葡萄糖醛酸化
中文名称
通路描述
葡萄糖醛酸化结合利用 UDP-葡萄糖醛酸转移酶（UGTs；EC 2.4.1.17）催化广泛多样的内源性和外源性化合物。葡萄糖醛酸化是相 II 代谢的主要途径，约占药物结合量的 35%。UGTs 是微膜膜结合的，催化将尿苷二磷酸葡萄糖醛酸（UDPGA，共底物）中的葡萄糖醛酸基团转移至特定底物的功能基团。UDPGA 由葡萄糖 -1-磷酸（G1P）合成。G1P 是糖酵解所需的，细胞中浓度很高，因此不太可能是 UDPGA 合成的限制因素。UDP 与 G1P 结合形成 UDP-葡萄糖，然后脱氢形成 UDPGA。基本反应为UDP-葡萄糖醛酸 + 受体 = UDP + 受体-β-D-葡萄糖醛酸。这种结合的效果是给底物赋予极性，使其易于通过尿液或胆汁排泄。受作用的基团包括羟基、羧酸根、氨基和硫酸基团。UGTs 有 2 个家族，UGT1 和 UGT2，进一步分为 3 个子家族，UGT1A、UGT2A 和 UGT2B。人类中有 26 种不同的同工酶，其中 18 种是功能性蛋白质。它们由 527-530 个残基组成，分子量 50-57KDa。UGT1 家族包含 9 种蛋白质（UGT1A1、1A3-1A10），但只有 5 种在人类中分离。UGT1A6 的底物乙酰苯胺，UGT1A1 的底物胆红素。UGT2 亚家族的成员由各自的基因编码，而 UGT1A 由 UGT1 位点编码。底物例子是 UGT2B7 的 Morphine 结合和 UGT2B17 的雄激素结合。与葡萄糖醛酸结合的异源性化合物可以是β-葡萄糖醛酸酶的底物，这是一种在肠道微生物中常见的酶。该酶可以释放母体或相 I 代谢物，可被重吸收。它可以再次发挥其原始作用或再次与葡萄糖醛酸结合。这种循环称为肠肝循环，可以延迟异源性化合物的消除。
英文描述
Glucuronidation Glucuronidation conjugation utilizes UDP-glucuronosyltransferases (UGTs; EC 2.4.1.17) to catalyze a wide range of diverse endogenous and xenobiotic compounds. Glucuronidation is the major pathway in phase II metabolism and accounts for approximately 35% of drug conjugation. UGTs are microsomal membrane-bound and catalyze the transfer of a glucuronate group of uridine diphosphoglucuronate (UDPGA, a co-substrate) to the functional group of specific substrates. UDPGA is synthesized from glucose-1-phosphate (G1P). G1P is required for glycolysis and is present in high concentrations in the cell, making it is unlikely to be a limiting factor in UDPGA synthesis. UDP is added to G1P to form UDP-glucose which is then dehydrogenated to form UDPGA. The basic reaction isUDP-Glucuronate + acceptor -> UDP + acceptor-beta-D-glucuronideThe effect of this conjugation is to confer polarity to the substrate which can then be easily excreted in urine or bile. Functional groups acted on include hydroxyl, carboxylate, amino and sulfate groups. There are 2 families of UGTs, UGT1 and UGT2 which are further sub-divided into 3 subfamilies, UGT1A, UGT2A and UGT2B. There are more than 26 different isozymes in humans, of which 18 are functional proteins. They are composed of 527-530 residues and have a molecular weight of 50-57KDa.
The UGT1 family comprises of 9 proteins (UGT1A1, 1A3-1A10) but only 5 have been isolated in humans. Example substrates which are glucuronidated are acetaminophen by UGT1A6 and bilirubin by UGT1A1. Members of the UGT2 subfamily are each encoded by their own genes, in contrast to UGT1As which are encoded at the UGT1 locus. Example substrates are morphine conjugation by UGT2B7 and androgenic steroid conjugation by UGT2B17.
Xenobiotics conjugated with glucuronic acid can be substrates for beta-glucuronidase, an enzyme common in gut microflora. This enzyme can release the parent or phase I metabolite which can be reabsorbed. It can then either re-exert it's original effects or be conjugated by glucuronic acid again. This cycle is called enterohepatic circulation and can delay the elimination of the xenobiotic.
The UGT1 family comprises of 9 proteins (UGT1A1, 1A3-1A10) but only 5 have been isolated in humans. Example substrates which are glucuronidated are acetaminophen by UGT1A6 and bilirubin by UGT1A1. Members of the UGT2 subfamily are each encoded by their own genes, in contrast to UGT1As which are encoded at the UGT1 locus. Example substrates are morphine conjugation by UGT2B7 and androgenic steroid conjugation by UGT2B17.
Xenobiotics conjugated with glucuronic acid can be substrates for beta-glucuronidase, an enzyme common in gut microflora. This enzyme can release the parent or phase I metabolite which can be reabsorbed. It can then either re-exert it's original effects or be conjugated by glucuronic acid again. This cycle is called enterohepatic circulation and can delay the elimination of the xenobiotic.
所含基因
22 个基因