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| Gene function, regulation and evolution in yeast: B-vitamin metabolism | |||||||||||||
We are investigating the molecular genetics of metabolism of the vitamins B1 (thiamine) and B6 (pyridoxine) in yeasts. Although the biochemical importance of these vitamins as enzyme cofactors has been recognised for a long time many details of their metabolism, biosynthesis and genetic regulation remain unresolved. We have now shown that thiamine and pyridoxine influence multiple cellular processes including their own biosyntheses and uptake through transcriptional control of biosynthetic genes, production of enzymes using them as cofactors, tolerance of free-radicals and damage to mitochondrial DNA. We have identified several genes encoding biosynthetic enzymes, and their transcriptional activators, and have started to define the cis-acting sites in thiamine-regulated gene promoters. We have also isolated yeast mutants that are defective in thiamine repression and define the negatively-acting components of the control system. One project concerns further dissection of this regulatory system to learn how these components interact. Another aspect concerns the molecular evolution of the biosynthetic genes. We are asking why some of the vitamin biosynthetic genes are present in multiple copies in baker's yeast, Saccharomyces cerevisiae, but as only a single copy in other yeasts. Although the individual members of these gene families encode functionally redundant enzymes, they may be subject to different types of regulation so that different genes are expressed under different growth conditions. Projects are available to investigate the evolution of these gene families. Certain thiamine mutants of yeast are susceptible to agents that damage DNA, generating mitochondrial respiratory mutants at high frequency. Also, mutants of pyridoxine biosynthesis are sensitive to free-radical damage. Another project could explore the molecular basis of these phenomena in order understand the role of the gene products in DNA damage tolerance. All projects will involve both classical and molecular methods of gene analysis in yeast as well as microbial physiology investigations. Hohmann S et al (1998) Biochim Biophys. Acta - Protein Structure & Molecular Enzymology. 1385, 201-219 Muller EH et al (1999) FEBS Letts 449, 245-250 Burrows RJ et al (2000) Yeast 16, 1497-1508 Byrne K L et. al. (2001) Microbiology 147; 2389-2398 |
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