression in vitro and in vivo. Farnesylated-only RhoB (F-RhoB) increased proliferative responses in cultured pulmonary vascular cells, mimicking the effects of hypoxia, while both geranylgeranylated-only RhoB (GG-RhoB), and tipifarnib had an inhibitory effect. Label-free proteomics linked F-RhoB with cell survival, activation of cell cycle and mitochondrial biogenesis. Hypoxia increased and tipifarnib reduced the levels of F-RhoB-regulated proteins in the lung, reinforcing the importance of RhoB as a signalling mediator. Unlike simvastatin, tipifarnib did not increase the expression levels of Rho proteins. Conclusions: Our study demonstrates the importance of protein farnesylation in pulmonary vascular remodelling and provides a rationale for selective targeting of this pathway in pulmonary hypertension.
[Mh] Termos MeSH primário: Anti-Hipertensivos/farmacologia
Inibidores Enzimáticos/farmacologia
Farnesiltranstransferase/antagonistas & inibidores
Hipertensão Pulmonar/prevenção & controle
Hipóxia/tratamento farmacológico
Artéria Pulmonar/efeitos dos fármacos
Quinolonas/farmacologia
[Mh] Termos MeSH secundário: Animais
Proliferação Celular/efeitos dos fármacos
Células Cultivadas
Modelos Animais de Doenças
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/enzimologia
Células Endoteliais/patologia
Farnesiltranstransferase/metabolismo
Seres Humanos
Hipertensão Pulmonar/enzimologia
Hipertensão Pulmonar/etiologia
Hipóxia/complicações
Hipóxia/enzimologia
Masculino
Camundongos Endogâmicos C57BL
Fenótipo
Prenilação de Proteína
Proteômica/métodos
Artéria Pulmonar/enzimologia
Artéria Pulmonar/patologia
Artéria Pulmonar/fisiopatologia
Fatores de Tempo
Transfecção
Vasoconstrição/efeitos dos fármacos
Vasodilatação/efeitos dos fármacos
Proteína rhoB de Ligação ao GTP/genética
Proteína rhoB de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antihypertensive Agents); 0 (Enzyme Inhibitors); 0 (Quinolones); EC 2.5.1.29 (Farnesyltranstransferase); EC 3.6.5.2 (rhoB GTP-Binding Protein); MAT637500A (tipifarnib)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170411
[St] Status:MEDLINE
[do] DOI:10.1093/cvr/cvw258


  10 / 1415 MEDLINE  
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[PMID]:28302510
[Au] Autor:Wills VS; Metzger JI; Allen C; Varney ML; Wiemer DF; Holstein SA
[Ad] Endereço:Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA.
[Ti] Título:Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase.
[So] Source:Bioorg Med Chem;25(8):2437-2444, 2017 Apr 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protein geranylgeranylation reactions are dependent on the availability of geranylgeranyl diphosphate (GGDP), which serves as the isoprenoid donor. Inhibition of GGDP synthase (GGDPS) is of interest from a drug development perspective as GGDPS inhibition results in impaired protein geranylgeranylation, which in multiple myeloma, disrupts monoclonal protein trafficking and induces apoptosis. We have recently reported a series of isoprenoid triazole bisphosphonates and have demonstrated that a 3:1 mixture of homogeranyl and homoneryl isomers potently, and in a synergistic manner, inhibits GGDPS. We now present the synthesis and biological evaluation of a novel series of bishomoisoprenoid triazoles which furthers our understanding of the structure-function relationship of this class. These studies demonstrate the importance of chain length and olefin stereochemistry on inhibitory activity.
[Mh] Termos MeSH primário: Difosfonatos/farmacologia
Inibidores Enzimáticos/farmacologia
Farnesiltranstransferase/antagonistas & inibidores
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Animais
Difosfonatos/química
Inibidores Enzimáticos/química
Seres Humanos
Relação Estrutura-Atividade
Triazóis/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Diphosphonates); 0 (Enzyme Inhibitors); 0 (Triazoles); EC 2.5.1.29 (Farnesyltranstransferase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE



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