UGT2B4

UGT2B4 Full Name

UDP glucuronosyltransferase 2 family, polypeptide B4

UGT2B4 Introduction

UGT2B4 encodes a UDP-glucuronosyltransferase belonging to the human UGT2B subfamily of phase II metabolizing enzymes. Like other family members, it catalyzes the transfer of glucuronic acid from UDP-glucuronic acid to acceptor molecules, generating water-soluble glucuronides that can be more readily excreted into bile or urine. UGT2B4 is expressed primarily in the liver, where it occupies a specialized role among the conjugation enzymes. The enzyme is most strongly associated with the metabolism of bile acids, particularly the detoxification of hydrophobic bile acids that would otherwise accumulate to toxic levels within hepatocytes. The UGT2B subfamily, to which UGT2B4 belongs, is organized as a cluster of closely related genes and produces enzymes that often overlap in their substrate preferences while retaining distinct specializations. Its tissue-restricted expression and narrow but critical substrate range distinguish it from broader-specificity isoforms such as those in the UGT1A family.

Figure 1. Synthesis and glucuronide conjugation of the major human bile acids. (Source: Barbier O, et al. 2009)

The defining activity of UGT2B4 is the glucuronidation of bile acids, notably hyodeoxycholic acid, which it conjugates with high selectivity at the 6-hydroxyl position. Antibodies raised against the enzyme can inhibit the large majority of hepatic hyodeoxycholic acid glucuronidation activity, confirming that UGT2B4 is the predominant isoform responsible for this reaction in human liver. The enzyme is also induced by the bile acid-activated nuclear receptor FXR, which binds a response element in the UGT2B4 promoter; this creates a feedback loop in which bile acids stimulate their own conjugation and clearance, blunting their intrinsic toxicity. Structural and mutagenesis work further shows that an aromatic residue at position 33 helps determine the substrate specificity shared between UGT2B4 and the related enzyme UGT2B7. Because impaired bile acid conjugation can contribute to cholestatic injury, the activity of UGT2B4 is relevant both to normal liver physiology and to liver disease, and its polymorphic variation contributes to interindividual differences in bile acid handling.

Alternate Names for UGT2B4

UGT2B4; UDP glucuronosyltransferase 2 family, polypeptide B4; UDP glycosyltransferase 2 family, polypeptide B4; UDP-glucuronosyltransferase 2B4; UGT2B11; UDPGTh-1; UDPGT 2B4; hyodeoxycholic acid; UDP glucuronosyltransferase 2B4; hyodeoxycholic acid-specific UDPGT

• 1. Barbier O, et al. Lipid-activated transcription factors control bile acid glucuronidation. Mol Cell Biochem. 2009 Jun;326(1-2):3-8.
  2. Barbier O, et al. FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity. Gastroenterology. 2003 Jun;124(7):1926-40.