Importance of Histidine Residues for the Function of the Human Liver UDP-Glucuronosyltransferase UGT1A6: Evidence for the Catalytic Role of Histidine 370

2000 ◽  
Vol 58 (6) ◽  
pp. 1609-1615 ◽  
Author(s):  
Mohamed Ouzzine ◽  
Laurence Antonio ◽  
Brian Burchell ◽  
Patrick Netter ◽  
Sylvie Fournel-Gigleux ◽  
...  
Keyword(s):  
Human Liver ◽  
Histidine Residues ◽  
Catalytic Role ◽  
Udp Glucuronosyltransferase

scholarly journals Glucuronidation of hyodeoxycholic acid in human liver. Evidence for a selective role of UDP-glucuronosyltransferase 2B4.

1993 ◽  
Vol 268 (34) ◽  
pp. 25636-25642
Author(s):  
T Pillot ◽  
M Ouzzine ◽  
S Fournel-Gigleux ◽  
C Lafaurie ◽  
A Radominska ◽  
...  
Keyword(s):  
Human Liver ◽  
Hyodeoxycholic Acid ◽  
Udp Glucuronosyltransferase

scholarly journals Enantiomer Selective Glucuronidation of the Non-Steroidal Pure Anti-Androgen Bicalutamide by Human Liver and Kidney: Role of the Human UDP-Glucuronosyltransferase (UGT)1A9 Enzyme

2013 ◽  
Vol 113 (2) ◽  
pp. 92-102 ◽  
Author(s):  
Laurent Grosse ◽  
Anne-Sophie Campeau ◽  
Sarah Caron ◽  
Frédéric-Alexandre Morin ◽  
Kim Meunier ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver And Kidney ◽  
Udp Glucuronosyltransferase

scholarly journals Role of cysteine residues in the function of human UDP glucuronosyltransferase isoform 1A1 (UGT1A1)

2005 ◽  
Vol 392 (3) ◽  
pp. 685-692 ◽  
Author(s):  
Siddhartha S. Ghosh ◽  
Yang Lu ◽  
Sung W. Lee ◽  
Xia Wang ◽  
Chandan Guha ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Nucleotide Sequence Analysis ◽  
Cysteine Residues ◽  
Thiol Groups ◽  
Functional Importance ◽  
Biliary Elimination ◽  
Udp Glucuronosyltransferase

Bilirubin glucuronidation, catalysed by UGT1A1 [UGT (UDP glucuronosyltransferase) isoform 1A1, EC 2.4.1.17], is critical for biliary elimination of bilirubin. UGT1A1 deficiency causes CN-1 (Crigler–Najjar syndrome type 1), which is characterized by potentially lethal unconjugated hyperbilirubinaemia. Nucleotide sequence analysis of UGT1A1 in two CN-1 patients revealed that patient A was homozygous for a nt 530 G→A (where nt 530 G→A means guanine to adenine transition at nucleotide 530) mutation, predicting a C177Y substitution, and patient B had a nt 466 T→C mutation on one allele and a nt 1070 A→G mutation on the other, predicting a C156R and a Q357R substitution respectively. All 11 cysteine residues of mature human UGT1A1 are highly conserved in other human UGT isoforms and in rat, mouse and Rhesus monkey UGT1A1, suggesting their functional importance. Expression of mutagenized UGT1A1 plasmids showed that substitution of any of the seven cysteine residues located within the endoplasmic reticulum cisternae (including those mutated in patients A and B) abolished UGT1A1 activity or markedly increased its apparent Km for bilirubin. Substitution of the three cysteine residues within the C-terminal cytosolic tail had minimal effect on basal UGT1A1 activity, but prevented UGT1A1 activation by UDP-GlcNAc. N-Ethylmaleimide did not inhibit UGT1A1 activity in native microsomes, but prevented UGT1A1 activation by UDP-GlcNAc and inhibited the activity in digitonin-permeabilized microsomes. Dithiothreitol did not affect UGT1A1 activity in human liver microsomes. Together, the results suggested that free thiol groups, but not disulphide bonding, of seven cysteine residues within the intracisternal region of human UGT1A1 are important for its catalytic activity, while cysteine residues in the cytosolic domain may be involved in its physiological activation by UDP-GlcNAc.

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