Bacterial sphingolipids - revealing hidden biosynthetic pathways of key players in host-microbe interactions.

细菌鞘脂 - 揭示宿主与微生物相互作用中关键参与者的隐藏生物合成途径。

• 批准号: BB/V001620/1
• 负责人: Dominic Campopiano
• 金额: $ 51.08万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV001620%2F1
• 关键词: Bacterial; sphingolipids; revealing; hidden; biosynthetic

Animal and bacterial cells have a protective, water-resistant outer shell that is composed of molecules with a water-loving (hydrophilic) head group and a long, water-hating (hydrophobic) tail. This large family of molecules are called lipids and include common things like saturated/unsaturated fats and cholesterol. One particular sub-family of lipids is called sphingolipids (SLs) and their more complex ceramide versions (which have two fatty tails). The SLs not only play structural roles in the outer shell that allow the cell membrane to resist water and let nutrients in and waste out; they are also able to stimulate the human immune system. SL levels are dynamic but also tightly controlled - any increase or decrease in the cellular SL levels is a sign that something has gone wrong. Changes in SL levels are strongly linked with old age and diseases such as Alzheimer's, diabetes, asthma, cancer and nerve-wasting diseases. An exciting area of research with direct implications for human health is the discovery that humans are hosts for many different types of bacteria - collectively these are known as the microbiota/microbiome. Current estimates are that for every human cell in our body, there is a bacterial one. These bacteria can be "bad" and cause disease (e.g. superbugs) but most are "good" bacteria and are beneficial to our well being. These bacteria live in our mouths, on our skin and in our gut and help us metabolise our food and are also thought to play protective roles. A surprising discovery was that the bacteria that live with us produce molecules that allow bacterial and human cells to communicate. One such family of molecules are the SLs - it is highly unusual that human and bacterial cells both make the same molecule and this suggests some sort of evolutionary link. Moreover, it has been calculated that we have several grams of SLs in our gut at any one time and they are making a vital contribution to our health. Recent studies have linked the microbiota to diseases such as diabetes, obesity and cancer.All cells make SLs by a multi-step pathway using simple building blocks - the steps are catalysed (sped up) by molecular machines called enzymes. Research has focussed on the enzymes involved in human SL biosynthesis but very little is known about SL biosynthesis in the microbiota. To fully understand the relationship between us and bacteria we must learn how bacteria make and transport such complex molecules as well as understanding how we metabolise them. We will study how gut and mouth bacteria make SLs with world experts in America and Germany with a collaborator from the UK. We will begin with a study of the enzyme serine palmitoyltransferase (SPT) that uses two main building blocks - an amino acid called L-serine and a long chain fatty acid, to make the first SL intermediate. We will determine the 3D structure of the SPT in each bacterium and compare their shapes and evolution. Of special interest, the structure of the bacterial SLs is unusual and contains distinctive chemical fingerprints and we will investigate their origins by feeding the bacteria heavy versions of the proposed building blocks and tracking their incorporation. Nothing is known about how the microbiota makes unusual branched chain SLs so we will study enzymes that convert can branch-chain amino acids into specific building blocks. Bacteria contain ceramides with an unsusual inositol sugar so we will purify and characterise the enzyme myo-inositol phosphate synthase (MIPS) that uses glucose phosphate as a substrate. At the end of our study we will have begun to define the biosynthetic blueprint of the microbiota. Our results will be of interest to academic microbiologists and chemists as well as those interested in human health. Moreover, a number of drug and healthcare companies are also interested in the microbiome and they could use our knowledge to develop therapies that may have impact on disease and long term well being.

动物和细菌细胞具有保护性的防水外壳，由带有热爱水（亲水性）头部组的分子组成，并且是较长的，疏水（疏水）的尾巴。这个大型分子家族称为脂质，包括饱和/不饱和脂肪和胆固醇等常见的东西。脂质的一个特定亚家族称为鞘脂（SLS）及其更复杂的神经酰胺版本（具有两个脂肪尾巴）。 SLS不仅在外壳中扮演结构角色，从而使细胞膜能够抵抗水，并使营养成分进入并浪费。他们还能够刺激人类免疫系统。 SL水平是动态的，但也受到严格控制 - 蜂窝SL水平的任何增加或减少都是出现问题的标志。 SL水平的变化与老年和疾病（例如阿尔茨海默氏症，糖尿病，哮喘，癌症和浪费神经疾病）密切相关。令人兴奋的研究领域对人类健康的直接影响是发现人类是许多不同类型细菌的宿主 - 总的来说，这些被称为微生物群/微生物组。当前的估计是，对于我们体内的每个人类细胞，都有一个细菌。这些细菌可能是“不良”的，并且会引起疾病（例如超级细菌），但大多数是“好”细菌，对我们的健康有益。这些细菌生活在我们的口中，皮肤和肠道中，并帮助我们代谢食物，也被认为扮演着保护角色。一个令人惊讶的发现是，与我们同住的细菌产生了允许细菌和人类细胞进行沟通的分子。这样的分子家族是SLS - 人类和细菌细胞都形成相同的分子是高度不寻常的，这表明了某种进化的联系。此外，已经计算出我们的肠道中有几克SLS，他们对我们的健康做出了重要的贡献。最近的研究将微生物群与糖尿病，肥胖和癌症等疾病联系起来。所有细胞都使用简单的构建模块通过多步途径使SLS进行SLS - 这些步骤是通过称为酶的分子机催化（加速）。研究的重点是与人类SL生物合成有关的酶，但对微生物群中的SL生物合成知之甚少。要充分了解我们与细菌之间的关系，我们必须学习细菌如何制造和运输这种复杂的分子，并了解我们如何代谢它们。我们将研究肠道和口腔细菌如何与来自英国的合作者与美国和德国的世界专家制作SLS。我们将从对使用两个主要构件的酶丝氨酸棕榈酰转移酶（SPT）进行研究，该块形成块 - 一种称为L丝氨酸和长链脂肪酸的氨基酸，使第一个SL中间体。我们将确定每个细菌中SPT的3D结构，并比较它们的形状和进化。特别感兴趣的是细菌SLS的结构是不寻常的，并且包含独特的化学指纹，我们将通过喂养所提出的构建块的细菌重型版本并跟踪其掺入来研究它们的起源。关于微生物群如何制造异常的支链链SL，因此我们将研究可以将分支链氨基酸转换为特定的构件的酶。细菌含有含不寻常肌醇糖的神经酰胺，因此我们将纯化并表征使用磷酸葡萄糖作为底物的酶肌醇磷酸合酶（MIPS）。在研究结束时，我们将开始定义微生物群的生物合成蓝图。我们的结果将引起学术微生物学家和化学家以及对人类健康感兴趣的人的关注。此外，许多药物和医疗保健公司也对微生物组感兴趣，他们可以利用我们的知识来开发可能影响疾病和长期健康的疗法。

项目成果

Characterization of inositol lipid metabolism in gut-associated Bacteroidetes.

• DOI: 10.1038/s41564-022-01152-6
• 发表时间: 2022-07
• 期刊: Nature microbiology
• 影响因子: 28.3