Tetrahydrofolate-mediated one-carbon metabolism is required for the biosynthesis of many central metabolites, including some amino acids, nucleobases, and nucleotides, and hence dysfunction of one-carbon metabolism is associated with many human diseases and disorders. The mitochondrial glycine decarboxylase complex (GDC) is an important component of one-carbon metabolism, generating 5,10-methylene-tetrahydrofolate (5,10-CH2-H??4folate) from glycine. Previous work has shown that the genes encoding the unique sub-units of the Saccharomyces cerevisiae GDC (GCV1, GCV2 and GCV3) are regulated in response to changes in the levels of cytosolic 5,10-CH2-H??4folate (Piper et al., 2000). Given the centrality of 5,10-CH2-H??4folate to many aspects of metabolism, it was hypothesised that other genes may be regulated by the same mechanism. Using microarray analysis of S. cerevisiae under a number of conditions that affect 5,10-CH2-H??4folate levels, the ??one-carbon regulon??, a group of genes that were co-regulated with the GCV genes was identified. The one-carbon regulon corresponds closely to genes whose promoters are bound by the purine biosynthesis regulator Bas1p, but not all one-carbon regulon members are significantly purine regulated. Genetic approaches demonstrated that the one-carbon unit response and the purine response are distinct, though both depend on the presence of Bas1p. This demonstrated that the close metabolic connections of one-carbon and purine metabolism are reflected in over-lapping, but separable regulatory mechanisms. The identity of the sensor of one-carbon unit depletion remains unknown, but in the course of investigation of the candidate regulator Caf17p, it was demonstrated that Caf17p is in fact involved in Fe/S cluster protein maturation. Examination of the effects of Caf17p depletion revealed that Caf17p is required for the function and maturation of the related mitochondrial Fe/S proteins aconitase and homoaconitase, as well as the function of, but not de novo iron incorporation into, the mitochondrial radical-SAM Fe/S protein biotin synthase. Because other Fe/S proteins were unaffected, Caf17p appears to be a specialised Fe/S maturation factor. The presence of a putative H4folate binding site indicates that Caf17p may constitute a metabolic link between one-carbon and iron metabolism.
| Identifer | oai:union.ndltd.org:ADTP/257677 |
| Date | January 2008 |
| Creators | Gelling, Cristy Lee, Biotechnology & Biomolecular Sciences, Faculty of Science, UNSW |
| Publisher | Publisher:University of New South Wales. Biotechnology & Biomolecular Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://unsworks.unsw.edu.au/copyright, http://unsworks.unsw.edu.au/copyright |
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