RESUMEN
Most opioid analgesics used clinically, including morphine and fentanyl, as well as the recreational drug heroin, act primarily through the mu opioid receptor, a class A Rhodopsin-like G protein-coupled receptor (GPCR). The single-copy mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, creating multiple splice variants or isoforms via a variety of alternative splicing events. These OPRM1 splice variants can be categorized into three major types based on the receptor structure: (1) full-length 7 transmembrane (TM) C-terminal variants; (2) truncated 6TM variants; and (3) single TM variants. Increasing evidence suggests that these OPRM1 splice variants are pharmacologically important in mediating the distinct actions of various mu opioids. More importantly, the OPRM1 variants can be targeted for development of novel opioid analgesics that are potent against multiple types of pain, but devoid of many side-effects associated with traditional opiates. In this review, we provide an overview of OPRM1 alternative splicing and its functional relevance in opioid pharmacology.
Asunto(s)
Empalme Alternativo/genética , Dolor/genética , Precursores del ARN/genética , Receptores Opioides mu/genética , Analgésicos Opioides/química , Analgésicos Opioides/uso terapéutico , Humanos , Morfina/química , Morfina/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/patología , Isoformas de Proteínas/genética , Empalme del ARN/genéticaRESUMEN
Miharamycins are peptidyl nucleoside antibiotics with a unique branched C9 pyranosyl amino acid core and a rare 2-aminopurine moiety. Inactivation of 19 genes in the biosynthetic gene cluster and identification of several unexpected intermediates suggest an alternative biosynthetic pathway, which is further supported by feeding experiments and in vitro characterization of an unusual adenylation domain recognizing a complex nucleoside derivative as the substrate. These results thereby provide an unprecedented biosynthetic route of high-carbon sugar catalyzed by atypical hybrid nonribosomal peptide synthetase-polyketide synthase.
Asunto(s)
Proteínas Bacterianas/metabolismo , Nucleósidos/metabolismo , Péptido Sintasas/metabolismo , Sintasas Poliquetidas/metabolismo , Streptomyces/metabolismo , Azúcares/metabolismo , Proteínas Bacterianas/genética , Vías Biosintéticas , Familia de Multigenes , Nucleósidos/genética , Péptido Sintasas/genética , Sintasas Poliquetidas/genética , Streptomyces/genéticaRESUMEN
Feeding studies indicate a possible synthetic pattern for the N-terminal cis-aminocyclopentane carboxylic acid (ACPC) and suggest an unusual source of the high-carbon sugar skeleton of amipurimycin (APM). The biosynthetic gene cluster of APM was identified and confirmed by in vivo experiments. A C9 core intermediate was discovered from null mutants of ACPC pathway, and an ATP-grasp enzyme (ApmA8) was reconstituted in vitro for ACPC loading. Our observations allow a first proposal of the APM biosynthetic pathway.
Asunto(s)
Antibacterianos/biosíntesis , Familia de Multigenes , Nucleósidos/biosíntesis , Purinas/biosíntesis , Azúcares/química , Adenosina Trifosfato/metabolismo , Antibacterianos/química , Vías Biosintéticas/genética , Cicloleucina/química , Enzimas/genética , Enzimas/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Mutación , Nucleósidos/química , Purinas/química , Streptomyces/genética , Streptomyces/metabolismoRESUMEN
Investigation of the roots of Flemingia philippinensis resulted in the isolation of two new chalcones, flemiphilippinones B (1) and C (2), and one new pterocarpoid, demethylwedelolactone-11-methyl ether (3), together with 12 known compounds (4-15). The antiproliferative activity against PC-3 cells was evaluated and most compounds showed cytotoxicity, among which, compound 2 exhibited GI50 value of 14.12µM. The antiproliferative activity of 2 against Bel-7402 and CaEs-17 cells was also measured, with GI50 values of 1.91 and 2.58µM, respectively. Intensive mechanism study showed that 2 caused cell-cycle arrest at S/G2 phase and induced apoptosis in Bel-7402 cells through mitochondria-related pathway.