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high. afinity. Cu(I). importers. (Dancis. et. al.. 1994,. Knight. et. al.. 1996).. The.
CTR1 ,. CTR3 ,.and. FRE1 .genes.are.under.the.regulation.of.the.copper-sens-
ing. MAC1. transcriptional. factor. (Georgatsou. et. al.. 1997,. Labbe. et. al.. 1997,.
Yamaguchi-Iwai.et.al..1997,.Zhu.et.al..1998)..Copper.deprivation.induces.a.
signal.transduction.system.in.which.MAC1.binds.to.the.promoter.elements.
of.the.copper.reductase.and.copper.transporter.genes.starting.transcription.
(Yamaguchi-Iwai.et.al..1997).
The.cellular.localization.of.the.Ctr2.transporter.has.been.debated.in.the.
past;. however,. recent. evidence. indicates. that. it. is. incorporated. into. the.
vacuolar. membrane. where. it. releases. copper. back. into. the. cytosol. when.
concentrations.are.critically.low.(Kampfenkel.et.al..1995,.Portnoy.et.al..2001,.
Rees.et.al..2004)..In.addition.to.the.Ctr.family.of.transporters. S. cerevisae .has.
a. P-type. ATPase.transporter,. Ccc2,. located. in.the. Golgi. (Yamaguchi. et.al..
1996).and.is.thought.to.translocate.copper.into.the.endomembrane.system..
The.ATX1.(Antioxidant1).protein.has.been.identiied.as.the.cytosolic.copper.
chaperone. for. the. Ccc2. transporter. (Lin. et. al.. 1997,. Yuan. et. al.. 1997).. Iron.
metabolism.has.been.linked.to.copper.homeostasis.in.yeast.through.a.cop-
per.requiring.oxidase,.Fet3,.needed.for.ferrous.iron.uptake.that.is.the.target.
for.copper.in.the.endomembrane.system.(Dancis.et.al..1994,.De.Silva.et.al..
1995,.Yuan.et.al..1995,.Askwith.et.al..1996).
Copper.transport.to.the.mitochondrion.for.integration.into.cytochrome.
c . oxidase. (Cco). in. yeast. has. been. highly. studied,. although. it. is. not. yet.
fully. understood.. Two. putative. chaperones,. Cox17. and. Cox19,. have. been.
implicated.in.cytosolic.transport.because.of.dual.localization.to.the.cyto-
plasm.and.intermitochondrial.membrane.space.(Beers.et.al..1997,.Nobrega.
et. al.. 2002).. However,. due. to. biochemical. and. mutant. analysis. both. pro-
teins.have.been.eliminated.as.the.chaperones.for.mitochondrial.shuttling.
(Cobine.et.al..2006)..As.a.result,.it.is.currently.unknown.which.protein.is.
responsible.for.copper.delivery.to.the.mitochondrion..Once.copper.is.in.the.
intermitochondrial.membrane.space.several.proteins.are.required.to.work.
in. concert. to. incorporate. the. ions. into. Cco.. The. existing. model. is,. Cox17.
donates. copper. to.Sco1. and. Cox11.(Horng.et. al..2004),.which.then.results.
in.the.integration.of.copper.into.the.Cu A .site.in.Cox2.subunit.and.Cu B .site.
in.the.Cox1.subunit.of.cytochrome.oxidase,.respectively.(Hiser.et.al..2000,.
Balatri.et.al..2003).
Lastly,.the.CCS.copper.chaperone.is.the.protein.for.ion.shuttle.to.a.copper-
requiring.SOD.(SOD1).(Schmidt.et.al..1999a,b)..In.addition.to.the.cytosol,.a.
small.fraction.of.both.SOD1.and.CCS.can.be.found.in.the.intermitochondrial.
space.even.though.there.is.no.presequence.for.targeting.to.the.mitochondria.
(Sturtz.et.al..2001)..Yeast.also.contain.two.known.metallothionein-like.pro-
teins,.Cup1.and.Crs5,.which.can.sequester.excess.copper.thereby.decreasing.
cell. toxicity. (Karin. et. al.. 1984,. Culotta. et. al.. 1994).. Whereas. the. sequence.
homology. between. the. Crs5. peptide. and. mammalian. metallothioneins. is.
high,.there.is.little.homology.between.the.Crs5.and.Cup1.proteins.(Culotta.
et. al.. 1994).. A. transcriptional. regulator,. Ace1,. has. been. identiied. that. can.
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