see also:

• caeruloplasmin
• Wilson's disease

• copper is an essential factor in all organisms, and once copper concentrations exceed the threshold maintained by homeostatic mechanisms, then copper in the body becomes toxic
• the balance of copper as an important cofactor is crucial, as dysregulation of intracellular copper bioavailability will induce cytotoxicity and oxidative stress
• in both prokaryotes and eukaryotes, copper homeostasis is finely regulated with the main aim of preventing excessive accumulation of copper ions in the cell and thus threatening cell survival
• copper delivery is accomplished by the concerted action of a set of evolutionarily conserved transporters and metallochaperones

• copper homeostasis in mammals requires complex regulation of absorption and excretion
• copper is taken up across the lumen surface of the small intestinal microvilli as cuprous ion by Ctr1
• within the cell, copper is escorted to specific compartments by metallo-chaperones ¹⁾
  • CCS, donates copper to superoxide dismutase
  • COX17, delivers copper to additional chaperones within the mitochondria for synthesis of cytochrome c oxidase
  • Atox1, delivers copper to the secretory pathway by docking with 2 P-type ATPases
  • ATP7A, is the protein nonfunctional in Menkes disease
    • ATP7A is required for cuproenzyme biosynthesis, and in the enterocyte it is required for copper efflux to portal blood
  • ATP7B, predominantly expressed in liver, is required for copper metallation of ceruloplasmin and biliary copper excretion
    • mutations in ATP7B lead to Wilson's disease
• intracellular hepatic copper-binding proteins COMMD1 (copper metabolism MURR1 domain) and XIAP (X-linked inhibitor of apoptosis protein) may also be required for copper excretion
• other proteins involved in copper homeostasis may include metallothionein and amyloid precursor protein
• copper transportation in plasma from the intestine to liver and in systemic circulation probably includes binding to both albumin and α2-macroglobulin

• cuprotosis - copper induced cell death
  • in human cells, copper-dependent death occurs through direct binding of copper to lipid acylated components, which leads to aggregation of lipid acylated proteins and loss of iron-sulfur cluster proteins, ultimately leading to cell death
  • the genes CDKN2A, FDX1, DLD, DLAT, LIAS, GLS, LIPT1, MTF1, PDHA1 and PDHB are closely associated with cuproptosis as a form of mortality
  • one of the causes of cell death is the depletion of pyrimidines
  • PDHA1
    • Pyruvate Dehydrogenase E1 Subunit Alpha 1, abbreviated as PDHA1, is a protein-encoded gene, and diseases associated with PDHA1 include pyruvate dehydrogenase E1-alpha deficiency and sudden infant death syndrome
    • PDHA1 is able to achieve consistent prostate cancer development in human xenograft tumor models by affecting lipid synthesis
    • lysine acetylation of PDHA1 and PDP1 is very common in both epidermal growth factor (EGF)-stimulated cells and various human cancer cells, and that acetylation of K202 is able to inhibit PDP1 by dissociating its fifth PDHA1, both of which have a great role in promoting glycolysis and tumor development in cancer cells
    • the KEGG pathway of PDHA1 is mainly enriched in ERBB signaling pathway, pyrimidine metabolism, ribosome and spliceosome
  • CDKN2A
    • Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) is a protein-encoded gene and diseases associated with CDKN2A include melanoma, cutaneous malignancies 2 and melanoma-pancreatic cancer syndrome
    • mutation of CDKN2A gene is an important factor for pancreatic cancer tumorigenesis
    • along with PDHA1 may be used as a marker of osteosarcoma ²⁾
    • the GO entries of CDKN2A are mainly enriched in phagocytosis, translation initiation and T-cell receptor complex entries

• Wilson's disease
  • by far the most common cause
  • an autosomal recessive genetic disorder caused by a mutation in ATP7B gene
• Indian childhood cirrhosis (ICC)
  • linked to mutations in the KRT8 and the KRT18 gene
• endemic Tyrolean infantile cirrhosis
• idiopathic copper toxicosis