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基于结构的Ala222Val和Glu429Ala亚甲基四氢叶酸还原酶（MTHFR）突变体活性降低模型。

A Structured-based Model for the Decreased Activity of Ala222Val and Glu429Ala Methylenetetrahydrofolate Reductase (MTHFR) Mutants.

作者信息

Shahzad Khuram, Hai Abdul, Ahmed Asifa, Kizilbash Nadeem, Alruwaili Jamal

机构信息

Illinois Informatics Institute, University of Illinois, Urbana-Champaign, Illinois, U.S.A ; Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.

出版信息

Bioinformation. 2013 Nov 11;9(18):929-36. doi: 10.6026/97320630009929. eCollection 2013.

DOI:10.6026/97320630009929
PMID:24307772
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3842580/
Abstract

The structure of human Methylenetetrahydrofolate Reductase (MTHFR) is not known either by NMR or by X-ray methods. Phosphorylation seems to play an important role in the functioning of this flavoprotein. MTHFR catalyzes an irreversible reaction in homocysteine metabolism. Phosphorylation decreases the activity of MTHFR by enhancing the sensitivity of the enzyme to SAdenosylmethione. Two common polymorphisms in MTHFR, Ala222Val and Glu429Ala, can result in a number of vascular diseases. Effects of the Glu429Ala polymorphism on the structure of human MTHFR remain undetermined due to limited structural information. Hence, structural models of the MTHFR mutants were constructed using I-TASSER and assessed by PROCHECK, DFIRE and Verify3D tools. A mechanism is further suggested for the decreased activity of the Ala222Val and Glu429Ala mutants due to a decrease in number of serine phosphorylation sites using information gleaned from the molecular models. This provides insights for the understanding of structure-function relationship for MTHFR.

摘要

无论是通过核磁共振（NMR）还是X射线方法，人类亚甲基四氢叶酸还原酶（MTHFR）的结构都尚不明确。磷酸化似乎在这种黄素蛋白的功能发挥中起着重要作用。MTHFR在同型半胱氨酸代谢中催化一个不可逆反应。磷酸化通过增强该酶对S-腺苷甲硫氨酸的敏感性来降低MTHFR的活性。MTHFR中的两种常见多态性，即Ala222Val和Glu429Ala，可导致多种血管疾病。由于结构信息有限，Glu429Ala多态性对人类MTHFR结构的影响仍未确定。因此，使用I-TASSER构建了MTHFR突变体的结构模型，并通过PROCHECK、DFIRE和Verify3D工具进行评估。利用从分子模型中收集到的信息，进一步提出了一种机制，解释由于丝氨酸磷酸化位点数量减少导致Ala222Val和Glu429Ala突变体活性降低的原因。这为理解MTHFR的结构-功能关系提供了见解。

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