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Cycloserine enantiomers are reversible inhibitors of human alanine:glyoxylate aminotransferase: implications for Primary Hyperoxaluria type 1
https://oist.repo.nii.ac.jp/records/1449
https://oist.repo.nii.ac.jp/records/144922c41b65-ef6e-4924-bbe6-f5bb1400827e
名前 / ファイル | ライセンス | アクション |
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bcj-2019-0507_proof (1.4 MB)
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Item type | 学術雑誌論文 / Journal Article(1) | |||||
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公開日 | 2020-05-02 | |||||
タイトル | ||||||
言語 | en | |||||
タイトル | Cycloserine enantiomers are reversible inhibitors of human alanine:glyoxylate aminotransferase: implications for Primary Hyperoxaluria type 1 | |||||
言語 | ||||||
言語 | eng | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
資源タイプ | journal article | |||||
著者(英) |
Dindo, Mirco
× Dindo, Mirco× Grottelli, Silvia× Annunziato, Giannamaria× Giardina, Giorgio× Pieroni, Marco× Pampalone, Gioena× Faccini, Andrea× Cutruzzolà, Francesca× Laurino, Paola× Costantino, Gabriele× Cellini, Barbara |
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書誌情報 |
en : Biochemical Journal 巻 476, 号 24, p. 3751-3768, 発行日 2019-12-20 |
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抄録 | ||||||
内容記述タイプ | Other | |||||
内容記述 | Peroxisomal alanine:glyoxylate aminotransferase (AGT) is responsible for glyoxylate detoxification in human liver and utilizes pyridoxal 5'-phosphate (PLP) as coenzyme. The deficit of AGT leads to Primary Hyperoxaluria Type I (PH1), a rare disease characterized by calcium oxalate stones deposition in the urinary tract as a consequence of glyoxylate accumulation. Most missense mutations cause AGT misfolding, as in the case of the G41R, which induces aggregation and proteolytic degradation. We have investigated the interaction of wild-type AGT and the pathogenic G41R variant with d-cycloserine (DCS, commercialized as Seromycin), a natural product used as a second-line treatment of multidrug-resistant tuberculosis, and its synthetic enantiomer l-cycloserine (LCS). In contrast with evidences previously reported on other PLP-enzymes, both ligands are AGT reversible inhibitors showing inhibition constants in the micromolar range. While LCS undergoes half-transamination generating a ketimine intermediate and behaves as a classical competitive inhibitor, DCS displays a time-dependent binding mainly generating an oxime intermediate. Using a mammalian cellular model, we found that DCS, but not LCS, is able to promote the correct folding of the G41R variant, as revealed by its increased specific activity and expression as a soluble protein. This effect also translates into an increased glyoxylate detoxification ability of cells expressing the variant upon treatment with DCS. Overall, our findings establish that DCS could play a role as pharmacological chaperone, thus suggesting a new line of intervention against PH1 based on a drug repositioning approach. To a widest extent, this strategy could be applied to other disease-causing mutations leading to AGT misfolding. | |||||
出版者 | ||||||
出版者 | Portland Press Limited on behalf of the Biochemical Society | |||||
ISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 0264-6021 | |||||
ISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 1470-8728 | |||||
PubMed番号 | ||||||
関連タイプ | isVersionOf | |||||
識別子タイプ | PMID | |||||
関連識別子 | info:pmid/31794008 | |||||
DOI | ||||||
関連タイプ | isVersionOf | |||||
識別子タイプ | DOI | |||||
関連識別子 | info:doi/10.1042/BCJ20190507 | |||||
権利 | ||||||
権利情報 | © 2019 The Author(s). | |||||
関連サイト | ||||||
識別子タイプ | DOI | |||||
関連識別子 | https://doi.org/10.1042/BCJ20190507 | |||||
著者版フラグ | ||||||
出版タイプ | AM | |||||
出版タイプResource | http://purl.org/coar/version/c_ab4af688f83e57aa |