Department of Biochemistry
School of Medicine & Biomedical Sciences
Faculty
Department of Biochemistry
School
of Medicine & Biomedical Sciences
Faculty
DANIEL J. KOSMAN, Ph.D.
Professor
Cellular Trafficking of Iron in Eukaryotes Small and Large
The transition metal iron is difficult to absorb, hard to get rid of, and toxic, and after all of that, it's an essential nutrient, particularly for aerobic organisms which pretty much includes all eukaryotes from fungi to plants to metazoans, that is, us. Consequently, cells and organisms have developed efficient means to scavenge Fe from the environment and to "handle" it so as to suppress the chemical reactivity that makes iron both toxic and essential to the function of most of the cell's reactions that take advantage of the cell's oxygen-containing environment. My lab investigates this iron trafficking in "simple" model organisms like the budding yeast, Saccharomyces cerevisiae; in mammalian cells in culture; and in whole animals. We investigate the structure and function of proteins involved in this iron handling by kinetic and spectral techniques in vitro and we assess these structure-activity relationships in vivo in the same systems. A primary focus is on a protein type that is essential the trafficking of Fe into the cells of lower eukaryotes, like fungi and alga, and out of cells of higher eukaryotes, like mice and humans. This protein is a ferroxidase enzyme, a member of a class of proteins known as multicopper oxidases, or MCOs. These copper enzymes support normal iron metabolism in all eukaryotes and their dependence on copper atom prosthetic groups for their enzyme activity makes all of iron metabolism copper-dependent. These ferroxidases not only assist in the accumulation and normal metabolism of iron, they also protect the cell and organism from iron toxicity. A simple example is found in S. cerevisiae:a yeast cell that doesn't make this enzyme is not only deficient in Fe, Fe is also toxic to it: a double whammy for this ferroxidase-deficient organism. The yeast ferroxidase is known as Fet3p, the protein product of the FET3 gene. Humans who lack their ferroxidase enzyme, ceruloplasmin (hCp), also become systemically iron-deficient, and, just like yeast, exhibit neuropathologies that follow from the damage that the iron in the brain causes to the neurons there because it is not being "handled" by the hCp that is absent. One of the goals of our work is to produce a protein replacement for this "missing" Cp, a therapeutic that can be used to suppress the iron imbalance and neuropathology in people whose Cp isn't up to doing the job.
Selected Recent Publications:
Kwok, E.Y., Severance, S. and Kosman, D.J. (2006) Evidence for iron channeling in the Fet3p, Ftr1p high affinity iron uptake complex in the yeast plasma membrane. Biochemistry, 45:6317-6327. [PDF]
Singh, A., Severance, S., Kaur, N., Wiltsie, W. and Kosman, D. J. (2006) Assembly, activation and trafficking of the Fet3p, Ftr1p high affinity iron permease complex in Saccharomyces cerevisiae. J. Biol. Chem., 281: 13355-13364 [PDF]
Kowk, E. Y., Stoj, C. S., Severance, S., and Kosman, D. J. (2006) An engineered bifunctional high affinity iron uptake protein in the yeast plasma membrane. J. Inorg. Biochem. 100:1053-1060 [PDF]
Taylor, A. B., Stoj, C. S., Ziegler, L., D. J. Kosman and P. J. Hart, (2005) The copper-iron connection in biology: the structure of the yeast metallo-oxidase, Fet3p. Proc. Natl. Acad. Sci. U.S.A. 102:15459-15464 [PDF]
Kwok, E., and Kosman, D. J. (2005) Iron in yeast: mechanisms involved in homeostasis. Top. Curr. Genet. 14, published on-line. [PDF]
Stoj, C. S., and Kosman, D. J. (2005) Copper Oxidases, in Encyclopedia of Bioinorganic Chemistry, 2nd Ed., R. B. King, ed, John Wiley, in press. [PDF]Quintanar, L., Gebhard, M., *Wang, T.-P., Kosman, D. J., and Solomon, E. I. 2004. Ferrous binding to the multicopper oxidases Saccharomyces cerevisiae Fet3p and human ceruloplasmin: contributions to ferroxidase activity. J. Amer. Chem. Soc. 126:6579-6589.
*Severance, S., *Chakraborty, S., and Kosman, D. J. 2004. The Ftr1p iron permease in the yeast plasma membrane: orientation, topology, and structure-function relationships. Biochem. J. 380:487–496.
Stoj, C., and Kosman, D. J. (2003) Cuprous Oxidase Activity of Yeast Fet3p and Human Ceruloplasmin: Implication for Function. FEBS Lett., 554:422-426. [PDF]
Wang, T.-P., Severance, S., Quintanar, L., Solomon, E. I., and Kosman, D. J. (2003) Targeted suppression of the ferroxidase and iron trafficking activities of the multicopper oxidase, Fet3p, from Saccharomyces cerevisiae. J. Inorg. Biol. Chem., 8:611-620. [PDF]
Palmer, A. E., Quintanar, L., Severance, S., Wang, T-P., Kosman, D. J., and Solomon, E. I. (2002) Spectroscopic Characterization and O2 Reactivity of the Trinuclear Cu Cluster of Mutants of the Multicopper Oxidase Fet3p. Biochemistry, 41:6438-6448. [PDF]
Romeo, A. S., Christen, L., Niles, E. G., and Kosman, D. J. (2001) Intracellular chelation of iron by bipyridyl inhibits DNA virus replication: Ribonucleotide Reductase maturation as a probe of intracellular iron pools, J. Biol. Chem., 276:24301-24308. [PDF]
Machonkin, T. E., Quintanar, L., Palmer, A. E., Hassett, R., Severance, S., Kosman, D. J. and Solomon, E. I. (2001) Spectroscopy and reactivity of the type 1 copper site in Fet3p from Saccharomyces cerevisiae: Correlation of structure with reactivity in the multicopper oxidases. J. Amer. Chem. Soc., 123:5507-5517. [PDF]
Hassett, R., Dix, D., Eide, D., and Kosman, D. J. (2000) Fet4p is a physiologically relevant low affinity copper transporter in Saccharomyces cerevisiae. Biochem. J., 351:477-484. [PDF].
Blackburn, N. J., Ralle, M., Hassett, R., and Kosman, D. J. (2000) Spectroscopic analysis of the trinuclear cluster in the Fet3 protein from yeast, a multinuclear copper oxidase. Biochemistry, 39:2316-2324. [PDF]
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