Pyroglutamyl Aminopeptidase I, as a Drug Metabolizing Enzyme, Recognizes Xenobiotic Substrates Containing L-2-Oxothiazolidine-4-carboxylic Acid(Biochemistry/Molecular Biology)
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概要
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Pyroglutamyl aminopeptidase I (PAP-I) is known for specifically removing the L-pyroglutamate (L-pGlu) residue from the amino terminus of L-pGlu proteins and peptides. In general, substrate recognition of PAP-I as to L-pGlu moiety is tightly regulated. However, we recently identified PAP-I as a metabolic enzyme of an organic nitrate compound, RS-7897, which contains L-2-oxothiazolidine-4-carboxylic acid (L-OTCA). L-OTCA is a latent sulfhydryl group, which has moiety structurally related to L-pGlu. In this study, we investigated the substrate specificity of PAP-I toward modified L-pGlu-containing substrates using recombinant rat, mouse and human PAP-Is. PAP-I was tolerant of replacement of a carbon atom at the 4-position of the L-pGlu moiety by a sulfur atom (L-OTCA), an oxygen atom (L-2-oxooxazolidine-4-carboxylic acid, L-OOCA) and an NH group (L-2-oxoimidazolidine-4-carboxylic acid, L-OICA). The Km values for rat PAP-I in hydrolyzing L-pGlu-L-Ala, L-OTCA-L-Ala, L-OOCA-L-Ala and L-OICA-L-Ala were 0.057, 0.43, 0.71 and 0.42 HIM, respectively. Similar results were observed in mouse and human PAP-Is as well. Moreover, the hydrolysis of RS-7897 in rat and mouse liver cytosols were both completely inhibited by an antibody against rat PAP-I, strongly suggesting that PAP-I is solely involved in the hydrolysis of L-OTCA-containing compounds in rat and mouse liver cytosols.
- 公益社団法人日本薬学会の論文
- 2004-01-01
著者
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Yamada Makiko
San-ei Gen F.f.i. Inc.
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Yamada Makiko
Drug Metabolism And Pharmacokinetics Research Laboratories Sankyo Co. Ltd.
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Yamada M
Pharmaceutical Research Division Takeda Pharmaceutical Company Limited
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Yoshida M
Tohoku Univ. Sendai Jpn
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ABE Koji
Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd.
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TOKUI Taro
Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd.
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SAITO Fujio
Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd.
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Saito Fujio
Drug Metabolism And Pharmacokinetics Research Laboratories Sankyo Co. Ltd.
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Tokui T
Drug Metabolism And Pharmacokinetics Research Laboratories Sankyo Co. Ltd.
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Tokui Taro
Drug Metabolism And Pharmacokinetics Research Laboratories Sankyo Co. Ltd.
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Abe K
Drug Metabolism And Pharmacokinetics Research Laboratories Sankyo Co. Ltd.
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Abe Koji
Drug Metabolism And Pharmacokinetics Research Laboratories Sankyo Co. Ltd.
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