A high degree of conservation of the
copper homeostasis pathway between yeast and humans makes yeast an ideal model organism for studying
copper-related disorders. In this study, a system based integrative approach was used to investigate the genome-wide effects of the deletion of the yeast ortholog of Wilson and
Menkes diseases encoding a Cu(2+)-transporting
P-type ATPase (CCC2) in different
copper containing media and to compare with the wild type. The experimental design applied in this study enabled the observation of the effect of CCC2 deletion, extracellular
copper levels and interactive effects of both factors in S. cerevisiae cells. The integrative analysis of the transcriptome with the interactome and regulome further elucidated the pathways affected by the disturbance of
copper homeostasis. The results demonstrated that
iron homeostasis is disturbed in the absence of CCC2 under
copper deficient conditions and also revealed the importance of this gene in the maintenance of
iron homeostasis under high
copper conditions.
NAD(+) metabolism was observed to be affected both by the deletion of CCC2 and the level of bio-available extracellular
copper. The regulation of
glucose transporters was also affected in the absence of CCC2 and a
starvation-like response was observed in a
copper level dependent manner. Alterations in the
amino acid metabolism and specifically in the
arginine metabolic process observed at the transcriptional level provided further support through the integration of the metabolomic data. This study also highlighted
pyridoxine deficiency caused by the absence of CCC2. The observation of the improvement in the respiratory capacity of CCC2 deleted cells by supplementation with
pyridoxine as well as with
nicotinic acid may shed light on novel therapeutic interventions for Wilson and
Menkes diseases.