Copper: Functions

Copper is an integral component of a number of metalloproteins and is essential for their enzyme function.Its two oxidation states enable the trace element to participate in electron-transferring enzyme reactions. As a cofactor of metalloenzymes, copper plays the role of receiver and donor of electrons and is thus of great importance for oxidation and reduction processes.Copper-dependent enzymes mostly belong to the class of oxidases or hydroxylases, which in turn belong to the group of oxidoreductases with high redox potential. Oxidases are enzymes that transfer electrons released during the oxidation of a substrate to oxygen.Hydroxylases are enzymes that introduce a hydroxyl group (OH) into a molecule via an oxidation reaction-chemical reaction in which a substance to be oxidized donates electrons.The copper-containing oxidoreductases are essential for the following processes.

  • Cellular energy metabolism and cellular oxygen utilization (respiratory chain), respectively.
  • Detoxification respectively neutralization of free radicals
  • Iron metabolism and hemoglobin synthesis – formation of red blood pigment (hemoglobin) of erythrocytes (red blood cells) and hematopoiesis (formation of blood cells from hematopoietic stem cells and their maturation, respectively).
  • Synthesis of connective tissue, the pigment melanin and neuroactive peptide hormones, such as catecholamines and enkephalins (endogenous pentapeptides from the class of opioid peptides).
  • Myelin formation – myelin makes up the myelin sheaths in neurons (nerve fibers), which serve to electrically insulate the axons of neurons and are essential for the transmission of excitation

In addition, copper affects various transcription factors and is thus integrated in the regulation of gene expression.

Cu-dependent metalloenzymes and their functions

CaeruloplasminCaeruloplasmin is a single-chain alpha-2 globulin with a carbohydrate content of 7%. A single caeruloplasmin molecule contains six copper atoms, which are predominantly present in their 2-valent form in biological systems and are essential for the oxidative function of the enzyme in the pH range 5.4-5.9.Caeruloplasmin exhibits several functions: As a binding and transport protein, caeruloplasmin contains 80-95% of plasma copper and distributes it to various tissues and organs as needed. In addition, it is involved in the transport of iron (Fe) and manganese (Mn) in the blood plasma.By binding free copper, iron and manganese ions, caeruloplasmin prevents the formation of free radicals. The latter represent highly reactive oxygen molecules or organic compounds containing oxygen, such as superoxide, hyperoxide or hydroxyl. In free form, both copper, iron and manganese are very aggressive elements that have a prooxidant effect. They strive to snatch electrons from an atom or molecule, creating free radicals, which in turn also snatch electrons from other substances. Thus, in a chain reaction, there is a steady increase of radicals in the body – oxidative stress. Free radicals are able to damage, among others, nucleic acids – DNA and RNA -, proteins, lipids and fatty acids, collagen, elastin as well as blood vessels. As a result of Cu, Fe andMn binding, caeruloplasmin prevents such oxidative cell and vascular damage.Furthermore, caeruloplasmin exhibits enzymatic functions. It catalyzes multiple oxidation reactions and is thus involved in iron metabolism. Caeruloplasmin is also referred to as ferroxidase I for this reason. Its essential task is to convert the trace element iron from its bivalent (Fe2+) to its trivalent form (Fe3+). For this purpose, the copper contained in the enzyme extracts electrons from the iron and accepts them, thereby itself changing its oxidation state from Cu2+ to Cu+.By oxidizing iron, caeruloplasmin enables Fe3+ to bind to plasma transferrin, a transport protein responsible for supplying iron to the body’s cells. Only in the form of Fe-transferrin can iron reach the erythrocytes (red blood cells) or cells – and be made available there for hemoglobin synthesis. Hemoglobin is the iron-containing red blood pigment of erythrocytes (red blood cells).The fact that iron transport to the body’s cells, especially to erythrocytes, is impaired by copper deficiency shows the importance of caeruloplasmin and its function.Finally, iron and copper metabolism are closely linked.In addition to iron, Cu-caeruloplasmin also oxidizes other substrates, such as p-phenylenediamine and its dimethyl derivatives.Superoxide dismutase (SOD)There are several forms of superoxide dismutase. It can be copper-, zinc-, and manganese-dependent. Zn-SOD is found exclusively in the cytosol of cells, Mn-SOD is found in mitochondria, and Cu-SOD is found in the cytosol of most body cells, including erythrocytes, as well as in blood plasma. The enzyme can only develop its activity optimally in the corresponding compartments if copper, zinc or manganese are present in sufficient quantities.Superoxide dismutase is an essential component of the endogenous antioxidant protection system. By reducing free radicals through the transfer of electrons, it acts as a radical scavenger, preventing the oxidation of sensitive molecules.SOD catalyzes the conversion of superoxide radicals to hydrogen peroxide and oxygen.The copper contained in SOD transfers electrons to the superoxide radical. The hydrogen peroxide molecule is subsequently reduced to water by catalase or selenium-dependent glutathione peroxidase, rendering it harmless. If superoxide radicals are not detoxified, they can lead to lipid peroxidation, membrane and vascular damage, and subsequently to “radical-related” diseases – radical diseases – such as atherosclerosis (arteriosclerosis, hardening of the arteries), coronary heart disease (CHD), tumor diseases, diabetes mellitus, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Cytochrome c oxidaseCytochrome c oxidase is a transmembrane protein in the inner mitochondrial membrane of somatic cells. The enzyme consists of several subunits, with a heme group and a copper ion forming the catalytic active site. The iron-containing heme groups and Cu ions of cytochrome c oxidase are essential for oxidation and reduction reactions. Accordingly, the function of the oxidase is limited in cases of pronounced copper or iron deficiency.As a mitochondrial enzyme complex, cytochrome c oxidase represents an essential component of the respiratory chain. The respiratory chain, also called oxidative phosphorylation, is the last step of glycolysis (glucose degradation) and thus integrated in energy metabolism. It consists of a chain of successive oxidation and reduction reactions that serve to synthesize ATP from ADP – adenosine diphosphate – and phosphate. ATP is the actual end product of glycolysis and provides energy to all kinds of cellular metabolic processes in the form of an energy-rich diphosphate bond.Cytochrome c oxidase is located as complex IV at the end of the respiratory chain and is responsible for both the oxidation of oxygen and the production of energy in the form of ATP. Both reaction steps are coupled via a mechanism that is not yet known.In a first step, subunit II of cytochrome c oxidase, the redox-active metal center Cu, accepts electrons from cytochrome c, which was previously loaded with electrons by cytochrome c reductase, complex III of the respiratory chain. In addition, cytochrome c oxidase removes protons (H+) from the mitochondrial matrix – the interior of a mitochondrion. The catalytically active center of the oxidase binds oxygen, on which the electrons and protons are transferred. The oxygen is thus reduced to water.In a second step, cytochrome c oxidase uses the energy released during the reduction of oxygen to water to pump protons from the mitochondrial matrix across the inner mitochondrial membrane into the intermembrane space. Through this proton transport, oxidase maintains the proton gradient that exists between the intermembrane space and the matrix.The electrochemical proton gradient across membranes is also called the pH gradient because the amount of protons reflects the pH. It represents a concentration gradient, where in mitochondria under normal conditions, the H+ concentration is high in the membrane interstitial space – acidic pH – and low in the matrix – basic pH. Thus, according to the laws of thermodynamics, there is a driving force of protons in the intermembrane space toward the matrix of the mitochondrion. Cytochrome c oxidase transports the protons against a concentration gradient, i.e. from low to high H+ concentration.This process is active and can only take place with the supply of energy.The H+ gradient at the inner mitochondrial membrane is essential for the energy metabolism of all known organisms and is an essential prerequisite for ATP synthesis.The ATP synthase – complex V of the respiratory chain – is responsible for the production of energy in the form of ATP.As a transmembrane protein, it forms a tunnel between the interior of the mitochondrion and the space between the inner and outer membrane. This enzyme utilizes the energy required for the production of ATP from ADP and phosphate from the proton gradient. Thus, protons pumped into the intermembrane space by oxidase flow “downhill” through the tunnel of ATP synthase toward the gradient in the mitochondrial matrix. This proton flow generates a rotational motion in the ATP synthase molecule. By means of this kinetic energy, the transfer of a phosphate residue to ADP occurs, resulting in the formation of ATP.Without the active proton transport (proton pump) into the intermembrane space by cytochrome c oxidase, the proton gradient would collapse, ATP synthase would no longer be able to produce ATP, and the body cell would ” starve to death” due to the deficient metabolic processes. In addition to cellular energy metabolism, cytochrome c oxidase is essential for the formation of phospholipids that form the myelin layer of the myelin sheaths in neurons – nerve fibers.Other Cu-dependent metalloenzymes and their functions.

Enzyme Localization Function
Ferroxidase II Plasma Oxidation of Fe2+ to Fe3+.
Dopamine ß-hydroxylase Adrenal medulla, central nervous system Synthesis of catecholamines, such as dopamine, epinephrine, and norepinephrineHydroxylation of tyrosine toL-dopa, the precursor of the neurotransmitter dopamine, which in turn can be converted to epinephrine and norepinephrineAntioxidant effect – neutralization of free radicals
Tyrosinase Skin, renal medulla and other tissues Oxidation of tyrosine to form melanin in melanocytes, which causes pigmentation of eyes, hair and skinHydroxylation of tyrosine toL-dopa, the precursor of the neurotransmitter dopamine, which in turn can be converted to adrenaline and noradrenaline
Lysyl oxidase Cartilage, bone, skin and other tissues Connective tissue and bone formationDesamination of lysine and hydrolysineCrosslinking of elastin and collagen microfibrils – formation of strong and equally elastic connective tissues, especially blood vessels and the heart.
Thiol oxidase Epithelia, cornea (anterior part of the outer eye skin), and other tissues Formation of disulfide bridges, for example in keratin – structural protein responsible for cell stability and shape
Uratoxidase – uricase Liver, spleen and kidneys Degradation of uric acid to allantoin, the end product of the breakdown of purine bases
Aminoxidase Mitochondria Oxidation of primary amines, such as histamine, tyramine, dopamine, serotonin, and putrescine, to aldehydes
Monoamine oxidase Central nervous system and other tissues in the body periphery Metabolism of the neurotransmitters epinephrine, norepinephrine, and dopamineDesamination of catecholamines, including breakdown of the neurotransmitter serotonin – this is the basis for the use of MAO inhibitors as antidepressants