Superoxide dismutase-4

Details Superoxide dismutase-4 Superoxide dismutase-4

1997-01-23

1999-02-16

Grimes, Eric

Drug, bio-affecting and body treating compositions

Enzyme or coenzyme containing

Oxidoreductases

435189, A61K 3844, C12N 902

Patent

active

058717293

DESCRIPTION:

BRIEF SUMMARY
This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and polypeptides, as well as the production of such polynucleotides and polypeptides. More particularly, the polypeptide of the present invention is Superoxide Dismutase-4 (SOD-4).
There is a very strong thermodynamic driving force for the reactions between oxygen and biochemical compounds in the body such as proteins, carbohydrates, lipids and nucleic acids. If such reactions go to completion, water, carbon dioxide and a number of waste products are formed as end products with the release of large amounts of energy. Oxidation of biological compounds is the source of energy of living organisms. Such reactions occur spontaneously but are very slow due to reaction barriers. These barriers are overcome by enzymes in intermediary metabolism, and the final reaction with oxygen takes place in the mitochondria, where the oxygen is reduced by four electrons to water without the liberation of any intermediate products. The reaction is accomplished by cytochrome oxidase complex in the electron transport chain and the energy is bound by the formation of ATP.
However, the direct four step reduction of oxygen to water is unique, and when oxygen reacts spontaneously or is catalyzed by enzymes it is forced to react one step at a time. A series of reactive and toxic intermediates are formed, namely the superoxide radical (O.sub.2.sup.-), hydrogen peroxide (H.sub.2 O.sub.2), and the hydroxyl radical (OH.sup.-) .
Two of these, O.sub.2.sup.- and OH.sup.-, have single unpaired electrons and are therefore called free radicals. A few percent of the oxygen consumption in the body has been estimated to lead to the formation of the toxic reduction intermediates. The toxic affects of oxygen are mainly ascribable to the actions of these intermediates.
Oxygen in itself reacts slowly with most biochemical compounds. The toxic reactions are in general initiated by processes giving rise to oxygen radicals, which in themselves cause direct damage to biochemical compounds or start chain reactions involving oxygen.
Some compounds react spontaneously with oxygen, i.e., they autoxidize. Virtually all autoxidations result in the formation of toxic oxygen reduction intermediates. Autoxidation of adrenalin, pyrogallol and several other compounds lead to the formation of the superoxide radical. When ionizing radiation passes through an aqueous solution containing oxygen, the superoxide radical is the radical found in the highest concentration. The toxic oxygen reduction products so formed are of fundamental importance for the killing ability of the cells, but may also lead to damage in the surrounding tissue.
Hydrogen peroxide is always formed when superoxide is formed by way of the dismutation reaction. Most oxidases in the body directly reduce oxygen to hydrogen peroxide.
Organisms living in the presence of oxygen have been forced to develop a number of protective mechanisms against the toxic oxygen reduction metabolites. The protective factors include superoxide dismutases (SOD) which dismutate the superoxide radical and are found in relatively constant amounts in mammalian cells and tissue. The best known of these enzymes is CuZnSOD which is a dimer with a molecular weight of 33,000 containing two copper and two zinc atoms. CuZnSOD is found in the cytosol and in the intermembrane space of the mitochondria. MnSOD is a tetramer with a molecular weight of 85,000 containing four Mn atoms, and is mainly located in the mitochondrial matrix. Until recently the extra cellular fluids were assumed to lack SOD activity. However U.S. Pat. No. 5,248,603 recently disclosed the presence of a superoxide dismutase in extracellular fluids (e.g., blood plasma, lymph, synovial fluid and cerebrospinal fluid) which was termed EC-SOD.
Crystallographic structures of recombinant human CuZnSOD have been determined, refined and analyzed at 2.5 A resolution for wild-type and a designed thermal stable double-mutant enzyme (Cys-6--Ala,

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