Human serum albumin copper binding (N-terminal ATCUN site) (HSA Cu(II)-binding site (ATCUN))

Human serum albumin (HSA) is the principal extracellular carrier of exchangeable Cu(II) in blood and binds copper mainly at its N-terminal ATCUN site, contributing substantially to the plasma Cu(II) pool and delivery to tissues[6]. Hepatocytes and other cells take up copper from Cu–albumin; evidence indicates cells recognize Cu–albumin and may preferentially bind a ternary Cu–albumin–histidine complex before releasing albumin/histidine and transporting copper across the membrane[2][5]. In pharmacology, HSA’s labile Cu(II) pool serves as a metal source for certain anticancer thiosemicarbazones, which chelate Cu(II) from HSA’s N-terminus and can form ternary conjugates with HSA, affecting drug activity and behavior[8][4]. Numerous synthetic Cu(II) complexes and chelators interact with serum albumin, with binding often occurring at defined albumin drug-binding sites and influencing complex stability and protein structure[1][3]. Overall, “albumin–copper complex formation” describes a physiological carrier–metal interaction rather than a discrete drug target, but it is crucial for copper homeostasis and can modulate the pharmacology of copper-interacting therapeutics[6][8][5][2][1][3].

Other names

Albumin–copper complexCopper–albumin complexCu(II)–human serum albumin complexCu–HSA complexN-terminal copper and nickel binding site of albumin (ATCUN/NSI)

For thiosemicarbazones: chelation of Cu(II) from the N-terminal Cu-binding site of HSA, formation of Cu(II)–TSC complexes and ternary HSA conjugates (likely via histidine), influencing anticancer activity and pharmacology[8][4]. Cellular uptake context: cells recognize Cu–albumin and preferentially a ternary Cu–albumin–histidine complex; albumin/histidine are released and copper is transported across the membrane after binding to the cell surface[2]. Multiple routes for cellular acquisition of copper from albumin and α2-macroglobulin; hepatic uptake partly via CTR1 for α2-macroglobulin, with additional unidentified systems for albumin-derived copper[5].