title: Copper transporters are responsible for copper isotopic fractionation in eukaryotic cells.
abstract: Copper isotopic composition is altered in cancerous compared to healthy tissues. However, the rationale for this difference is yet unknown. As a model of Cu isotopic fractionation, we monitored Cu uptake in Saccharomyces cerevisiae, whose Cu import is similar to human. Wild type cells are enriched in63Cu relative to65Cu. Likewise,63Cu isotope enrichment in cells without high-affinity Cu transporters is of slightly lower magnitude. In cells with compromised Cu reductase activity, however, no isotope fractionation is observed and when Cu is provided solely in reduced form for this strain, copper is enriched in63Cu like in the case of the wild type. Our results demonstrate that Cu isotope fractionation is generated by membrane importers and that its amplitude is modulated by Cu reduction. Based on ab initio calculations, we propose that the fractionation may be due to Cu binding with sulfur-rich amino acids: methionine and cysteine. In hepatocellular carcinoma (HCC), lower expression of the STEAP3 copper reductase and heavy Cu isotope enrichment have been reported for the tumor mass, relative to the surrounding tissue. Our study suggests that copper isotope fractionation observed in HCC could be due to lower reductase activity in the tumor.
authors.affiliation: Univ Lyon, ENS de Lyon, Université Claude Bernard Lyon 1, CNRS, UMR 5276, Lyon, France.
authors.forename: Jean-Loup
authors.initials: JL
authors.lastname: Cadiou
authors.affiliation: Univ Lyon, ENS de Lyon, Université Claude Bernard Lyon 1, CNRS, UMR 5276, Lyon, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Pichat
authors.affiliation: Univ Lyon, ENS de Lyon, Université Claude Bernard Lyon 1, CNRS, UMR 5276, Lyon, France.
authors.forename: Victor P
authors.initials: VP
authors.lastname: Bondanese
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, INSA-Lyon, CNRS, UMR5240, Villeurbanne, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Soulard
authors.affiliation: Division of Sustainable Energy and Environmental Engineering, Graduate School of Engineering, Osaka University, Osaka, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Univ Lyon, ENS de Lyon, Université Claude Bernard Lyon 1, CNRS, UMR 5276, Lyon, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Albarède
authors.affiliation: Univ Lyon, ENS de Lyon, Université Claude Bernard Lyon 1, CNRS, UMR 5276, Lyon, France.|Univ Lyon, Université Claude Bernard Lyon 1, INSA-Lyon, CNRS, UMR5240, Villeurbanne, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Oger
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D003300:Copper / Q000378:metabolism*; D003301:Copper Radioisotopes / Q000737:chemistry / Q000378:metabolism; D000079923:Copper Transporter 1; D019583:Dose Fractionation, Radiation; D005057:Eukaryotic Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D013455:Sulfur / Q000737:chemistry
chemical_list: D027682:Cation Transport Proteins; D018797:Cell Cycle Proteins; D003301:Copper Radioisotopes; D000079923:Copper Transporter 1; D026901:Membrane Transport Proteins; D015513:Oncogene Proteins; D013455:Sulfur; D003300:Copper; D010088:Oxidoreductases; C486677:STEAP3 protein, human