Cyclooxygenases are enzymes involved in the production of prostaglandins. These, in turn, cause inflammation.
What are cyclooxygenases?
Cyclooxygenases (COX) are among the enzymes. They participate in arachidone metabolism. There, they catalyze the production of thromboxanes and prostaglandins. The COX enzymes are centrally involved in the regulation of inflammation. Cyclooxygenase has been known to humans since the 1930s. The first purified production of cyclooxidases occurred in the 1970s from sheep and bovine tissue homogenates. Starting in 1972, speculation also began as to whether there was more than one cyclooxygenase. In the 1990s, the protein structures of cyclooxygenase-1 and cyclooxygenase-2 could be sequenced. The two isoenzymes differ from each other by their gene locus. In addition, their structures were elucidated, which allowed the production of drugs that affect the enzymes.
Function, action, and roles
Cyclooxygenases are divided into two subtypes. These are cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). These are two different forms of the enzyme. Their amino acids are 68 percent identical. Furthermore, there is evidence that another cyclooxygenase exists, known as cyclooxygenase-3. COX-1 and COX-2 play an important role in therapeutic medicine. Cyclooxygenase-1 is an enzyme that is constitutively expressed. It also synthesizes prostaglandins to a greater extent within a healthy body. Larger amounts of COX-1 are primarily found in the kidneys and the stomach wall. COX-2 is expressed particularly in tissues that are inflamed or damaged. This is where the prostaglandins are produced. These either maintain inflammation or even intensify it. The cyclooxygenases have the function of catalyzing the conversion of arachidonic acid into prostaglandin-H2. This is also true for eicosapentaenoic acid (EPA) and dihomogammalinolenic acid (DGLA). The process takes place in two steps, which occur in the reaction centers of the enzyme. Step 1 is carried out in the catalytic center. It consists of a ring closure between carbon atoms C8 and C12. In addition, the insertion of two oxygen atoms occurs at C9 and C11. These then form a covalent bond with each other, resulting in the formation of a peroxide bridge in prostaglandin-G2. The prostaglandin-G2 that is formed can diffuse out of the channel. The second step takes place by catalyzing the reaction center with peroxidase activity. In this process, prostaglandin-H2 is formed from the prostaglandin-G2. This provides for the synthesis of further prostaglandins.
Formation, occurrence, properties, and optimal values
Cyclooxygenases are found in the inner portion of the endoplasmic reticulum, inside the nuclear envelope, and in the Golgi apparatus. In this process, they attach to the inner sides of cell compartment membranes. They are also present in the cells of animals. In contrast, they are not found in insects, plants or unicellular organisms. However, related enzymes such as pathogen-inducible oxygenases are found in these. The presence of COX-1 occurs in the endothelial cells of normal blood vessels, whereas COX-2 is found in the endothelial cells of proliferating blood vessels of inflamed tissues. In addition, COX-2 is often present in tumor cells, where it proliferates. Physicians suspect that the enzyme plays a role in tumor growth. COX-2 is also produced to an increased extent in the brain in the context of inflammation. The enzyme is found in the endothelial cells of the hypothalamus vessels. In this process, the fever-inducing PGE2 is formed. Sometimes COX-2 is also formed in neurons and glial cells. Within the kidneys, cyclooxygenase-2 is primarily found in the macula densa. This results in increased production of prostacyclin, which starts the formation of the enzyme renin. COX-2 is always present in the spinal cord. There it serves to process pain stimuli.
Diseases and disorders
Cyclooxygenases play a significant role in disease, and this is especially true for cyclooxygenase-2. Thus, increased transcription of COX-2 occurs during inflammatory processes, and so-called COX-2 inhibitors are administered to treat the associated symptoms, such as pain and fever.These are anti-inflammatory drugs that belong to the group of non-steroidal anti-inflammatory drugs (NSAIDs). Unlike classical antipyretics, which affect both COX-1 and COX-2, COX-2 inhibitors focus on blocking cyclooxygenase-2. COX-2 is frequently detected in malignant cancer tumors. Prostaglandins such as PGE2, which are produced in tumor tissue, directly affect tumor cells and tumor stroma. For this reason, cancer research is pinning hopes on a positive effect of COX-2 inhibitors. which is especially true for cancers of the gastrointestinal tract. These drugs attack both the invariable stroma and the highly variable cells of the tumor. This reduces the likelihood of resistance developing. What functions cyclooxygenase-2 plays in brain cells has not yet been clarified. Therefore, the question of whether prolonged use of COX-2 inhibitors has a physiological effect on the brain has also remained unanswered. However, numerous stimuli elicit the generation of COX-2 in neurons, astrocytes, and microglia. These include epileptic seizures, inflammation, hypoxia, and toxins that have an excitatory effect. However, the effects of this process are still unclear. Furthermore, physicians suspect an influence of cyclooxygenases on the development of Alzheimer’s disease. Cyclooxygenase inhibitors are primarily antirheumatic drugs, analgesics, antiphlogistics and antipyretics. These include acetylsalicylic acid and ibuprofen, among others.
