Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
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In silico and in vitro Approaches to Elucidate the Thermal Stability of Human UDP-glucuronosyltransferase (UGT) 1A9
Ryoichi FUJIWARAMiki NAKAJIMATetsunori YAMAMOTOHidemi NAGAOTsuyoshi YOKOI
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Volume 24 (2009) Issue 3 Pages 235-244

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Abstract

  UDP-Glucuronosyltransferases (UGTs) are predominant drug metabolizing enzymes in the liver and extrahepatic tissues. Human UGT1A9 is uniquely stable against heat treatment. To understand the unique properties of UGT1A9, the three-dimensional structure was constructed by homology modeling using a crystal structure of TDP-epi-vancosaminyltransferase as template. Sequence alignment analysis revealed that 13 amino acid residues (Arg42, Lys91, Ala92, Tyr106, Gly111, Tyr113, Asp115, Asn152, Leu173, Leu219, His221, Arg222, and Glu241) are unique to UGT1A9 as compared with UGT1A7, UGT1A8 and UGT1A10. To examine the roles of these residues in the conformational stability of UGT1A9, molecular dynamics simulation of the structures was carried out at 310 K and 360 K in aqueous solution for 3.0 nanoseconds. Root mean square deviation analyses revealed that Arg42, Leu173, Leu219, His221 and Arg222 were responsible for the thermal stability. Root mean square fluctuation analyses and a dynamical cross correlation map revealed that Lys91, Ala92, Tyr106, Gly111, Tyr113, Asp115, Leu219, His221, Arg222 and Glu241 were responsible for the thermal stability. In vitro study using mutants of these residues demonstrated that all these amino acids may be collectively involved in the thermal stability of UGT1A9. The results presented here provide a molecular basis for the thermal stability of human UGT1A9.

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© 2009 by The Japanese Society for the Study of Xenobiotics
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