The crucial step in ether phospholipild biosynthesis: Structural basis of a noncanonical reaction associated with a peroxisornal disorder
The crucial step in ether phospholipild biosynthesis: Structural basis of a noncanonical reaction associated with a peroxisornal disorder
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DOI：
10.1016/j.str.2007.04.009
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发表时间：
2007-06-01
期刊：
影响因子：
5.7
通讯作者：
Mattevi, Andrea
中科院分区：
文献类型：
--
作者：
Razeto, Adelia;Mattiroli, Francesca;Mattevi, Andrea
醚磷脂是真核细胞膜的重要组成部分。点状肢根性软骨发育不良3型是一种严重的过氧化物酶体疾病，由先天性烷基二羟丙酮磷酸合成酶（ADPS）缺陷引起。该酶进行醚磷脂生物合成中最具特征的步骤：形成醚键。来自盘基网柄藻的ADPS的晶体结构显示了一个脂肪醇分子结合在一个狭窄的疏水通道中，对16个碳的脂肪链具有特异性。进入隧道是由蛋白质-膜界面处的柔性环和门控螺旋控制的。结构和诱变研究确定了一组亲水性催化残基，包括一个必需的酪氨酸，可能参与底物质子提取，和精氨酸，是突变的ADP缺陷型患者。我们建议，醚键的形成可能是通过与黄素的共价亚胺中间体，占非典型就业的黄素辅因子在nonredox反应精心策划的。
Ether phospholipids are essential constituents of eukaryotic cell membranes. Rhizomelic chondrodysplasia punctata type 3 is a severe peroxisomal disorder caused by inborn deficiency of alkyldihydroxyacetonephosphate synthase (ADPS). The enzyme carries out the most characteristic step in ether phospholipid biosynthesis: formation of the ether bond. The crystal structure of ADPS from Dictyostelium discoideum shows a fatty-alcohol molecule bound in a narrow hydrophobic tunnel, specific for aliphatic chains of 16 carbons. Access to the tunnel is controlled by a flexible loop and a gating helix at the protein-membrane interface. Structural and mutagenesis investigations identify a cluster of hydrophilic catalytic residues, including an essential tyrosine, possibly involved in substrate proton abstraction, and the arginine that is mutated in ADPS-deficient patients. We propose that ether bond formation might be orchestrated through a covalent imine intermediate with the flavin, accounting for the noncanonical employment of a flavin cofactor in a nonredox reaction.