Enzymes, copper-dependent

The copper transport function of ceruloplasmin has been documented in several reviews (e.g. see refs. 15, 42, 43) and a transport function established. The turnover of ceruloplasmin allows copper ions to move from the major sites of ceruloplasmin synthesis in liver cells [44,45] to peripheral tissues for incorporation into copper-dependent enzymes [46,47], but transport mechanisms may also be active which involve copper atoms in the intact protein. However, the complexity of the protein has made it difficult to determine which, if any, of the six integral copper atoms are involved in copper delivery or whether there exist additional... 

This copper-dependent enzyme [EC 1.1.3.9] catalyzes the reaction of o-galactose with dioxygen to produce d-gfl/flcto-hexodialdose and hydrogen peroxide. 

This copper-dependent enzyme [EC 1.14.18.1] (also known as tyrosinase, phenolase, monophenol oxidase, and cresolase) catalyzes the reaction of L-tyrosine with L-dopa and dioxygen to produce L-dopa, dopaquinone, and water. This classification actually represents a set of copper proteins that also catalyze the reaction of catechol oxidase [EC 1.10.3.1] if only 1,2-benzenediols are available as substrates. 

Copper-dependent enzymes, ASCORBATE OXIDASE CATECHOL OXIDASE FERROXIDASE GAACTOSE OXIDASE ACCASE... 

In recent history, the therapeutic potential for copper in the treatment of rheumatic diseases was recognized by Hangartner in 1939 when he learned that copper miners in Finland were free of rheumatism. Sorenson25 has reviewed the literature on changes in copper concentrations in patients with rheumatoid arthritis. In patients with active disease there are marked increases in serum or plasma copper, an accelerated turnover rate of ceruloplasmin, and an increase of synovial fluid copper. A number of copper-dependent enzymes are known to be required for repair of inflamed tissues. 

Pesticidal Mercury Compounds. Owens (98) established in 1953 that mercury produced in vitro inhibition of amino-dependent, sulfhydryl-dependent, iron-dependent, and copper-dependent enzymes. It is well known that mercury in high concentrations acts as a protein denaturant. For example, Sohler et al. (109) have shown that mercury compounds inhibit catalase activity at high concentrations. The inhibition of enzymes... 

The biological effect of copper consists in activating copper-dependent enzymes needed for several cellular metabolic actions ... 

The differential sensitivity of central nervous system and mesenchymal tissues to copper histidine may be due to heterogeneity in the responses of different copper-dependent enzymes. 

Failure of the neuron to myelinate because of copper deficiency leads to abnormalities of the nervous system. This was first described in lambs and was referred to as "swaybacks. It is not known whether this is attributable to a diminished level of tyrosine hydroxylase, which is a copper-dependent enzyme. It is known, however, that epinephrine and norepinephrine are decreased in animals that are deficient in copper (II). In ruminants, copper is shown to be necessary for myelination of nerves and for the maintenance of normal skin pigmentation (33, 61),... 

Copper-dependent enzymes include tyrosinase (which is involved in melanin pigment formation) and the various oxidases (i.e., cytochrome oxidase, superoxide dismutase, amine oxidase, and uricase). Copper plays a major role in the incorporation of iron into the heme of hemoglobin. Copper deficiency is characterized by hypochromic, microcytic anemia resulting from defective hemoglobin synthesis. 

The major clinical feature of patients with deficiency of dopamine p-hydroxylase is orthostatic hypotension caused by reduced synthesis and release of norepinephrine by sympathetic nerves. The deficiency is characterized neuro-chemically by decreased levels of norepinephruie and norepinephrine metabolites and increased levels of dopamine and dopamine metabolites. Diagnosis is best achieved from an increased ratio of plasma dopamine to norepinephrine. Copper deficiency in Menkes disease is due to defects in the gene coding for a copper-transporting adenosine triphosphatase. Because dopamine p-hydroxylase is a copper-dependent enzyme, the deficiency is associated with decreased activity of the enzyme and reduced production of norepinephrine from dopamine. Prompt diagnosis at childbirth is essential for copper-replacement therapy, and... 

Menkes syndrome (Menkes steely-hair syndrome) is a rare, X-linked recessive disorder in which infants have low levels of copper in serum and in most tissues except kidney and intestine, where the concentration is very high. They also have greatly reduced plasma ceruloplasmin levels. Hair of the affected infants has a characteristic color and texture (pili torti, twisted hair ). It appears tangled and dull, has an ivory or grayish color, and is friable. Weakness and depigmentation of hair and defects in arterial walls (leading to aneurysms) are explained by loss of activity of copper-dependent enzymes (Table 37-5). Cerebral dysfunction may be due to a disturbance in energy metabolism or neurotransmitter synthesis secondary to decreased activity of cytochrome oxidase and dopamine... 

Dopamine-j8-hydroxylase (Dj H) inhibitors such as diethyldithiocarbamate (DDC) and l-phenyl-3-(2-thiazoyl)-2-thiourea (PTT) are known to remove copper from this copper-dependent enzyme and, in addition, potentiate antagonist-reversible morphine analgesia [202,203]. Watanabe, Matsui and Iwata [202] were the first to report that DDC elevated pain threshold and potentiated morphine analgesia in the tail-clip and hot-plate pain models. Bhargava and Way [203] subsequently reported that PTT also elevated pain threshold and reversed or prevented morphine tolerance by potentiating analgesia in naive and morphine-tolerant mice and prevented symptoms of abrupt morphine withdrawal and symptoms of naloxone-precipitated withdrawal. 

Maintenance and repair of duodenal and gastric collagen and elastin connective tissue components also seems to be an important copper-dependent enzyme function in preventing or repairing duodenal or gastric ulcers. Induction or facilitation of de novo synthesis of lysyl oxidase by copper complexes [16] merits consideration to account for the observed rapid and normal replacement of connective tissue components in the surgically placed gastric ulcer model [178]. 

Epileptic patients also have elevated blood copper concentrations [302-304]. As shown in Table 6.1, the brain contains more copper than any other nonstorage tissue in the human body [2], and brain tissues are known to require copper-dependent enzymes listed in Table 6.2 for normal development and function [ 1,8,135]. In addition, it has been pointed out that copper-dependent processes are required for modulation of prostaglandin syntheses [135], lysosomal membrane stability [135], and the activity of histamine (see previous Section on gastrointestinal ulcers), which are also important for normal brain functions. 

A symptom of copper deficiency in man and animals is seizures, which subside with copper supplementation [135, 305-310]. Seizures following treatment with tremor-inducing drugs are accompanied by a concomitant reduction in brain copper levels [311-314]. Also, brain norepinephrine and epinephrine concentrations are reduced in association with seizures [1, 311, 315-320]. This latter observation is particularly relevant, since two copper-dependent enzymes are required for the synthesis of norepinephrine and epinephrine. 

Copper complexes of thioureas and N-substituted thioureas have also been suggested to account for the effectiveness of the parent compounds as antitubercular agents [537]. On the other hand, Ueno [538] suggested that the parent thioureas acted by removing copper from some M. tuberculosis copper-dependent enzyme and that the antitubercular activity was dependent on the relative stabilities of the enzyme complex and thiourea complex. However, the activities of two series of N-substituted (2-pyridyl and 4-pyryl) thioureas [539] could not be correlated with copper complex stability [540]. 

Copper deficiency is extremely rare, and there is no evidence that copper ever need be added to a normal diet. Even in chnical states associated with hypocupremia (sprue, celiac disease, and nephrotic syndrome), effects of copper deficiency usually are not demonstrable. Anemia due to copper deficiency has been described in individuals who have undergone intestinal bypass surgery, in those who are receiving parenteral nutrition, in malnourished infants, and in patients ingesting excessive amounts of zinc. While an inherited disorder affecting copper transport (Menkes disease) is associated with reduced activity of several copper-dependent enzymes, this disease is not associated with hematological abnormalities. 

The metabolic role of many minerals and vitamins is as prosthetic groups or coenzymes in different enzyme systems. Consequently, mineral and vitamin deficiencies can cause a breakdown of the processing system and precipitate metabolic disease. For example, methylmalonyl-CoA isomerase (see p. 203) is an important vitamin Bi2-dependent enzyme in the gluconeogenic pathway. A deficiency of vitamin B12 (or cobalt) may reduce enzyme activity, decrease the efficiency of glucose synthesis and predispose the animal to ketosis. Similarly, ceruloplasmin is a copper-dependent enzyme responsible for releasing iron from cells into blood plasma. A copper deficiency may reduce ceruloplasmin activity, decrease the efficiency of iron utilisation for haemoglobin synthesis and predispose the animal to anaemia. 

We have shown, in stoichiometric experiments, that reaction of copper(I) with TEMPO affords a piperidinyloxyl copper(II) complex. Reaction of the latter with a molecule of alcohol afforded the alkoxycopper(II) complex and TEMPOH. Reaction of the alkoxycopper(II) complex with a second molecule of TEMPO gave the carbonyl compound, copper(I), and TEMPOH. This mechanism resembles that proposed for the aerobic oxidation of alcohols catalyzed by the copper-dependent enzyme, galactose oxidase, and mimics thereof. Finally, TEMPOH is reoxidized to TEMPO by oxygen. We have also shown that copper in combination with PIPO affords an active and recyclable catalyst for alcohol oxidation [18]. 

Since all copper-dependent enzymes and metabolism are affected, biosynthesis of elastin and collagen is defective. Menkes victims usually die before 3 years of age, frequently from neurodegenerative defects or connective tissue disorders (Danks 1989). Identification of the Menkes gene or the Wilson s gene will not provide a cure. However, as with other hereditary diseases, early diagnosis gives promise for a major reduction in the frequencies of these diseases. 

Calcium, potassium, and sodium are the three most abundant metals in the human body. Present in a much smaller amount, copper is nonetheless vitally important to human health. Copper-dependent enzymes known as cuproenzymes play a critical role in a host of biochemical processes, including cellular energy production, connective tissue formation. and reactions essential to normal functioning of the brain and central nervous system. Two hereditary diseases that involve errors of copper metabolism are Menkes disease and Wilson s disease. 

Interchain links in collagen and elastin, formed by the oxidation of lysine residues. This reaction is catalysed by a copper-dependent enzyme, and copper deficiency... 

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