Epoxide hydrolase
Encyclopedia
Epoxide hydrolase functions in detoxication
during drug metabolism
. It converts epoxide
s to trans-dihydrodiols, which can be conjugated and excreted from the body. Epoxides result from the degradation of aromatic compounds. Deficiency in this enzyme in patients receiving aromatic-type anti-epileptic drugs such as phenytoin
is reported to lead to DRESS syndrome
.
Epoxides are significant as cytochrome P450 oxidase
metabolites of unsaturated carbon
-carbon bonds, but are also mutagenic. Epoxide hydrolase is present in large quantity on endoplasmic reticulum
.
The structure of hydrolase B contains a cap domain, which is hypothesized to regulate the active site of the hydrolase. Furthermore, Asp104, His333, and Asp302 form the catalytic triad of the protein and is critical to function of the protein.
At present, other structures of Mycobacterium tuberculosis hydrolase have not been solved.
s of epoxide hydrolase:
Detoxication
Detoxication products are the major metabolites formed from most drug metabolism.There are two common patterns observed:#A drug with potent pharmacological activity is converted to a major metabolite with markedly reduced or no pharmacological activity #A drug is converted to a metabolite with...
during drug metabolism
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
. It converts epoxide
Epoxide
An epoxide is a cyclic ether with three ring atoms. This ring approximately defines an equilateral triangle, which makes it highly strained. The strained ring makes epoxides more reactive than other ethers. Simple epoxides are named from the parent compound ethylene oxide or oxirane, such as in...
s to trans-dihydrodiols, which can be conjugated and excreted from the body. Epoxides result from the degradation of aromatic compounds. Deficiency in this enzyme in patients receiving aromatic-type anti-epileptic drugs such as phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
is reported to lead to DRESS syndrome
DRESS syndrome
DRESS syndrome stands for Drug Reaction with Eosinophilia and Systemic Symptoms. The term was coined in a 1996 report in an attempt to simplify terminology for a syndrome recognized as early as 1959...
.
Epoxides are significant as cytochrome P450 oxidase
Cytochrome P450 oxidase
The cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances...
metabolites of unsaturated carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
-carbon bonds, but are also mutagenic. Epoxide hydrolase is present in large quantity on endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
.
Drug target
Mycobacterium tuberculosis, the major causative agent of tuberculosis, expresses at least six different forms of epoxide hydrolase (forms A-F). The structure of epoxide hydrolase B reveals that the enzyme is a monomer and contains an alpha/beta hydrolase fold. In addition to providing insights into the enzyme mechanism, this hydrolase currently serves as a platform for rational drug design of potent inhibitors. In particular, urea based inhibitors have been developed. These inhibitors directly target the catalytic cavity. It is hypothesized that the structure of epoxide hydrolase B may allow for drug design to inhibit all other Mycobacterium tuberculosis hydrolases as long as they contain similar alpha/beta folds.The structure of hydrolase B contains a cap domain, which is hypothesized to regulate the active site of the hydrolase. Furthermore, Asp104, His333, and Asp302 form the catalytic triad of the protein and is critical to function of the protein.
At present, other structures of Mycobacterium tuberculosis hydrolase have not been solved.
Isozymes
Humans express the following four isozymeIsozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...
s of epoxide hydrolase: