Harpers

588 / CHAPTER 50Copper Is a Cofactor for Certain EnzymesCopper is an essential trace element. It is required inthe diet because it is the metal cofactor for a variety ofenzymes (see Table 50–5). Copper accepts and donateselectrons and is involved in reactions involving dismutation,hydroxylation, and oxygenation. However, excesscopper can cause problems because it can oxidizeproteins and lipids, bind to nucleic acids, and enhancethe production of free radicals. It is thus important tohave mechanisms that will maintain the amount ofcopper in the body within normal limits. The body ofthe normal adult contains about 100 mg of copper, locatedmostly in bone, liver, kidney, and muscle. Thedaily intake of copper is about 2–4 mg, with about50% being absorbed in the stomach and upper smallintestine and the remainder excreted in the feces. Copperis carried to the liver bound to albumin, taken upby liver cells, and part of it is excreted in the bile. Copperalso leaves the liver attached to ceruloplasmin,which is synthesized in that organ.The Tissue Levels of Copper & of CertainOther Metals Are Regulated inPart by MetallothioneinsMetallothioneins are a group of small proteins (about6.5 kDa), found in the cytosol of cells, particularly ofliver, kidney, and intestine. They have a high content ofcysteine and can bind copper, zinc, cadmium, and mercury.The SH groups of cysteine are involved in bindingthe metals. Acute intake (eg, by injection) of copper andof certain other metals increases the amount (induction)of these proteins in tissues, as does administration ofcertain hormones or cytokines. These proteins mayfunction to store the above metals in a nontoxic formand are involved in their overall metabolism in thebody. Sequestration of copper also diminishes theamount of this metal available to generate free radicals.Menkes Disease Is Due to Mutationsin the Gene Encoding a Copper-Binding P-Type ATPaseMenkes disease (“kinky” or “steely” hair disease) is adisorder of copper metabolism. It is X-linked, affectsTable 50–5. Some important enzymes thatcontain copper.• Amine oxidase• Copper-dependent superoxide dismutase• Cytochrome oxidase• Tyrosinaseonly male infants, involves the nervous system, connectivetissue, and vasculature, and is usually fatal in infancy.In 1993, it was reported that the basis of Menkesdisease was mutations in the gene for a copper-bindingP-type ATPase. Interestingly, the enzyme showed structuralsimilarity to certain metal-binding proteins in microorganisms.This ATPase is thought to be responsiblefor directing the efflux of copper from cells. When alteredby mutation, copper is not mobilized normallyfrom the intestine, in which it accumulates, as it does ina variety of other cells and tissues, from which it cannotexit. Despite the accumulation of copper, the activitiesof many copper-dependent enzymes are decreased, perhapsbecause of a defect of its incorporation into theapoenzymes. Normal liver expresses very little of theATPase, which explains the absence of hepatic involvementin Menkes disease. This work led to the suggestionthat liver might contain a different copper-bindingATPase, which could be involved in the causation ofWilson disease. As described below, this turned out tobe the case.Wilson Disease Is Also Due to Mutationsin a Gene Encoding a Copper-BindingP-Type ATPaseWilson disease is a genetic disease in which copper failsto be excreted in the bile and accumulates in liver,brain, kidney, and red blood cells. It can be regarded asan inability to maintain a near-zero copper balance, resultingin copper toxicosis. The increase of copper inliver cells appears to inhibit the coupling of copper toapoceruloplasmin and leads to low levels of ceruloplasminin plasma. As the amount of copper accumulates,patients may develop a hemolytic anemia, chronic liverdisease (cirrhosis, hepatitis), and a neurologic syndromeowing to accumulation of copper in the basal gangliaand other centers. A frequent clinical finding is theKayser-Fleischer ring. This is a green or golden pigmentring around the cornea due to deposition of copperin Descemet’s membrane. The major laboratorytests of copper metabolism are listed in Table 50–6. IfWilson disease is suspected, a liver biopsy should beperformed; a value for liver copper of over 250 µg pergram dry weight along with a plasma level of ceruloplasminof under 20 mg/dL is diagnostic.The cause of Wilson disease was also revealed in1993, when it was reported that a variety of mutationsin a gene encoding a copper-binding P-type ATPasewere responsible. The gene is estimated to encode aprotein of 1411 amino acids, which is highly homologousto the product of the gene affected in Menkes disease.In a manner not yet fully explained, a nonfunctionalATPase causes defective excretion of copper intothe bile, a reduction of incorporation of copper into