Domain architecture of pyruvate carboxylase, a biotin-dependent multifunctional enzyme
Domain architecture of pyruvate carboxylase, a biotin-dependent multifunctional enzyme
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DOI：
10.1126/science.1144504
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发表时间：
2007-08-24
期刊：
影响因子：
56.9
通讯作者：
Rayment, Ivan
中科院分区：
文献类型：
--
作者：
St Maurice, Martin;Reinhardt, Laurie;Rayment, Ivan
生物素依赖的多功能酶进行代谢上重要的羧基转移反应，是治疗肥胖和2型糖尿病的潜在靶点。这些酶使用系留的生物素辅因子在相距较远的活性部位之间携带活化的羧基。这种转移的机制仍然知之甚少。在这里，我们报道了丙酮酸羧基酶在2.0埃分辨率下的完整结构，这表明了它的结构域排列。当结合突变分析时，该结构表明中间转移发生在不同多肽链上的活性部位之间。此外，与激活子结合相关的结构域重排减少了活性位点对之间的距离，为变构激活提供了一种机制。这一描述提供了对生物素依赖酶功能的洞察，并为多功能酶催化提供了一种新的范例。
Biotin-dependent multifunctional enzymes carry out metabolically important carboxyl group transfer reactions and are potential targets for the treatment of obesity and type 2 diabetes. These enzymes use a tethered biotin cofactor to carry an activated carboxyl group between distantly spaced active sites. The mechanism of this transfer has remained poorly understood. Here we report the complete structure of pyruvate carboxylase at 2.0 angstroms resolution, which shows its domain arrangement. The structure, when combined with mutagenic analysis, shows that intermediate transfer occurs between active sites on separate polypeptide chains. In addition, domain rearrangements associated with activator binding decrease the distance between active-site pairs, providing a mechanism for allosteric activation. This description provides insight into the function of biotin-dependent enzymes and presents a new paradigm for multifunctional enzyme catalysis.