最先端研究セミナー

Abstract:

In silico approach which is based on structural biology has recently become a powerful tool for biomedical research (1-4). We started our molecular simulation analysis about 10 years ago, and the first research mimicked the enzyme reaction of glucuronidation by UDP-glucuronosyltransferase 1A1 (UGT1A1). It is localized in endoplasmic reticulum (ER) membrane, and has been reported to have large number of amino acid substitutions leading to the reduction of glucuronidation ability. In particular, adverse drug reactions are caused by its amino acid substitutions in the patients dosed with CPT-11 as cancer chemotherapy. We previously found that the ratio of in silico docking correlated with in vitro conjugation capacity when the hydroxyl residue of bilirubin oriented toward UDPGA (5). Here, we present our mathematical model that can correctly predict conjugation capacity of mutant UGT1A1s by using the results of in silico molecular simulation and in vitro analysis for the glucuronidation with several substrates. Our results suggest that the conjugation capacity of unknown mutant UGT1A1s with any substrate can be predicted in silico.

References:

1. Eiji Nakano, Ryusuke Ono, Taro Masaki, Seiji Takeuchi, Yutaka Takaoka, Eiichi Maeda, Chikako Nishigori. :Differences in clinical phenotype among patients with XP complementation group D: 3D structure and ATP-docking of XPD in silico. Journal Investigative Dermatology. 134(6) : 1775-1778, 2014
2. Masahito Ogasawara, Yutaka Nakamura, Naoto Morikawa, Hiroto Nitanai, Satoshi Moriguchi, Ryosuke Chiba, Heisuke Saito, Mika Ohta, Tatsuo Tanita, Tamotsu Sugai, Kazutaka Maeyama, Kohei Yamauchi, Yutaka Takaoka :Analysis of a single codon E746 deletion in exon 19 of the epidermal growth factor receptor. Cancer Chemotherapy and Pharmacology. 77(5) : 1019-1029, 2016
3. Lixia Qiang, Yanxia Guan, Xiangshun Li, Yanshuang Mu, Aki Sugano, Yutaka Takaoka, Bruno P. Imbimbo, Ken-ichi Yamamura, Shoude Jin, Zhenghua Li :CSP-1103 (CHF5074) stabilizes human transthyretin in healthy human subjects. Amyloid. 24 : 42-51, 2017
4. Yutaka Nakamura, Aki Sugano, Mika Ohta, Yutaka Takaoka :Docking analysis and the possibility of prediction efficacy for an anti-IL-13 biopharmaceutical treatment with tralokinumab and lebrikizumab for bronchial asthma. PLOS ONE. 12(11): e0188407., 2017
5. Yutaka Takaoka, Mika Ohta, Atsuko Takeuchi, Kenji Miura, Masafumi Matsuo, Toshiyuki Sakaeda, Aki Sugano, Hisahide Nishio :Ligand orientation governs conjugation capacity of UDP-glucuronosyltransferase 1A1. J Biochemistry. 148(1) : 25-28, 2010

担当分野：　損傷修復　立石（内線：6603）

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