Copper is a vital metal ion for sustaining life. Dietary and genetic disorders in copper metabolism and copper-implicated degenerative diseases provide striking evidence that optimal copper metabolism is a critical biological process. The mechanism underlying copper uptake and distribution has been an active research question;however, there are significant gaps in our understanding of the biosynthesis of cuproproteins. In particular, it is not known how copper-containing enzymes, such as ferroxidases, superoxide dismutase 3, lysyl oxidase, tyrosinase, and dopamine beta-hydroxylase, assemble copper cofactor(s) at the secretory pathway. This is an important problem because functional defects of these enzymes lead to serious disorders, including iron-deficiency anemia, cardiovascular disorders, cancer, and neuronal diseases. A successful attempt for identification of new genes involved in copper utilization revealed that an intracellular potassium-proton antiporter conserved in eukaryotes is a critical molecular factor for copper metabolism. Several lines of study indicate that potassium transport into the lumen of the cellular secretory pathway facilitates copper incorporation into ferroxidases. This exciting research progress has opened new avenues by which the mechanisms underlying the biosynthesis of functional ferroxidases and possibly other metalloproteins are better understood. Multi-disciplinary approaches using purified ferroxidases, mammalian cells, and mouse models will be employed to pursue the following specific aims: (1) Characterize the roles for potassium in copper and iron metabolism using a mouse strain where a secretory pathway potassium transporter is deleted;(2) Gain mechanistic insights into potassium-facilitated copper metallation of ferroxidases;(3) Define the modes of action and metal-responsive regulation of the potassium transporter;and (4) Determine the effects of potassium in the diet on copper and iron absorption and distribution. This proposed research is significant and innovative in that it (1) characterizes a new molecular factor involved in the metabolism of vital metal ions, copper, iron, and potassium;(2) discovers a novel functional role for potassium, a major intracellular cation;(3) gains better insights into the interactions among nutritional metal ions;and (4) would lead to the development of methods that facilitate absorption and distribution of copper, iron, and potassium. The outcomes of this project should have broad impacts on gaining mechanistic insights into metal metabolism, biosynthesis of metalloproteins, and combating various metal ion-related disorders, such as defects in normal growth and development, anemia, and metabolic and degenerative diseases.
Copper is a mineral vital for sustaining life, yet it is toxic when misplaced or accumulated in excess. Copper levels in the diet and molecular factors involved in copper metabolism have been proposed as a therapeutic target. This project aims to gain mechanistic insights into copper absorption and utilization in the body to enhance our ability to combat various metal-related human diseases, such as anemia, metabolic and degenerative diseases, and cancer.
|Wei, Wenzhong; Smith, Nathan; Wu, Xiaobin et al. (2014) YCF1-mediated cadmium resistance in yeast is dependent on copper metabolism and antioxidant enzymes. Antioxid Redox Signal 21:1475-89|
|Frey, Avery G; Nandal, Anjali; Park, Jong Hwan et al. (2014) Iron chaperones PCBP1 and PCBP2 mediate the metallation of the dinuclear iron enzyme deoxyhypusine hydroxylase. Proc Natl Acad Sci U S A 111:8031-6|
|Kim, Heejeong; Wu, Xiaobin; Lee, Jaekwon (2013) SLC31 (CTR) family of copper transporters in health and disease. Mol Aspects Med 34:561-70|
|Willis, Melanie Neely; Liu, Yilin; Biterova, Ekaterina I et al. (2011) Enzymatic defects underlying hereditary glutamate cysteine ligase deficiency are mitigated by association of the catalytic and regulatory subunits. Biochemistry 50:6508-17|
|White, Carine; Kambe, Taiho; Fulcher, Yan G et al. (2009) Copper transport into the secretory pathway is regulated by oxygen in macrophages. J Cell Sci 122:1315-21|
|Wu, Xiaobin; Sinani, Devis; Kim, Heejeong et al. (2009) Copper transport activity of yeast Ctr1 is down-regulated via its C terminus in response to excess copper. J Biol Chem 284:4112-22|
|White, Carine; Lee, Jaekwon; Kambe, Taiho et al. (2009) A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity. J Biol Chem 284:33949-56|
|Kim, Heejeong; Son, Hwa-Young; Bailey, Sarah M et al. (2009) Deletion of hepatic Ctr1 reveals its function in copper acquisition and compensatory mechanisms for copper homeostasis. Am J Physiol Gastrointest Liver Physiol 296:G356-64|
|Adle, David J; Wei, Wenzhong; Smith, Nathan et al. (2009) Cadmium-mediated rescue from ER-associated degradation induces expression of its exporter. Proc Natl Acad Sci U S A 106:10189-94|
|Adle, David J; Lee, Jaekwon (2008) Expressional control of a cadmium-transporting P1B-type ATPase by a metal sensing degradation signal. J Biol Chem 283:31460-8|
Showing the most recent 10 out of 11 publications