The Dynamics of Circulatory Zinc Handling and Transport

循环锌处理和运输的动态

• 批准号: BB/J006467/1
• 负责人: Alan Stewart
• 金额: $ 64.64万
• 依托单位: University of St Andrews
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ006467%2F1
• 关键词: Dynamics; Circulatory; Zinc; Handling; Transport

There are 25 chemical elements that are required for mammalian life, 15 of these elements are metals. Zinc, in its ionised form Zn2+, is an essential metal ion in mammals and performs a wide range of important physiological functions by allowing many vital chemical reactions to occur. Zinc is known to play roles in fertility and development, the immune system, ageing, and major diseases such as Alzheimer's, diabetes, and cancer. Unfortunately however, the molecular mechanisms that enable zinc to get to where it is needed after it enters the bloodstream, following sequestration from the diet, are not fully understood.It is known that a particular protein called serum albumin (that is highly abundant in the blood) plays an important role in transporting zinc (and other metals including calcium and magnesium) in the blood. Serum albumin not only carries zinc through the circulatory system but also mediates its uptake into cells. The molecular mechanisms that control the interaction between zinc and serum albumin and its uptake into cells are largely unknown. It is important that these interactions are understood. Albumin also transports other types of molecules (e.g. fatty acids, hormones) and binding of one particular molecule can affect binding of another at a separate site. For example, we previously identified a zinc site that is perturbed by fatty acid-binding elsewhere on the molecule. Physiological events that alter the small molecule composition of blood can therefore alter metal transport processes. Such events may be short-term (e.g. fasting, eating, infection, stroke) or long-term (obesity, disease). Long-term alterations in blood chemistry are particularly likely to have serious consequences due to the knock-on effects caused by altered metal binding/delivery.We have identified three regions on the molecule that are likely to form novel metal binding sites. We will examine whether these regions that are involved in or impact upon zinc transport by synthesising mutant serum albumin proteins with chemical alterations at each site. These alterations will remove important chemical groups that are likely to participate in metal binding. The ability of each "altered protein" to bind zinc and other relevant metals will be examined and compared to the native (or "normal") protein using complementary approaches. We will also examine whether binding of molecules (including metals) at other sites alters the binding properties of each site.The importance of known and newly identified zinc-binding sites in mediating zinc uptake into cultured vascular endothelial cells (a particular type of cell that lines the blood vessels) will be determined by incubating these cells with albumins that contain alterations at each zinc site and physiological levels of zinc. The amount of zinc taken up by the cells will then be measured. The outcome of these experiments will allow a better understanding of how metal ions are transported in the circulatory system. Particularly with regard to the events that can alter this process and the importance of albumin in mediating cellular zinc uptake. This provides important physiological information that will help us to understand a variety of physiological and disease processes that involve metals and will aid in their study.

哺乳动物生命所需的化学元素有25种，其中15种是金属。锌，以其离子化形式Zn 2+，是哺乳动物中的必需金属离子，并通过允许许多重要的化学反应发生来执行广泛的重要生理功能。众所周知，锌在生育和发育，免疫系统，衰老以及阿尔茨海默氏症，糖尿病和癌症等主要疾病中发挥作用。然而不幸的是，锌进入血液后，从饮食中分离出来，使其到达需要的地方的分子机制还没有完全了解。已知一种称为血清白蛋白的特殊蛋白质（在血液中含量很高）在血液中转运锌（以及其他金属，包括钙和镁）方面起着重要作用。血清白蛋白不仅携带锌通过循环系统，而且还介导其进入细胞的摄取。控制锌和血清白蛋白之间的相互作用及其被细胞摄取的分子机制在很大程度上是未知的。理解这些相互作用是很重要的。白蛋白还转运其他类型的分子（例如脂肪酸、激素），一种特定分子的结合可能影响另一种分子在不同位点的结合。例如，我们以前确定了一个锌位点，该位点被分子上其他地方的脂肪酸结合所干扰。因此，改变血液小分子组成的生理事件可以改变金属转运过程。这些事件可能是短期的（如禁食、进食、感染、中风）或长期的（肥胖、疾病）。血液化学的长期改变特别可能产生严重的后果，这是由于金属结合/传递改变引起的连锁效应。我们已经确定了分子上可能形成新金属结合位点的三个区域。我们将研究这些区域是否参与或影响锌转运通过合成突变血清白蛋白与化学改变在每个网站。这些改变将去除可能参与金属结合的重要化学基团。每种“改变的蛋白质”结合锌和其他相关金属的能力将被检查，并使用互补方法与天然（或“正常”）蛋白质进行比较。我们还将研究是否结合的分子（包括金属）在其他网站改变每个site.The已知的和新发现的锌结合位点的重要性，介导锌摄取到培养的血管内皮细胞（一种特殊类型的细胞，线的血管）将被确定孵育这些细胞与白蛋白，含有改变在每个锌网站和锌的生理水平的结合特性。然后测量细胞吸收的锌量。这些实验的结果将使人们更好地了解金属离子在循环系统中的运输方式。特别是关于可以改变这一过程的事件以及白蛋白在介导细胞锌摄取中的重要性。这提供了重要的生理信息，将帮助我们了解涉及金属的各种生理和疾病过程，并有助于其研究。

项目成果

Ischemia-modified albumin: Crosstalk between fatty acid and cobalt binding.

• DOI: 10.1016/j.plefa.2018.07.014
• 发表时间: 2018-08
• 期刊: Prostaglandins, leukotrienes, and essential fatty acids
• 作者: Coverdale JPC;Katundu KGH;Sobczak AIS;Arya S;Blindauer CA;Stewart AJ
• 通讯作者: Stewart AJ

Albumin-mediated extracellular zinc speciation drives cellular zinc uptake.

• DOI: 10.1039/d2cc02278h
• 发表时间: 2022-06-30
• 期刊: CHEMICAL COMMUNICATIONS
• 影响因子: 4.9
• 作者: Coverdale, James P. C.;van den Berg, Hugo A.;Khazaipoul, Siavash;Bridgewater, Hannah E.;Stewart, Alan J.;Blindauer, Claudia A.
• 通讯作者: Blindauer, Claudia A.

Crosstalk between zinc and free fatty acids in plasma.

• DOI: 10.1016/j.bbalip.2018.09.007
• 发表时间: 2019-04
• 期刊: Biochimica et biophysica acta. Molecular and cell biology of lipids
• 作者: Coverdale JPC;Khazaipoul S;Arya S;Stewart AJ;Blindauer CA
• 通讯作者: Blindauer CA

Native electrospray mass spectrometry approaches to probe the interaction between zinc and an anti-angiogenic peptide from histidine-rich glycoprotein.

• DOI: 10.1038/s41598-018-26924-1
• 发表时间: 2018-06-05
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Martin EM;Kondrat FDL;Stewart AJ;Scrivens JH;Sadler PJ;Blindauer CA
• 通讯作者: Blindauer CA

Circulatory zinc transport is controlled by distinct interdomain sites on mammalian albumins.

• DOI: 10.1039/c6sc02267g
• 发表时间: 2016-11-01
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Handing KB;Shabalin IG;Kassaar O;Khazaipoul S;Blindauer CA;Stewart AJ;Chruszcz M;Minor W
• 通讯作者: Minor W