STRUCTURAL BASIS OF VITAMIN B12 (COBALAMIN) DEFICIENCY
维生素 B12(钴胺素)缺乏的结构基础
基本信息
- 批准号:6476091
- 负责人:
- 金额:$ 8.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-02-15 至 2002-11-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The mammalian protein transcobalamin II (TCII) is responsible for the transport of vitamin B12 (more accurately termed cobalamin) through the bloodstream. Vitamin B12 is ingested and passed through gut ileal cells to the bloodstream where it is carried by transcobalamin II to cells presenting a specific TCII/cobalamin surface receptor. After receptor mediated endocytosis the vitamin requires further modification before adopting an active cofactor structure required for two enzymes, cytoplasmic methionine synthase (methyl-B12) and mitochondrial methylmalonyl CoA mutase (5'-deoxyadenosyl-B12). Genetic mutants of TCII cause an autosomal recessive disorder that presents itself in infancy with megaloblastic anemia. The 3-dimensional structure of transcobalamin II bound to cobalamin will be solved using X-ray crystallography, and will provide a molecular explanation of a human genetic disorder. The intestinal transport protein, intrinsic factor, shares high homology with TCII and will also be pursued structurally, either by homology modeling or direct structure determination. Specific Aims: 1) Solve the three-dimensional structure of transcobalamin II by X-ray diffraction techniques, and investigate the structural basis for the physiological disruption of vitamin B12 transport. 2) Determine the critical interactions between TCII and cobalamin, and map the surface of the protein which interacts with the specific cell-surface receptor that recognises the TCII/cobalamin complex. 3) Produce a model of intrinsic factor (IF), haptocorrin and transcobalamin I (TCI) based on the high amino acid sequence identity with TCII.
哺乳动物蛋白质转钴胺II(TCII)负责通过血液运输维生素B12(更准确地说是钴胺)。维生素B12被摄取并通过肠道回肠细胞进入血流,在那里它被转钴胺II携带到呈现特定TCII/钴胺表面受体的细胞。在受体介导的内吞作用后,维生素需要进一步修饰,才能采用两种酶所需的活性辅因子结构,细胞质蛋氨酸合成酶(甲基-B12)和线粒体甲基丙二酰辅酶A变位酶(5‘-脱氧腺苷-B12)。TCII基因突变导致一种常染色体隐性遗传病,这种疾病在婴儿时期表现为巨幼细胞性贫血。转钴胺II与钴胺结合的三维结构将使用X射线结晶学来解决,并将为人类遗传疾病提供分子解释。肠道运输蛋白是一种内在因子,与TCII有很高的同源性,也将通过同源建模或直接结构确定来寻找结构。具体目的:1)用X射线衍射法解析转钴胺II的三维结构,探讨维生素B12转运受到生理干扰的结构基础。2)确定TCII与钴胺之间的关键相互作用,并绘制与识别TCII/钴胺复合体的特定细胞表面受体相互作用的蛋白质表面。3)根据与转钴胺I的高氨基酸序列同源性,建立了内源因子(IF)、结合角蛋白和转钴胺I(TCI)的模型。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('HEIDI L SCHUBERT', 18)}}的其他基金
STRUCTURAL BASIS OF VITAMIN B12 (COBALAMIN) DEFICIENCY
维生素 B12(钴胺素)缺乏的结构基础
- 批准号:
6031996 - 财政年份:2000
- 资助金额:
$ 8.47万 - 项目类别:
STRUCTURAL BASIS OF VITAMIN B12 (COBALAMIN) DEFICIENCY
维生素 B12(钴胺素)缺乏的结构基础
- 批准号:
6329263 - 财政年份:2000
- 资助金额:
$ 8.47万 - 项目类别:
STRUCTURAL AND MECHANISTIC STUDY OF SIROHEME SYNTHASE
西罗血红素合成酶的结构和机理研究
- 批准号:
2136627 - 财政年份:1997
- 资助金额:
$ 8.47万 - 项目类别:
STRUCTURAL AND MECHANISTIC STUDY OF SIROHEME SYNTHASE
西罗血红素合成酶的结构和机理研究
- 批准号:
2136626 - 财政年份:1997
- 资助金额:
$ 8.47万 - 项目类别:
STRUCTURAL AND MECHANISTIC STUDY OF SIROHEME SYNTHASE
西罗血红素合成酶的结构和机理研究
- 批准号:
2518213 - 财政年份:1997
- 资助金额:
$ 8.47万 - 项目类别:
STRUCTURAL AND MECHANISTIC STUDY OF SIROHEME SYNTHASE
西罗血红素合成酶的结构和机理研究
- 批准号:
2694548 - 财政年份:1997
- 资助金额:
$ 8.47万 - 项目类别:
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