A molecular switch and proton wire synchronize the active sites in thiamine enzymes
A molecular switch and proton wire synchronize the active sites in thiamine enzymes
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DOI：
10.1126/science.1101030
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发表时间：
2004-10-29
期刊：
影响因子：
56.9
通讯作者：
Perham, RN
中科院分区：
文献类型：
--
作者：
Frank, RAW;Titman, CM;Perham, RN
硫胺素二磷酸(ThDP)是许多关键代谢酶的辅因子。我们提供的证据表明，丙酮酸脱氢酶复合体E1(EC 1.2.4.1)的两个活性位点上的ThDP通过可逆地将质子穿梭在蛋白质中的酸性隧道中而进行20埃的通信。这种“质子线”允许辅因子在催化中作为普通的酸/碱相互作用，并改变关键活性部位肽环的构象。这同步了化学事件的进展，并可以解释E1和其他硫胺素依赖酶的寡聚组织、构象不对称性和“乒乓球”动力学特性。
Thiamine diphosphate (ThDP) is used as a cofactor in many key metabolic enzymes. We present evidence that the ThDPs in the two active sites of the E1 (EC 1.2.4.1) component of the pyruvate dehydrogenase complex communicate over a distance of 20 angstroms by reversibly shuttling a proton through an acidic tunnel in the protein. This "proton wire" permits the cofactors to serve reciprocally as general acid/base in catalysis and to switch the conformation of crucial active-site peptide loops. This synchronizes the progression of chemical events and can account for the oligomeric organization, conformational asymmetry, and "ping-pong" kinetic properties of E1 and other thiamine-dependent enzymes.