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Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal
glycosyltransferase Glycosyltransferases (GTFs, Gtfs) are enzymes (EC 2.4) that establish natural glycosidic linkages. They catalyze the transfer of saccharide moieties from an activated nucleotide sugar (also known as the "glycosyl donor") to a nucleophilic glyco ...
() that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is a
glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...
reaction. ''Alternative names:'' *glucuronyltransferase *UDP-glucuronyl transferase *UDP-GT


Function

Glucuronosyltransferases are responsible for the process of
glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...
, a major part of
phase II metabolism Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set ...
. 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 most frequently prescribed 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 A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to gl ...
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 The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
s.


Diseases

A deficiency in the
bilirubin Bilirubin (BR) ( Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from t ...
specific form of glucuronosyltransferase is thought to be the cause of
Gilbert's syndrome Gilbert syndrome (GS) is a syndrome in which the liver of affected individuals processes bilirubin more slowly than the majority. Many people never have symptoms. Occasionally jaundice (a slight yellowish color of the skin or whites of the eyes) ...
, 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 Chloramphenicol is an antibiotic useful for the treatment of a number of bacterial infections. This includes use as an eye ointment to treat conjunctivitis. By mouth or by injection into a vein, it is used to treat meningitis, plague, chole ...
which requires glucuronidation. This leads to a condition known as
gray baby syndrome Gray baby syndrome (also termed Gray or Grey syndrome) is a rare but serious, even fatal, side effect that occurs in newborn infants (especially premature babies) following the accumulation of antibiotic chloramphenicol. Chloramphenicol is a broad ...
.


Causes

Causes of unconjugated hyperbilirubinemia are divided into three main categories, namely, excessive
bilirubin Bilirubin (BR) ( Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from t ...
synthesis, liver bilirubin uptake malfunction, and bilirubin conjugation compromise. As to excessive bilirubin synthesis, both
intravascular hemolysis Intravascular hemolysis describes hemolysis that happens mainly inside the vasculature. As a result, the contents of the red blood cell are released into the general circulation, leading to hemoglobinemia and increasing the risk of ensuing hyperb ...
and
extravascular hemolysis Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo ...
can involve in the pathophysiology. Additionally,
dyserythropoiesis Dyserythropoiesis refers to the defective development of red blood cells, also called erythrocytes. This problem can be congenital, acquired, or inherited. Some red blood cells may be destroyed within the bone marrow during the maturation process, ...
and extravasation of
blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...
into tissues such as
angioedema Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are ...
and
edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area ma ...
can also lead to indirect hyperbilirubinemia, along with
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
,
medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
-induced, ethinyl estradiol,
chronic hepatitis Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pain ...
, and
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...
that are, otherwise, attributed to hepatic bilirubin mal-uptake and bilirubin conjugation compromise, respectively.


Genes

Human genes which encode UGT enzymes include: * B3GAT1, B3GAT2, B3GAT3 *
UGT1A1 UDP-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 glucuronosyltransferase (UDP-glucuronosyltransferase, UDPGT), an enzyme of the glucuronidation pat ...
, UGT1A3,
UGT1A4 UDP-glucuronosyltransferase 1-4 is an enzyme that in humans is encoded by the ''UGT1A4'' gene. This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as ster ...
,
UGT1A5 UDP-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, suc ...
,
UGT1A6 UDP-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 ...
, UGT1A7, UGT1A8,
UGT1A9 UDP-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 a ...
,
UGT1A10 UDP-glucuronosyltransferase 1-10 is an enzyme that in humans is encoded by the ''UGT1A10'' gene. This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroid ...
* UGT2A1, UGT2A2,
UGT2A3 Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is ...
,
UGT2B4 UDP glucuronosyltransferase 2 family, polypeptide B4, also known as UGT2B4, is an enzyme that in humans is encoded by the ''UGT2B4'' gene. Function UGT2B4 is mainly involved in the glucuronidation of hyodeoxycholic acid, a bile acid, and cate ...
, UGT2B7, UGT2B10,
UGT2B11 UDP glucuronosyltransferase 2 family, polypeptide B4, also known as UGT2B4, is an enzyme that in humans is encoded by the ''UGT2B4'' gene. Function UGT2B4 is mainly involved in the glucuronidation of hyodeoxycholic acid, a bile acid, and catec ...
, UGT2B15,
UGT2B17 UDP-glucuronosyltransferase 2B17 is an enzyme that in humans is encoded by the ''UGT2B17'' gene. UGT2B17 belongs to the family of UDP-glucuronosyltransferases (UGTs; EC 2.4.1.17), enzymes that catalyze the transfer of glucuronic acid from urid ...
, UGT2B28


References


External links

* {{Portal bar, Biology, border=no Transferases EC 2.4.1