Regulation of uridine diphosphate‐glucuronosyltransferase 1A3 activity by protein phosphorylation. (16th July 2015)

• Record Type: Journal Article
• Authors: Xiao, Yongsheng; Yao, Yan; Jiang, Huidi; Lu, Chuan; Zeng, Su; Yu, Lushan
• Is Part Of: Biopharmaceutics & drug disposition. Volume 36:Number 8(2015:Nov.)
• Page Start: 520
• Page End: 528
• Publication Date: 2015-07-16
• Subjects: calphostin C -- curcumin -- PKC -- phosphorylation -- UGT1A3; Biopharmaceutics -- Periodicals; Drugs -- Metabolism -- Periodicals; Pharmacology -- Periodicals; Biopharmaceutics -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; 615.19
• DOI: 10.1002/bdd.1963
• Languages: English
• ISSNs: 0142-2782

Abstract

Abstract: Protein phosphorylation is a vital post‐translational modification. This study investigated the effect of phosphorylation on human uridine diphosphate (UDP)‐glucuronosyltransferase 1A3 (UGT1A3) activity. Curcumin and calphostin C suppressed the activity and phosphorylation of recombinant UGT1A3 expressed in Sf9 cells. These results indicate that UGT1A3 undergoes phosphorylation, which is required for its catalytic activity. Calphostin C is a highly specific protein kinase C (PKC) inhibitor, so three predicted PKC phosphorylation sites in UGT1A3 were examined. Site‐directed mutation analysis at residues 28, 43 and 436 (from serine to glycine) was conducted. Compared with the wild‐type, the S43G‐mutant showed significantly decreased UGT1A3 catalytic activity. Furthermore, the UGT1A3 activity of wild‐type and S43G‐mutant was down‐regulated by calphostin C, whereas the calphostin C inhibitory effect was much weaker on the S43G‐mutant than the wild‐type. In conclusion, phosphorylation plays an important role in UGT1A3 activity, and the serine at site 43 in UGT1A3 is most likely a phosphorylation site. Copyright © 2015 John Wiley & Sons, Ltd.