Enzymatic synthesis of a selective inhibitor for α-glucosidases:: α-Acarviosinyl-(1→9)-3-α-D-glucopyranosylpropen
Enzymatic synthesis of a selective inhibitor for α-glucosidases:: α-Acarviosinyl-(1→9)-3-α-D-glucopyranosylpropen
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DOI：
10.1021/jf703655k
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发表时间：
2008-07-09
影响因子：
6.1
通讯作者：
Park, Kwan-Hwa
中科院分区：
文献类型：
--
作者：
Lee, Young-Su;Lee, Myoung-Het;Park, Kwan-Hwa
在这里，我们描述了新的抑制剂的酶促合成使用阿卡维辛-葡萄糖，作为供体和3-α-D-吡喃葡萄糖基丙烯（α GP）作为受体。来自栖热菌属的麦芽糖淀粉酶（ThMA）催化阿卡维苷部分转糖基化为α GP。使用色谱法分离两种主要反应产物。结构分析显示，阿卡维苷被转移到α GP的C-7或C-9，其对应于葡萄糖的C-4和C-6。两者都竞争性抑制大鼠肠β-葡萄糖苷酶，但对人胰腺α-淀粉酶表现出混合型抑制模式。α-阿卡维糖基-（1 -> 7）-3-α-D-吡喃葡萄糖基丙烯显示出比阿卡波糖对两种α-糖苷酶更弱的抑制效力。相比之下，α-阿卡波糖基-（1 -> 9）-3-α-D-吡喃葡萄糖基丙烯相对于阿卡波糖表现出对大鼠肠α-葡糖苷酶的3.0倍改善的抑制效力，对人胰腺α-淀粉酶的0.3倍抑制效力。总之，α-阿卡维辛基-（1 -> 9）-3-α-D-吡喃葡萄糖基丙烯是一种新的α-葡萄糖苷酶选择性抑制剂，相对于阿卡波糖，其对α-葡萄糖苷酶的选择性比对α-淀粉酶的选择性高10倍，并且其可以用作有效的降血糖剂。
Here, we describe the enzymatic synthesis of novel inhibitors using acarviosine-glucose, as a donor and 3-alpha-D-glucopyranosylpropen (alpha GP) as an acceptor. Maltogenic amylase from Thermus sp. (ThMA) catalyzed the transglycosylation of the acarviosine moiety to alpha GP. The two major reaction products were isolated using chromatographies. Structural analyses revealed that acarviosine was transferred to either C-7 or C-9 of the alpha GP, which correspond to C-4 and C-6 of glucose. Both inhibited rat intestine (x-glucosidase competitively but displayed a mixed-type inhibition mode against human pancreatic alpha-amylase. The alpha-acarviosinyl-(1 -> 7)-3-alpha-D-glucopyranosylpropen showed weaker inhibition potency than acarbose against both alpha-glycosidases. In contrast, the alpha-acarviosinyl-(1 -> 9)-3-alpha-D-glucopyranosylpropen exhibited a 3.0-fold improved inhibition potency against rat intestine a-glucosidase with 0.3-fold inhibition potency against human pancreatic a-amylase relative to acarbose. In conclusion, alpha-acarviosinyl-(1 -> 9)-3-alpha-D-glucopyranosylpropen is a novel alpha-glucosidase-selective inhibitor with 10-fold enhanced selectivity toward alpha-glucosidase over alpha-amylase relative to acarbose, and it could be applied as a potent hypoglycemic agent.