Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease
Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease
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DOI：
10.1074/jbc.m507528200
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发表时间：
2005-12-09
影响因子：
4.8
通讯作者：
Schofield, CJ
中科院分区：
文献类型：
--
作者：
McDonough, MA;Kavanagh, KL;Schofield, CJ
Refsum病（RD）是一种神经系统综合征，其特征在于成人发作的视网膜色素变性、嗅觉丧失、感觉神经病和植烷酸血症，其由植烷酸水平升高引起。许多RD病例与植烷酰基-CoA 2-羟化酶（PAHX）的突变相关，PAHX是一种Fe（II）和2-酮戊二酸（2 OG）依赖性加氧酶，其催化过氧化物酶体中的植烯酸降解中的初始α-氧化步骤。我们描述了PAHX与Fe（II）和2 OG复合的X射线晶体结构，分辨率为2.5埃，并预测了导致RD的突变的分子后果。与其他2 OG加氧酶一样，PAHX具有双链β-螺旋核心，其支持三个铁结合配体（His（175）、Asp（177）和His（264））（;）2 OG的2-含氧酸基团以双齿方式与Fe（II）结合。PAHX与Fe（II）和2 OG结合的方式，以及在其活性位点处存在离Fe（II）6.7埃的半胱氨酸残基（Cys（191））和另外两个组氨酸残基（His（155）和His（281）），使其与其他结构可用的人2 OG加氧酶（缺氧诱导因子抑制因子）的结合方式区别开来。在RD患者中观察到突变的15个PAHX残基中，11个聚簇在Fe（II）（Pro（173）、His（175）、Gln（176）、Asp（177）和His（220））和2 OG结合位点（Trp（193）、Glu（197）、Ile（199）、Gly（204）、Asn（269）和Arg（275））周围的两个不同组中。PAHX可能是辅酶A结合2 OG加氧酶新亚家族的第一个成员。
Refsum disease (RD), a neurological syndrome characterized by adult onset retinitis pigmentosa, anosmia, sensory neuropathy, and phytanic acidaemia, is caused by elevated levels of phytanic acid. Many cases of RD are associated with mutations in phytanoyl-CoA2-hydroxylase (PAHX), an Fe(II) and 2- oxoglutarate (2OG)dependent oxygenase that catalyzes the initial alpha- oxidation step in the degradation of phytenic acid in peroxisomes. We describe the x- ray crystallographic structure of PAHX to 2.5 angstrom resolution complexed with Fe(II) and 2OG and predict the molecular consequences of mutations causing RD. Like other 2OG oxygenases, PAHX possesses a double-stranded beta-helix core, which supports three iron binding ligands (His(175), Asp(177), and His(264))(;) the 2-oxoacid group of 2OG binds to the Fe( II) in a bidentate manner. The manner in which PAHX binds to Fe( II) and 2OG together with the presence of a cysteine residue (Cys(191)) 6.7 angstrom from the Fe(II) and two further histidine residues (His(155) and His(281)) at its active site distinguishes it from that of the other human 2OG oxygenase for which structures are available, factor inhibiting hypoxia-inducible factor. Of the 15 PAHX residues observed to be mutated in RD patients, 11 cluster in two distinct groups around the Fe(II) (Pro(173), His(175), Gln(176), Asp(177), and His(220)) and 2OG binding sites (Trp(193), Glu(197), Ile(199), Gly(204), Asn(269), and Arg(275)). PAHX may be the first of a new subfamily of coenzyme A- binding 2OG oxygenases.