Award details

Comparative and functional genomics of microbial metabolism

Reference	BB/E024467/1
Principal Investigator / Supervisor	Dr Anthony Michael
Co-Investigators / Co-Supervisors
Institution	Quadram Institute Bioscience
Department	H1 Programme
Funding type	Research
Value (£)	105,559
Status	Completed
Type	Fellowships
Start date	01/03/2008
End date	31/03/2009
Duration	13 months

Abstract

Polyamines are small, ubiquitous organic polycations found in all cells and are of primordial origin. The characterisation of polyamine biosynthesis was made in E. coli, yeast, human and Arabidopsis. However, the diversity of polyamine biosynthesis is much greater in bacteria than previously realised. Most work with polyamine metabolism represents only a small part of evolutionary space. The structure of bacterial polyamine biosynthetic pathways has not been analysed systematically and there is a need for an atlas of polyamine metabolism in the diverse archaeal and eubacterial phyla. The biosynthetic pathway of norspermidine is still incompletely characterised and part of this proposal will fill in the gaps. Most other enzymatic steps are probably identified at the gene level but there is considerable variety in which steps are used in which bacteria. In bacteria there are two folds each of the key polyamine biosynthetic enzymes ornithine decarboxylase, arginine decarboxylase, S-adensoyl methionine decarboxylase, used to synthesise spermidine. None of these enzymes are involved in norspermidine biosynthesis. Many other steps in polyamine biosynthesis have alternate versions eg., agmatine can be converted directly to putrescine by agmatinase or it can be converted by a two step process requiring agmatine iminohydrolase and N-carbamoylputrescine amidohydrolase. Although the tiny genome of Mycoplasma genitalium does not contain any polyamine biosynthetic enzymes the three components of the ABC transporter that takes up putrescine and spermidine are each essential for growth of M. genitalium. Thus polyamines can be regarded as part of the minimal metabolome of life. This project will fill in the few remaining gaps in the structure of polyamine biosynthetic pathways and will use bioinformatics to produce an atlas of polyamine metabolism in the sequenced archaeal and eubacterial genomes.

Summary

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.

Committee	Closed Committee - Plant & Microbial Sciences (PMS)
Research Topics	Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	Fellowship - Institute Development Fellowship (IDF) [2006-2010]
Funding Scheme	X – not Funded via a specific Funding Scheme

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