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UDP –Glucuronyl Transferase- reaction catalyzed and significance- Semester Paper
This is an enzyme of Uronic acid pathway. Uronic acid pathway is an alternative pathway for the oxidation of glucose that does not provide a means of producing ATP, but is utilized for the generation of the activated form of glucuronate, UDP-glucuronate which is mainly used for detoxification of foreign chemicals, some endogenous compounds like bilirubin,certain hormones, metabolites and for the synthesis of mucopolysaccharides.This pathway also produces Ascorbic acid in certain animals.
The unutilized Glucuronate produced in this pathway is converted to Xylulose-5 P which is further metabolized through HMP pathway.(Figure-1)
Figure1-showing the overview of Uronic acid pathway
Biological significance of UDP –Glucuronyl Transferase
UDP glucuronate the active form of Glucuronic acid, can readily donate the Glucuronic acid component under the catalytic activity of UDP –Glucuronyl Transferase for the following functions-
1) Detoxification of foreign compounds and drugs- During detoxification, the glucuronate residues are covalently attached to lipid soluble substances. Since glucuronate residues are strongly polar, their attachment imparts polar character to these substances, making them water-soluble and readily excretable. Bilirubin, certain hormones and drugs are made more polar for renal excretion in this manner. UDP-Glucuronic acid is the Glucuronyl donor, and a variety of glucuronosyl transferases, present in both the endoplasmic reticulum and cytosol, are the catalysts. Molecules such as 2-acetylaminofluorene (a carcinogen), aniline,benzoic acid, meprobamate (a tranquilizer), phenol, and many steroids are excreted as glucuronides. The glucuronide may be attached to oxygen, nitrogen,or sulfur groups of the substrates. Glucuronidation is probably the most frequent conjugation reaction.
2) Synthesis of Mucopolysaccharides-UDP Glucuronic acid is an essential component of Hyaluronic acid and heparin.
3) Conjugation of Bilirubin-Bilirubin is nonpolar and would persist in cells (eg, bound to lipids) if not rendered water-soluble. Hepatocytes convert bilirubin to a polar form, which is readily excreted in the bile, by adding Glucuronic acid molecules to it. This process is called conjugation.
The conjugation of bilirubin is catalyzed by a specific Glucuronyl transferase.The enzyme is mainly located in the endoplasmic reticulum, uses UDP-Glucuronic acid as the glucuronosyl donor, and is referred to as bilirubin-UGT. BilirubinMonoglucuronide is an intermediate and is subsequently converted to the diglucuronide. Most of the bilirubin excreted in the bile of mammals is in the form of bilirubin diglucuronide.(Figure-2)
Figure- 2-showing the conjugation of bilirubin
Clinical significance Diminished activity of Bilirubin UDP Glucuronyl Transferase (UGT)
1) Neonatal “Physiologic Jaundice”
This transient condition is the most common cause of Unconjugated hyper-bilirubinemia. It results from an accelerated hemolysis around the time of birth and an immature hepatic system for the uptake, conjugation, and secretion of bilirubin. Not only is the bilirubin-UGT activity reduced, but there probably is reduced synthesis of the substrate for that enzyme,UDP-glucuronic acid. Since the increased amount of bilirubin is unconjugated,it is capable of penetrating the blood-brain barrier when its concentration in plasma exceeds that which can be tightly bound by albumin (20–25 mg/dL). This can result in a hyperbilirubinemic toxic encephalopathy, or kernicterus,which can cause mental retardation. Because of the recognized inducibility of this bilirubin UGT enzyme system, phenobarbital has been administered to jaundiced neonates and is effective in this disorder. In addition, exposure to blue light (phototherapy) promotes the hepatic excretion of unconjugated bilirubin by converting some of the bilirubin to other derivatives such as maleimide fragments and geometric isomers that are excreted in the bile.
2) Crigler-Najjar Syndrome, Type I; Congenital Nonhemolytic Jaundice
a) TypeI Crigler-Najjar syndrome -is a rare autosomal recessive disorder. It is characterized by severe congenital jaundice(serum bilirubin usually exceeds 20 mg/dL) due to mutations in the gene encoding bilirubin-UGT activity in hepatic tissues. The disease is often fatal within the first 15 months of life. Children with this condition have been treated with phototherapy, resulting in some reduction in plasma bilirubinlevels. Phenobarbital has no effect on the formation of bilirubin glucuronides in patients with type I Crigler-Najjar syndrome. A liver transplant may be curative. It should be noted that the gene encoding human bilirubin-UGT is part of a large UGT gene complex situated on chromosome 2. Many different substrates are subjected to glucuronosylation, so many glucuronosyl transferases are required.
b) Crigler-Najjar Syndrome Type II-This rare inherited disorder also results from mutations in the gene encoding bilirubin-UGT, but some activity of the enzyme is retained and the condition has a more benign course than type I. Serum bilirubin concentrations usually do not exceed 20 mg/dL. Patients with this condition can respond to treatment with large doses of phenobarbital.
3) Gilbert Syndrome
Again,this relatively prevalent condition is caused by mutations in the gene encoding bilirubin-UGT. It is more common among males. Approximately 30% of the enzyme’s activity is preserved and the condition is entirely harmless.