Multipoint linkage detection in the presence of by Chiu Y.-F.

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2000). 5 Regulation of Cu metabolism by stress and other nutritional factors The Cu transport machinery is not only regulated by extracellular Cu levels but also by growth conditions such as pH and nutrient limitations. First, many other genes relevant to Cu and Fe metabolism such as Fre1, Ctr1, Lys7, and Ccc2 are induced when cultured in an alkaline media (Serrano et al. 2002, 2004). Consistently, yeast cells with deletions in any of these genes are sensitive to alkaline pH, and overexpression of the Ctr1 or Fet4 Cu transporters confers resistance to alkaline pH (Serrano et al.

Cerevisiae in addition to Ccc2 has been designated as Pca1 (putative P-type cation-transporting ATPase) (Rad et al. 1994). Pca1’s role in Cu homeostasis remains obscure. Pca1 is a large 132kD transmembrane protein consisting of 1216 amino acid residues. Pca1 has one N-terminal MTCXXC metal binding motif compared to the two found in Ccc2. Mammals possess two P-type ATPases, which are WND and MNK, and another yeast species C. albicans expresses two P-type ATPases that play independent roles, Cu incorporation at the secretory pathway and Cu export to reduce intracellular Cu accumulation.

Cox23 unlike Δcox19 mutants can be rescued by exogenous Cu, however, only when transformed with a Cox17 high copy plasmid. Conversely, overexpression of Cox23 does not suppress the Δcox17 respiratory deficient phenotype suggesting that Cox17 functions downstream of Cox23 in the same pathway possibly involving Cox19 (Barros et al. 2004). One thing that is apparent now is that Cu homeostasis in the mitochondria is much more complicated than once previously thought. Recently, the role of Cox17 as the main mitochondrial Cu shuttle has come into doubt.