Key Amino Acid Residues Responsible for the Differences in Substrate Specificity of Human UDP-Glucuronosyltransferase (UGT)1A9 and UGT1A8

Fujiwara, Ryoichi; Nakajima, Miki; Yamanaka, Hidetoshi; Yokoi, Tsuyoshi

doi:10.1124/dmd.108.022913

Cited by 20 publications

(14 citation statements)

References 24 publications

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“…Such a suggestion is in agreement with the finding of Fujiwara et al (2009). Assuming that both Phe117 and Asn152 of UGT1A9 affect substrate specificity and interact with the bound substrate, we prepared the double mutant 9F117L-N152T and assayed its activity.…”

Section: Itä Aho Et Alsupporting

confidence: 75%

“…Our results with chimera 910A do not lead to the same conclusion. Nonetheless, the other residue these authors depicted, the one at position 152 (Fujiwara et al, 2009), also affected activity in some of our assays in the current study, when combined with segment B (Figs. 4, A-C, and 8).…”

Section: Itä Aho Et Almentioning

confidence: 81%

“…9) and be crucial for activity but not to the selectivity differences between these enzymes. Segment A also contains the residue at position 42 that was recently reported to be involved in a substrate selectivity difference between UGT1A9 and UGT1A8 (Fujiwara et al, 2009). Our results with chimera 910A do not lead to the same conclusion.…”

Section: Itä Aho Et Almentioning

confidence: 99%

“…Nishiyama et al (2008) obtained comparable results with UGT1A8-UGT1A9 chimeras and concluded that amino acids within the 69 to 132 segment are important for the substrate specificity of UGT1A9. More specifically, Fujiwara et al (2009) observed that amino acids 42 and 152 are important in determining the differences in substrate specificity of UGT1A9 and UGT1A8.…”

mentioning

confidence: 99%

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How Many and Which Amino Acids Are Responsible for the Large Activity Differences between the Highly Homologous UDP-Glucuronosyltransferases (UGT) 1A9 and UGT1A10?

Itäaho

Laakkonen²,

Finel³

2010

Drug Metab Dispos

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ABSTRACT:The amino acid sequences of the human UDP-glucuronosyltransferases (UGTs) 1A9 and 1A10 are 93% identical, yet there are large differences in their activity and substrate selectivity. For example, the regioselectivity in propranolol glucuronidation, the regioselectivity in dobutamine glucuronidation, and the glucuronidation rate of ␣-and ␤-estradiol differ greatly between UGT1A9 and UGT1A10. To identify the residue responsible for the activity differences, we divided the N-terminal half of the two UGTs into five comparable segments by inserting four unique restriction sites at identical positions in both genes and constructing chimeras in which segments of UGT1A9 were individually replaced by the corresponding segments from UGT1A10. indicated that more than one residue is responsible for the differences between UGT1A9 and UGT1A10. We next prepared four double chimeras, in which two of the above UGT1A9 segments were replaced simultaneously by the corresponding UGT1A10 segments. However, none of the double chimeras glucuronidated either estradiol, propranolol, or dobutamine at rates that resembled those of UGT1A10. On the other hand, studying the kinetics of 1-naphthol glucuronidation yielded more focused results, indicating that residues within segment B (84-147) contribute directly to the K m value for this substrate. Further mutagenesis and activity assays suggested that Phe117 of UGT1A9 participates in 1-naphthol binding. In addition, it appears that residues within segment C of the N-terminal domain, mainly at positions 152 and 169, contribute to the higher glucuronidation rates of UGT1A10.

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Section: Itä Aho Et Alsupporting

confidence: 75%

Section: Itä Aho Et Almentioning

confidence: 81%

Section: Itä Aho Et Almentioning

confidence: 99%

mentioning

confidence: 99%

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How Many and Which Amino Acids Are Responsible for the Large Activity Differences between the Highly Homologous UDP-Glucuronosyltransferases (UGT) 1A9 and UGT1A10?

Itäaho

Laakkonen²,

Finel³

2010

Drug Metab Dispos

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“…In one study, two residues of UGT1A9, Arg42 and Asn152, were identified as contributing to substrate specificity of the enzyme (Fujiwara et al, 2009). The importance of Arg42 and Asn152 was determined using mutational analysis of these amino acids analogous to those found in UGT1A8.…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of Low-Prevalence Missense Polymorphisms in the UDP-Glucuronosyltransferase 1A9 Gene

Olson¹,

Dellinger²,

Zhong³

et al. 2009

Drug Metab Dispos

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ABSTRACT:The UDP-glucuronosyltransferase (UGT) 1A9 has been shown to play an important role in the detoxification of several carcinogens and clearance of anticancer and pain medications. The goal of the present study was to identify novel polymorphisms in UGT1A9 and characterize their effect on glucuronidation activity. The UGT1A9 gene was analyzed by direct sequencing of buccal cell genomic DNA from 90 healthy subjects. In addition to a previously identified single nucleotide polymorphism (SNP) at codon 33 resulting in an amino acid substitution (Met>Thr), two low-prevalence (<0.02) novel missense SNPs at codons 167 (Val>Ala) and 183 (Cys>Gly) were identified and are present in both white and African-American subjects. Glucuronidation activity assays using HEK293

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UDP‐Glucuronosyltransferases: Pharmacogenetics, Functional Characterization, and Clinical Relevance

Foti

Fisher

2012

Encyclopedia of Drug Metabolism and Interactions

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UDP‐glucuronosyltransferase (UGT)‐catalyzed conjugation reactions play an important role in the metabolism of both xenobiotics and endogenous compounds. The frequency of UGT involvement in xenobiotic drug metabolism has increased as the ability to design out other routes of metabolism (i.e., cytochrome P450) has improved. To this end, the primary goal of this chapter is to serve as a compendium for the significant amount of information surrounding UGTs that has been compiled to date. Where relevant, the chapter covers expression, regulation and polymorphisms, substrates and inhibitors, active site characterization, and finally, clinical relevance of the various UGT isoforms.

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Key Amino Acid Residues Responsible for the Differences in Substrate Specificity of Human UDP-Glucuronosyltransferase (UGT)1A9 and UGT1A8

Cited by 20 publications

References 24 publications

How Many and Which Amino Acids Are Responsible for the Large Activity Differences between the Highly Homologous UDP-Glucuronosyltransferases (UGT) 1A9 and UGT1A10?

How Many and Which Amino Acids Are Responsible for the Large Activity Differences between the Highly Homologous UDP-Glucuronosyltransferases (UGT) 1A9 and UGT1A10?

Functional Characterization of Low-Prevalence Missense Polymorphisms in the UDP-Glucuronosyltransferase 1A9 Gene

UDP‐Glucuronosyltransferases: Pharmacogenetics, Functional Characterization, and Clinical Relevance

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