Copper-Dependent Enzymes

Important Copper-Dependent Enzymes

Enzyme Name	Gene	Functions
Ceruloplasmin	CP	major ferroxidase in the blood; each enzyme binds 6–7 Cu2+ (cupric) ions; plays a major role in ensuring no free iron in the circulation; oxidizes Fe2+ (ferrous) iron to Fe3+ (ferric) iron which can then be bound to transferrin, the major iron transporting protein in the blood; ceruloplasmin is often misrepresented as the major copper transporting protein of the blood due to the fact that up to 95% of copper in the blood is found in this enzyme, however, the major function of ceruloplasmin is as a ferroxidase not as a copper transporter; two CP isoforms generated via alternative mRNA splicing, one form is secreted the other is attached to the plasma membrane via a GPI linkage; secreted CP synthesized exclusively by the liver, the GPI-linked CP is expressed by numerous organs including the brain, liver, kidneys, and lungs; the GPI-linked CP is primarily responsible for iron efflux from tissues; aceruloplasminemia, due to defects in the CP gene, doesn't affect copper homeostasis but manifests with iron overload of a form referred to as hemosiderosis
Cytochrome c oxidase	13 genes	composed of 13 subunits that comprise the mitochondrial oxidative phosphorylation complex IV; mitochondrial genome harbors MT-CO1, MT-CO2, and MT-CO3 genes; nuclear genome harbors the other ten genes: COX4, COX5A, COX5B, COX6A, COX6B, COX6C, COX7A, COX7B, COX7C, COX8; functions to re-oxidized reduced cytochrome c while subsequently reducing molecular oxygen to water; the ferric (Fe3+) iron in complex IV is the site of cyanide (CN–) binding
Dopamine β-hydroxylase (dopamine β-monooxygenase)	DBH	involved in catecholamine synthesis, catalyzes hydroxylation of dopamine to norepinephrine; expression limited to adrenal medulla and post-ganglionic sympathetic neurons
Hephaestin	HEPH	functions as a ferroxidase (similar to ceruloplasmin); expression is limited to intestinal enterocytes; required for iron transport from intestinal enterocytes to the blood; dietary iron is transported from enterocytes to the blood via the action of ferroportin with simultaneous oxidation of Fe2+ (ferrous) iron to Fe3+ (ferric) iron by hephaestin; ensures the iron can be bound to transferrin for delivery to the tissues
Lysyl oxidase	LOX	catalyzes the oxidative deamination of the ε-amino group of lysine and hydroxylysine residues in collagens and lysine residues of elastin; results in cross-linking of protein forming fibrils
Methionine synthase (homocysteine methyltransferase)	MTR	official name is 5-methyltetrahydrofolate-homocysteine S-methyltransferase; catalyzes the conversion of homocysteine to methionine; is one of only two enzymes that require vitamin B12 (as methylcobalamin); as the name implies the enzyme also requires N5-methyl-THF for activity; defects in the MTR gene, or deficiency in either folate or B12 (or both), result in homocysteinemia/homocystinemia and macrocytic anemia
Cu-Zn Superoxide dismutase	SOD1	major cytoplasmic anti-oxidant enzyme; catalyzes conversion of superoxide free radicals to molecular oxygen (O2) and hydrogen peroxide (H2O2); the major mitochondrial superoxide dismutase (SOD2) is a manganese-dependent enzyme