RESUMO
Human UDP-glucuronosyltransferases (UGTs) play a pivotal role in phase II metabolism by catalyzing the glucuronidation of endobiotics and xenobiotics. The catalytic activities of UGTs are highly impacted by both genetic polymorphisms and oligomerization. The present study aimed to assess the inter-isoform hetero-dimerization of UGT1A1, 1A9, and 2B7, including the wild type (1A1*1, 1A9*1, and 2B7*1) and the naturally occurring (1A1*1b, 1A9*2/*3/*5, and 2B7*71S/*2/*5) variants. The related enzymes were double expressed in Bac-to-Bac systems. The fluorescence resonance energy transfer (FRET) technique and co-immunoprecipitation (Co-IP) revealed stable hetero-dimerization of UGT1A1, 1A9, and 2B7 allozymes. Variable FRET efficiencies and donor-acceptor distances suggested that genetic polymorphisms resulted in altered affinities to the target protein. In addition, the metabolic activities of UGTs were differentially altered upon hetero-dimerization via double expression systems. Moreover, protein interactions also changed the regioselectivity of UGT1A9 for querectin glucuronidation. These findings provide in-depth understanding of human UGT dimerization as well as clues for complicated UGT dependent metabolism in humans.
Assuntos
Glucuronosiltransferase/química , Multimerização Proteica , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , UDP-Glucuronosiltransferase 1ARESUMO
A new indole alkaloidal glucoside together with three known compounds aurantiamide acetate (2), eleutheroside E (3) and 1-O-caffeoyl-ß-D-glucopyranoside (4) has been isolated from ethanol extract of the aerial parts of Clematis terniflora DC. On the basis of their spectroscopic and chemical evidence, the new compound was elucidated as (6-O-ß-D-glucopyranosyl-1H-indol-3-yl) carboxylic acid methyl ester (1). Compounds 1 and 3 showed significant cytotoxicity against human ECA-109.
Assuntos
Clematis/química , Glucosídeos/química , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Componentes Aéreos da Planta/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glucosídeos/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Two new compounds with five known compounds have been isolated from EtOH extract of the seeds of Nigella glandulifera. On the basis of their spectroscopic and chemical evidence, the new compounds were elucidated as methoxynigeglanine (1) and 6-methoxythymol-3-O-ß-D-glucopyranoside (4). Compounds 1-4 showed moderate antitubercular activity against Mycobacterium tuberculosis strain H37Rv with minimal inhibitory concentration (MIC) values of 32-250 µg/mL.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Nigella/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Antituberculosos/isolamento & purificação , Glucosídeos/química , Glucosídeos/isolamento & purificação , Glucosídeos/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Extratos Vegetais/isolamento & purificação , Sementes/química , Tuberculose/tratamento farmacológicoRESUMO
Five series totalling 51 of sinapyl alcohol derivatives were designed and synthesized. Their cytotoxicity analyses were performed on six human tumor cell lines such as PC-3, CNE, KB, A549, BEL-7404, and HeLa. Certain sinapyl alcohol derivatives showed significant cytotoxic activities. Compound 14d exhibited especially potent cytotoxicity against the BEL-7404 cell line with an IC50 value of 0.7 microM, which showed more cytotoxic activity than the positive control, cisplatin. The structure-cytotoxicity relationships were discussed and the CoMFA analysis was performed using the cytotoxic data against HeLa cells as a template.