Comparative and functional genomics of microbial metabolism

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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.