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鸟氨酸转氨甲酰酶缺乏症的分子基础:人类酶的建模及突变的影响

The molecular basis of ornithine transcarbamylase deficiency: modelling the human enzyme and the effects of mutations.

作者信息

Tuchman M, Morizono H, Reish O, Yuan X, Allewell N M

机构信息

Department of Pediatrics, Medical School, University of Minnesota, Minneapolis 55455, USA.

出版信息

J Med Genet. 1995 Sep;32(9):680-8. doi: 10.1136/jmg.32.9.680.

Abstract

Human ornithine transcarbamylase is a trimer with 46% amino acid sequence homology to the catalytic subunit of E coli aspartate transcarbamylase. Secondary structure predictions, distributions of hydrophilic and hydrophobic regions, and the pattern of conserved residues suggest that the three dimensional structures of the two proteins are likely to be similar. A three dimensional model of ornithine transcarbamylase was generated from the crystal structure of the catalytic subunit of E coli aspartate transcarbamylase in the holoenzyme, by aligning the sequences, building in gaps, and minimising the energy. The binding sites for carbamyl phosphate in both enzymes are similar and the ornithine binding site in ornithine transcarbamylase appears to be in the same location as the L-aspartate binding site in aspartate transcarbamylase, with negatively charged side chains replaced by positively charged residues. Mutations in the ornithine transcarbamylase gene found in patients with hyperammonaemia of the "neonatal type" are clustered in important structural or functional domains, either in the interior of the protein, at the active site, or at the interchain interface, while mutations found in patients with milder "late onset" disease are located primarily on the surface of the protein. The predicted effects of all known missense mutations and in frame deletions in the ornithine transcarbamylase gene on the structure and function of the mature enzyme are described.

摘要

人鸟氨酸转氨甲酰酶是一种三聚体,与大肠杆菌天冬氨酸转氨甲酰酶的催化亚基具有46%的氨基酸序列同源性。二级结构预测、亲水和疏水区域分布以及保守残基模式表明,这两种蛋白质的三维结构可能相似。通过序列比对、插入空位和能量最小化,从全酶中大肠杆菌天冬氨酸转氨甲酰酶催化亚基的晶体结构生成了鸟氨酸转氨甲酰酶的三维模型。两种酶中氨甲酰磷酸的结合位点相似,鸟氨酸转氨甲酰酶中的鸟氨酸结合位点似乎与天冬氨酸转氨甲酰酶中的L-天冬氨酸结合位点处于同一位置,带负电荷的侧链被带正电荷的残基取代。在“新生儿型”高氨血症患者中发现的鸟氨酸转氨甲酰酶基因突变聚集在重要的结构或功能域,要么在蛋白质内部、活性位点,要么在链间界面,而在症状较轻的“迟发型”疾病患者中发现的突变主要位于蛋白质表面。描述了鸟氨酸转氨甲酰酶基因中所有已知错义突变和框内缺失对成熟酶结构和功能的预测影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8371/1051666/fcf9a739408b/jmedgene00276-0012-a.jpg

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