Vascular Biochemistry of Vitamin B12

维生素 B12 的血管生物化学

基本信息

批准号：
7048477
负责人：
Donald Weldon Jacobsen
金额：
$ 33.62万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-01 至 2008-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The micronutrient B12 (cobalamin, Cbl) plays an essential role in homocysteine metabolism in most if not all cells in the body. Hyperhomocysteinemia is a major independent risk factor for cardiovascular disease and is also associated with other devastating conditions such as neural tube defects and Alzheimer's disease. The determinants of hyperhomocysteinemia are multifactorial and include both genetic and acquired conditions. Cobalamin transport, processing and coenzyme formation by cardiovascular cells and tissues is a neglected area of research. The long-term objectives of this proposal are to gain an understanding of 1) Cbl transport processes in cultured human aortic endothelial cells and smooth muscle cells, 2) Cbl processing within these cells, and 3) the conversion of Cbl vitamers to methylcobalamin and adenosylcobalamin, coenzymes for cytosolic methionine synthase and mitochondrial methylmalonyI-CoA mutase, respectively. This study is driven by the hypotheses that 1) the vascular endotheliurn plays an essential role in maintaining Cbl homeostasis throughout the body; 2) it does so by a//owing the Cbl-binding protein transcobalarnin to transcytose from the/urinal/(apical/) space to the ablurninal (basolateral) space with Cbl as its cargo; 3) endothelial ceil injury, as occurs in atherogenesis and atherosclerosis, may cause localized disruption of Cbl homeostasis; and 4) Cbl deficiency itself/f is a cause of vascular ceil dysfunction due to a breakdown of the hornocysteine rernethylation machinery, which leads to hyperhornocysteinernia. The Specific Aims of this proposal are: 1) to establish the mechanisms of Cbl transport and transcytosis in cultured human aortic endothelial and smooth muscle cells; 2) to determine how Cbl is processed in cultured vascular cells and the role that glutathionyl-Cbl plays in this processing; and 3) to elucidate the mechanisms of Cbl coenzyme formation in cultured human aortic endothelial and smooth muscle cells.

描述（由申请人提供）：微量营养素B12（钴胺素，CBL）在体内大多数（如果不是所有的）（如果不是全部）中的同型半胱氨酸代谢中起着至关重要的作用。高脑结晶质血症是心血管疾病的主要独立危险因素，也与其他毁灭性疾病（例如神经管缺陷和阿尔茨海默氏病）有关。高层结晶血症的决定因素是多因素的，包括遗传和获得的疾病。心血管细胞和组织的钴胺素转运，加工和辅酶形成是一个被忽视的研究领域。该提案的长期目标是了解1）培养的人主动脉内皮细胞和平滑肌细胞中的CBL传输过程，2）在这些细胞内进行CBL处理，以及3）3）CBL脂肪酸转化为甲基核癌和腺苷基核苷酸甲基核酸甲酶，辅助甲基二氧化二氧化二氧化氢二氧化氢酶，分别。这项研究是由1）血管内皮在维持整个体内CBL稳态中起着至关重要的作用的推动的； 2）这样做是通过a //将CBL结合蛋白转钉蛋白归因于从/尿布/（顶式/）空间转移到以CBL为货物的流量（基底外侧）空间； 3）在动脉粥样硬化和动脉粥样硬化中发生的内皮天花板损伤可能导致CBL稳态的局部破坏； 4）CBL缺乏症本身/F是由于Hornocysenine rentethylation机械的分解而导致血管CEIL功能障碍的原因，这导致了高义型层静脉。该提案的具体目的是：1）建立人类主动脉内皮和平滑肌细胞中CBL转运和转胞膜的机制； 2）确定在培养的血管细胞中如何处理CBL，以及谷胱甘肽-CBL在该加工中起的作用； 3）阐明培养的人主动脉内皮和平滑肌细胞中CBL辅酶形成的机制。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product.

DOI：
10.1016/j.ymgme.2009.04.005
发表时间：
2009-08
期刊：
MOLECULAR GENETICS AND METABOLISM
影响因子：
3.8
作者：
Hannibal, Luciana;Kim, Jihoe;Brasch, Nicola E.;Wang, Sihe;Rosenblatt, David S.;Banerjee, Ruma;Jacobsen, Donald W.
通讯作者：
Jacobsen, Donald W.

Mechanistic studies on the reaction between R2N-NONOates and aquacobalamin: evidence for direct transfer of a nitroxyl group from R2N-NONOates to cobalt(III) centers.

DOI：
10.1002/anie.200904360
发表时间：
2009
期刊：
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
影响因子：
16.6
作者：
Hassanin, Hanaa A.;Hannibal, Luciana;Jacobsen, Donald W.;El-Shahat, Mohamed F.;Hamza, Mohamed S. A.;Brasch, Nicola E.
通讯作者：
Brasch, Nicola E.

NMR spectroscopy and molecular modelling studies of nitrosylcobalamin: further evidence that the deprotonated, base-off form is important for nitrosylcobalamin in solution.