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首页> 外文学位 >The X-ray crystallographic structure of phytanoyl-coenzyme A hydroxylase, an iron(II) 2-oxoglutarate dependent dioxygenase involved in Refsum's disease.
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The X-ray crystallographic structure of phytanoyl-coenzyme A hydroxylase, an iron(II) 2-oxoglutarate dependent dioxygenase involved in Refsum's disease.

机译：植脂酰辅酶A羟化酶的X射线晶体结构，这是一种与Refsum病有关的2-氧代戊二酸铁（II）依赖性双加氧酶。

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摘要

Phytanoyl-coenzyme A 2-hydroxylase (PAHX) is a non-heme iron(II) 2-oxoglutarate (2-OG) dependent dioxygenase that catalyzes the 2-hydroxylation of phytanoyl-coenzyme A in mammalian peroxisomes. The 2-hydroxylation of phytanoyl CoA is the first step in the metabolism of phytanic acid, a branched-chain isoprenoid fatty acid derived from chlorophyll. Loss of PAHX activity and the associated increase in phytanic acid characterize the autosomal recessive disorder, Refsum's disease. The 1.45 A atomic resolution structure of H. sapiens PAHX bound to iron (Fe) and the 2-OG co-substrate has been determined by protein X-ray crystallography to learn more about its enzymatic mechanism and its role in Refsum's disease. The structure contains a 7 stranded jelly-roll motif that is conserved among members of the Fe(II) 2-OG family, which share very little sequence identity (25%). The coordination of the Fe resembles that of other Fe(II) 2-OG enzymes. It is hexa-coordinated in an octahedral geometry by PAHX with the HisXAsp/Glu...His iron-binding motif, H2O, and the planar 1-carboxylate and 2-carbonyl groups of the 2-OG. The 2-OG does not adopt the active conformation with the 5-carboxylate group making direct contact with a highly conserved arginine residue on the 7th strand in the conserved jelly-roll motif. Instead, 2-OG adopts multiple binding modes in which the flexible 2-OG tail, composed of its 3-ethyl, 4-ethyl and 5-carboxylate groups, is disordered. These binding modes may prevent 2-OG oxidation from occurring in the absence of substrate thereby protecting PAHX from auto-inactivation due to oxidation of a side chain residue. The structure of PAHX explains the effects of clinical mutations observed in Refsum's disease patients that cause enzyme inactivation. Clinical mutations mapped onto the surface of PAHX provide insight into potential regions that are important to substrate binding.
机译：植酰辅酶A 2-羟化酶（PAHX）是非血红素铁（II）2-氧代戊二酸酯（2-OG）依赖性双加氧酶，可催化哺乳动物过氧化物酶体中植酸酰辅酶A的2-羟化反应。植烷酰基辅酶A的2-羟基化是植烷酸（一种衍生自叶绿素的支链异戊二烯脂肪酸）代谢的第一步。 PAHX活性的丧失和植酸的相关增加是常染色体隐性遗传病（Refsum病）的特征。通过蛋白质X射线晶体学确定了H.sapiens PAHX与铁（Fe）和2-OG共底物的1.45 A原子拆分结构，以进一步了解其酶促机制及其在Refsum病中的作用。该结构包含一个7链的果冻卷基序，该基序在Fe（II）2-OG家族成员之间是保守的，它们几乎没有序列同一性（<25％）。 Fe的配位类似于其他Fe（II）2-OG酶。 PAHX通过HisHAsp / Glu ... His的铁结合基序H2O以及2-OG的平面1-羧基和2-羰基在八面体几何结构上进行六配位。 2-OG不采用具有5-羧酸盐基团的活性构象，而后者与保守的果冻卷基序中第7条链上的高度保守的精氨酸残基直接接触。取而代之的是，2-OG采用多种结合模式，其中由其3-乙基，4-乙基和5-羧酸酯基组成的柔性2-OG尾部是无序的。这些结合模式可防止在不存在底物的情况下发生2-OG氧化，从而保护PAHX避免由于侧链残基的氧化而自动失活。 PAHX的结构解释了在Refsum病患者中观察到的引起酶失活的临床突变的影响。映射到PAHX表面的临床突变可洞悉对底物结合很重要的潜在区域。

著录项

  • 作者

    Odell, Lindsay Thomas.;

  • 作者单位

    The Johns Hopkins University.;

  • 授予单位 The Johns Hopkins University.;
  • 学科 Biophysics General.; Chemistry Biochemistry.; Health Sciences Pathology.
  • 学位 Ph.D.
  • 年度 2004
  • 页码 182 p.
  • 总页数 182
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物物理学;生物化学;病理学;
  • 关键词

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