Glucuronosyltransferase
Encyclopedia
Uridine 5'-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT) is a glycosyltransferase
that catalyzes addition of the glycosyl
group from a UTP
-sugar to a small hydrophobic molecule.
This is glucuronidation
reaction.
Alternative names:
, a major part of phase II metabolism. Arguably the most important of the Phase II (conjugative) enzymes, UGTs have been the subject of increasing scientific inquiry since the mid-to-late 1990s.
The reaction catalyzed by the UGT enzyme involves the addition of a glucuronic acid moiety to xenobiotics and is the most important pathway for the human body's elimination of the top 200 drugs. It is also the major pathway for foreign chemical (dietary, environmental, pharmaceutical) removal for most drugs, dietary substances, toxins and endogenous substances. UGT is present in humans, other animals, plants, and bacteria. Famously, UGT enzymes are not present in the genus Felis, and this accounts for a number of unusual toxicities in the cat family.
The glucuronidation reaction consists of the transfer of the glucuronosyl
group from uridine 5'-diphospho-glucuronic acid (UDPGA) to substrate
molecules that contain oxygen, nitrogen, sulfur or carboxyl functional groups.
The resulting glucuronide
is more polar (e.g. hydrophilic) and more easily excreted than the substrate molecule. The product solubility in blood is increased allowing it to be eliminated from the body by the kidney
s.
, which is characterized by unconjugated hyperbilirubinemia.
It is also associated with Crigler-Najjar syndrome
, a more serious disorder where the enzyme's activity is either completely absent (Crigler-Najjar syndrome type I) or less than 10% of normal (type II).
Infants may have a developmental deficiency in UDP-glucuronyl transferase, and are unable to hepatically metabolize the antibiotic drug chloramphenicol
which requires glucuronidation. This leads to a condition known as Gray baby syndrome
.
Glycosyltransferase
Glycosyltransferases are enzymes that act as a catalyst for the transfer of a monosaccharide unit from an activated nucleotide sugar to a glycosyl acceptor molecule, usually an alcohol....
that catalyzes addition of the glycosyl
Glycosyl
A glycosyl group is a univalent free radical or substituent structure obtained by removing the hemiacetal hydroxyl group from the cyclic form of a monosaccharide and, by extension, of a lower oligosaccharide....
group from a UTP
UTP
UTP may refer to:* Unlisted Trading Privileges - in finance - the statutory basis for, and by extension, an electronic network which carries quotes and trades for the New York-based NASDAQ stock_exchange....
-sugar to a small hydrophobic molecule.
This is glucuronidation
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
reaction.
Alternative names:
- glucuronyltransferase
- UDP-glucuronyl transferase
- UDP-GT
Function
Glucuronosyltransferases are responsible for the process of glucuronidationGlucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
, a major part of phase II metabolism. Arguably the most important of the Phase II (conjugative) enzymes, UGTs have been the subject of increasing scientific inquiry since the mid-to-late 1990s.
The reaction catalyzed by the UGT enzyme involves the addition of a glucuronic acid moiety to xenobiotics and is the most important pathway for the human body's elimination of the top 200 drugs. It is also the major pathway for foreign chemical (dietary, environmental, pharmaceutical) removal for most drugs, dietary substances, toxins and endogenous substances. UGT is present in humans, other animals, plants, and bacteria. Famously, UGT enzymes are not present in the genus Felis, and this accounts for a number of unusual toxicities in the cat family.
The glucuronidation reaction consists of the transfer of the glucuronosyl
Glucuronic acid
Glucuronic acid is a carboxylic acid. Its structure is similar to that of glucose. However, glucuronic acid's sixth carbon is oxidized to a carboxylic acid...
group from uridine 5'-diphospho-glucuronic acid (UDPGA) to substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
molecules that contain oxygen, nitrogen, sulfur or carboxyl functional groups.
The resulting glucuronide
Glucuronide
A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond...
is more polar (e.g. hydrophilic) and more easily excreted than the substrate molecule. The product solubility in blood is increased allowing it to be eliminated from the body by the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s.
Diseases
A deficiency in the bilirubin specific form of glucuronosyltransferase is thought to be the cause of Gilbert's syndromeGilbert's syndrome
Gilbert's syndrome , often shortened to GS, also called Gilbert-Meulengracht syndrome, is the most common hereditary cause of increased bilirubin and is found in up to 5% of the population...
, which is characterized by unconjugated hyperbilirubinemia.
It is also associated with Crigler-Najjar syndrome
Crigler-Najjar syndrome
Crigler-Najjar Syndrome or CNS is a rare disorder affecting the metabolism of bilirubin, a chemical formed from the breakdown of blood. The disorder results in an inherited form of non-hemolytic jaundice, which results in high levels of unconjugated bilirubin and often leads to brain damage in...
, a more serious disorder where the enzyme's activity is either completely absent (Crigler-Najjar syndrome type I) or less than 10% of normal (type II).
Infants may have a developmental deficiency in UDP-glucuronyl transferase, and are unable to hepatically metabolize the antibiotic drug chloramphenicol
Chloramphenicol
Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...
which requires glucuronidation. This leads to a condition known as Gray baby syndrome
Gray baby syndrome
Gray baby syndrome is a rare but serious side effect that occurs in newborn infants following the intravenous administration of the antimicrobial chloramphenicol.-Pathophysiology:...
.
Genes
Human genes which encode UGT enzymes include:- B3GAT1B3GAT1Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 is an enzyme that in humans is encoded by the B3GAT1 gene.In immunology, the CD57 antigen is a protein which is also called HNK1 or LEU7...
, B3GAT2B3GAT2Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 2 is an enzyme that in humans is encoded by the B3GAT2 gene.-Use of HNK-1 Antibody for Neural Crest Research:...
, B3GAT3B3GAT3Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 is an enzyme that in humans is encoded by the B3GAT3 gene.-Further reading:... - UGT1A1UGT1A1UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the UGT1A1 gene.UGT-1A is a uridine diphosphate glucuronyltransferase , an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and...
, UGT1A3UGT1A3UDP-glucuronosyltransferase 1-3 is an enzyme that in humans is encoded by the UGT1A3 gene.-Further reading:...
, UGT1A4UGT1A4UDP-glucuronosyltransferase 1-4 is an enzyme that in humans is encoded by the UGT1A4 gene. It is the main enzyme responsible for glucuronidation of the anticonvulsant lamotrigine.-Further reading:...
, UGT1A5UGT1A5UDP-glucuronosyltransferase 1-5 is an enzyme that in humans is encoded by the UGT1A5 gene.- Function :This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into...
, UGT1A6UGT1A6UDP-glucuronosyltransferase 1-6 is an enzyme that in humans is encoded by the UGT1A6 gene.- Function :UDP-glucuronosyltransferase 1-6 is a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and...
, UGT1A7, UGT1A8UGT1A8UDP-glucuronosyltransferase 1-8 is an enzyme that in humans is encoded by the UGT1A8 gene.- Function :This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into...
, UGT1A9UGT1A9UDP-glucuronosyltransferase 1-9 is an enzyme that in humans is encoded by the UGT1A9 gene.- Function :This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into...
, UGT1A10UGT1A10UDP-glucuronosyltransferase 1-10 is an enzyme that in humans is encoded by the UGT1A10 gene.-Further reading:... - UGT2A1UGT2A1UDP glucuronosyltransferase 2 family, polypeptide B1, also known as UGT2B1, is an enzyme that in humans is encoded by the UGT2B1 gene.- Function :...
, UGT2A2UGT2A2UDP glucuronosyltransferase 2 family, polypeptide A2, also known as UGT2A2, is an enzyme that in humans is encoded by the UGT2A2 gene.- Function :...
, UGT2A3, UGT2B4UGT2B4UDP glucuronosyltransferase 2 family, polypeptide B4, also known as UGT2B4, is an enzyme that in humans is encoded by the UGT2B4 gene.- Function :...
, UGT2B7UGT2B7UGT2B7 is a phase II metabolism isoenzyme found to be active in the liver, kidneys, epithelial cells of the lower gastrointestinal tract and also has been reported in the brain...
, UGT2B10UGT2B10UDP-glucuronosyltransferase 2B10 is an enzyme that in humans is encoded by the UGT2B10 gene.-Further reading:...
, UGT2B11, UGT2B15UGT2B15UDP-glucuronosyltransferase 2B15 is an enzyme that in humans is encoded by the UGT2B15 gene.-Further reading:...
, UGT2B17UGT2B17UDP-glucuronosyltransferase 2B17 is an enzyme that in humans is encoded by the UGT2B17 gene.-Further reading:...
, UGT2B28