10.1021/acs.molpharmaceut.5b00954.s001
Shinichi Ikushiro
Shinichi
Ikushiro
Miyu Nishikawa
Miyu
Nishikawa
Yuuka Masuyama
Yuuka
Masuyama
Tadashi Shouji
Tadashi
Shouji
Miharu Fujii
Miharu
Fujii
Masahiro Hamada
Masahiro
Hamada
Noriyuki Nakajima
Noriyuki
Nakajima
Moshe Finel
Moshe
Finel
Kaori Yasuda
Kaori
Yasuda
Masaki Kamakura
Masaki
Kamakura
Toshiyuki Sakaki
Toshiyuki
Sakaki
Biosynthesis of Drug Glucuronide Metabolites in the
Budding Yeast <i>Saccharomyces cerevisiae</i>
American Chemical Society
2016
compound
Budding Yeast Saccharomyces cerevisiae Glucuronidation
Drug Glucuronide Metabolites
acid
acyl glucuronides
UGT
coexpression system
1A
yeast cells coexpressing UGDH
2016-05-30 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Biosynthesis_of_Drug_Glucuronide_Metabolites_in_the_Budding_Yeast_i_Saccharomyces_cerevisiae_i_/3423327
Glucuronidation
is one of the most common pathways in mammals for
detoxification and elimination of hydrophobic xenobiotic compounds,
including many drugs. Metabolites, however, can form active or toxic
compounds, such as acyl glucuronides, and their safety assessment
is often needed. The absence of efficient means for <i>in vitro</i> synthesis of correct glucuronide metabolites frequently limits such
toxicological analyses. To overcome this hurdle we have developed
a new approach, the essence of which is a coexpression system containing
a human, or another mammalian UDP-glucuronosyltransferases (UGTs),
as well as UDP-glucose-6-dehydrogenase (UGDH), within the budding
yeast, <i>Saccharomyces cerevisiae</i>. The system was first
tested using resting yeast cells coexpressing UGDH and human UGT1A6,
7-hydroxycoumarin as the substrate, in a reaction medium containing
8% glucose, serving as a source of UDP-glucuronic acid. Glucuronides
were readily formed and recovered from the medium. Subsequently, by
selecting suitable mammalian UGT enzyme for the coexpression system
we could obtain the desired glucuronides of various compounds, including
molecules with multiple conjugation sites and acyl glucuronides of
several carboxylic acid containing drugs, namely, mefenamic acid,
flufenamic acid, and zomepirac. In conclusion, a new and flexible
yeast system with mammalian UGTs has been developed that exhibits
a capacity for efficient production of various glucuronides, including
acyl glucuronides.