Comparative and functional genomics of microbial metabolism

微生物代谢的比较和功能基因组学

• 批准号: BB/E024467/1
• 负责人: Anthony Michael
• 金额: $ 13.45万
• 依托单位: Quadram Institute
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE024467%2F1
• 关键词: Comparative; functional; genomics; microbial; metabolism

Metabolic pathways are groups of enzymes that convert one chemical compound to a different product or metabolite. Some of the metabolites found in nature are found in all living cells eg, a small group of metabolites known as polyamines are found in all bacteria and higher organisms. How metabolic pathways evolve is of fundamental biological interest. We can map the evolution of metabolic pathways by analysing complete genome sequences. Biological science has changed radically during the last ten years since the publication of the first complete genome sequence. The genome is the total inventory of biological information of an organism encoded in its DNA. There are now nearly 400 complete bacterial genome sequences and a rising number of completed eukaryotic, i.e. higher organism genomes including human, chicken, mouse and yeast. It is expected that several thousand bacterial genomes will be completed in the near future. In the case of the polyamine metabolic pathway, the enzymes of the pathway were first characterised in the genetic model bacterium Escherichia coli. However, it has become clear recently that other types of bacteria use very different enzymes and pathways to make the same polyamines. Furthermore, there are many different types of polyamines in bacteria compared to higher organisms. There are still some gaps in our knowledge about the identity of the genes encoding some of the enzymatic steps involved in bacterial polyamine metabolism. One complicating factor with polyamine metabolism and perhaps with most metabolic pathways is that genes are exchanged between bacteria by a process known as horizontal gene transfer. Sometimes genes from higher organisms are transferred to bacteria. The outcome of this is that it is difficult to know a priori what the structure of the polyamine pathway is in any given bacterial species unless the pathway is mapped out from the genome sequence. The key aims of this project are to characterise some of the novel polyamine biosynthetic genes in bacteria, particularly gene fusions, to identify the genes encoding some of the less characterised enzymatic steps and to map out the structure of the polyamine pathway in different bacteria by bioinformatic analysis of genome sequences. In addition, this project will involve work with bacteria that are commonly found in the human gut or that are pathogens associated with food. The research will be carried out in Southwestern Medical, Dallas and in the University of Texas in Austin. This will build on a collaboration that was initially supported by a travel grant from the Department of Trade and Industry. The first three months would involve characterising specific polyamine pathway genes from a methanogenic bacterium, of the type found in the human gut, in the Department of Chemistry and Biochemistry at UT Austin. Prof. Karen Browning, an expert in the control of protein synthesis will be the host and there will be extensive collaboration with Dr. David Graham, an expert in methanogenic bacteria and Dr. Edward Marcotte, an expert in functional analysis of proteins and bioinformatics. The following nine months would involve characterising and identifying polyamine pathway genes from eubacteria in Southwestern Medical School. Prof. Margaret Phillips of the Pharmacology Department, an expert in enzymology and drug discovery will be the host and there will be extensive collaboration with Drs. Vanessa Sperandio and Lora Hooper of the Microbiology Department and Drs. Nick Grishin (bioinformatics) and Hong Zhang of the Biochemistry Department. Work in Southwestern would also involve gene knockout technology in the food pathogen Vibrio vulnificus, often found in shellfish. In both institutions, bioinformatics would also be used to construct an atlas of the structure of the polyamine metabolic pathways in different types of bacteria.

代谢途径是将一种化合物转化为另一种产物或代谢物的酶群。自然界中发现的一些代谢物存在于所有活细胞中，例如，在所有细菌和高等生物中都发现了一小群被称为多胺的代谢物。代谢途径如何进化是一个基本的生物学问题。我们可以通过分析完整的基因组序列来绘制代谢途径的进化图谱。自从第一个完整的基因组序列发表以来，生物科学在过去的十年里发生了根本性的变化。基因组是生物体DNA编码的生物信息的总库。现在有近400个完整的细菌基因组序列和越来越多的完整的真核生物，即高等生物基因组，包括人类、鸡、小鼠和酵母。预计在不久的将来将完成数千个细菌基因组。在多胺代谢途径的情况下，该途径的酶首先在遗传模型细菌大肠杆菌中被表征。然而，最近已经清楚的是，其他类型的细菌使用非常不同的酶和途径来制造相同的多胺。此外，与高等生物相比，细菌中有许多不同类型的多胺。关于编码细菌多胺代谢过程中一些酶的步骤的基因的身份，我们的知识仍然存在一些空白。多胺代谢和大多数代谢途径的一个复杂因素是，基因在细菌之间通过一种被称为水平基因转移的过程进行交换。有时来自高等生物的基因会转移到细菌中。这样做的结果是，除非从基因组序列中绘制出多胺途径，否则很难先验地知道任何给定细菌物种的多胺途径的结构。该项目的主要目的是表征细菌中一些新的多胺生物合成基因，特别是基因融合，识别编码一些较少表征的酶促步骤的基因，并通过基因组序列的生物信息学分析绘制出不同细菌中多胺途径的结构。此外，该项目还将涉及人类肠道中常见的细菌或与食物相关的病原体。这项研究将在达拉斯的西南医学院和奥斯汀的德克萨斯大学进行。这将建立在一项合作的基础上，该合作最初得到了贸易和工业部的旅行补助金的支持。前三个月将在德克萨斯大学奥斯汀分校的化学与生物化学系，对一种产甲烷细菌的特定多胺途径基因进行表征，这种细菌存在于人类肠道中。蛋白质合成控制专家Karen Browning教授将担任主持人，并将与产甲烷细菌专家David Graham博士和蛋白质功能分析和生物信息学专家Edward Marcotte博士进行广泛合作。接下来的9个月，我将在西南医学院对真菌体中的多胺途径基因进行表征和鉴定。药学系的玛格丽特·菲利普斯教授是酶学和药物发现方面的专家，她将担任主持人。微生物系的Vanessa Sperandio和Lora Hooper博士。Nick Grishin（生物信息学），生物化学系张宏。西南地区的工作还将涉及食品病原体创伤弧菌的基因敲除技术，创伤弧菌通常存在于贝类中。在这两个机构中，生物信息学也将用于构建不同类型细菌中多胺代谢途径结构的图谱。

项目成果

Independent evolutionary origins of functional polyamine biosynthetic enzyme fusions catalysing de novo diamine to triamine formation.

• DOI: 10.1111/j.1365-2958.2011.07757.x
• 发表时间: 2011-08
• 期刊: Molecular microbiology
• 影响因子: 3.6
• 作者: Green R;Hanfrey CC;Elliott KA;McCloskey DE;Wang X;Kanugula S;Pegg AE;Michael AJ
• 通讯作者: Michael AJ

A profusion of upstream open reading frame mechanisms in polyamine-responsive translational regulation.

• DOI: 10.1093/nar/gkp1037
• 发表时间: 2010-01
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Ivanov IP;Atkins JF;Michael AJ
• 通讯作者: Michael AJ

Spermine synthase.

• DOI: 10.1007/s00018-009-0165-5
• 发表时间: 2010-01
• 期刊: CELLULAR AND MOLECULAR LIFE SCIENCES
• 影响因子: 8
• 作者: Pegg, Anthony E.;Michael, Anthony J.
• 通讯作者: Michael, Anthony J.