Because copper is used by all living entities in cellular enzymes like cytochrome c oxidase, it is an important trace element. However, due to its radical character, copper is also very toxic and, because it is so widely used in mining, industry, and agriculture, high levels of copper may exist in some environments. Copper toxicity is based on the production of hydroperoxide radicals  and on interaction with the cell membrane . As such, bacteria have evolved several types of mechanisms to resist toxicity due to high copper concentrations. Copper metabolism has been studied in E. coli; some species related to Pseudomonas; the Gram-positive bacterium Enterococus hirae; and in S. cerevisiae, which sheds some light on the copper metabolism of higher organisms [194-199].
The mechanism of a plasmid-encoded copper resistance  in E. coli is based on an efflux mechanism. The efflux proteins are expressed by plasmid-bound pco genes (structural genes, pcoABCDE; and the regulatory genes pcoR and pcoS), which in turn depend on the expression of chromosomal cut genes. Two cut genes, cutC and cutF, were shown to encode a copper-binding protein and an outer membrane lipoprotein [201-206]. In Pseudomonas syringae, resistance to copper via accumulation and compartmentalization in the periplasm and outer membrane is due to four proteins encoded on the plasmid-borne cop operon.
The two periplasmic blue copper proteins are CopA and CopC, and the inner and the outer membrane proteins are CopD and CopB, respectively. However, a mutant cop operon containing copD but lacking one or more of the other genes conferred hypersensitivity and hyperaccumulation of cellular copper, indicating a role for CopD in copper uptake by the cell [196,197,207-209]. As in E. coli, copper resistance in Pseudomonas is regulated by a two-component regulatory system composed of a membrane-bound histidine kinase and a soluble response regulator, which is phos-phorylated by the kinase and switches on transcription of the cop genes [210,211].
The copper transport and resistance system in the Gram-positive bacterium Enterococcus hirae is the best understood system. The two genes, copA and copB, determining uptake and efflux P-type ATPases, respectively, are found in a single operon. Although CopA is probably responsible for copper uptake and copper nutrition, the 35% identical CopB is responsible for copper efflux and detoxification [167,212]. Copper and silver induce the system and they seem to transport silver besides copper ; obviously, the monovalent cations are being transported . The first two genes in the cop operon, copY and copZ, determining a repressor and activator, respectively, constitute the regulatory protein pair [214,215].
P-type ATPases also seem to control copper flow in two pathogens: Helicobacter pylori  and Listeria monocytogenes . Copper-transporting P-type ATPases have been found in cyano-bacteria [218,219] and in yeast. The copper P-type ATPase does not transport copper across the cytoplasmic membrane. In yeast cells, the iron/copper-specific reductases FRE1p and FRE2p reduce Cu (II) to Cu (I) [220,221], which is transported into the cell by the CTR1p transporter [221-223]. A functional homologue of a novel protein in yeast with two related possible copper transporters (CTR2p, CTR3p)  is found in man . Additionally, Cu (II) is accumulated by the CorA-related transporters ALR1p and ALR2p [221,223].
The metallothioneins of yeast, CUP1p and CRS5p, are probably copper-storage devices in yeast . COX1p delivers copper into the mitochondria for the synthesis of cytochrome c oxidase [226-228]. A copper P-type ATPase, CCC2p, and a "copper chaperone," ATX1p, are also capable of transporting copper [229,230]. The protein factors, ACE1p, ACE2p, and MAC1p factors regulate the copper homoeostasis [220,231-234]. The progress in understanding of the copper homoeostasis in yeast has contributed significantly to copper homoeostasis in general [235-239]. In man, defects in function or expression of copper transporting P-type ATPases are responsible for two heredity diseases: Menke's and Wilson's diseases ; their functional homologues have been identified in mouse, rat, and Caenorhabditis elegans [241-243]. Thus, the copper-dependent cycling of the transporter may be true for all animals or maybe even for all eukaryotes.
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