Bioconversion of AS1387392: bioconversion studies involving Amycolatopsis azurea JCM 3275

Sasamura, Satoshi; Ohsumi, Keisuke; Takase, Shigehiro; Yamada, Toshiko; Muramatsu, Hideyuki; Fujie, Akihiko; Mori, Hajime; Fujii, Takashi; Hino, Motohiro; Sakamoto, Kazutoshi; Hashimoto, Michizane

doi:10.1038/ja.2010.108

Cited by 4 publications

(2 citation statements)

References 11 publications

(15 reference statements)

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“…12 AS1429716 potently inhibited histone deacetylase activity with an IC 50 value of 22 nM, demonstrating this compound to be as potent as AS1387392 (IC 50 ¼22 nM). 9,12 Given that several biochemical analyses indicated that cytochrome P450 was responsible for this hydroxylation, we attempted to clone a gene encoding bacterial cytochrome P450 that would catalyze the hydroxylation of AS1387392 to AS1429716. Furthermore, to confirm its function, we attempted to produce its expression in a Streptomycetes host.…”

Section: Introductionmentioning

confidence: 99%

Cloning and heterologous expression of P450Um-1, a novel bacterial P450 gene, for hydroxylation of immunosuppressive agent AS1387392

et al. 2010

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Biotransformation technology involving enzymatic modification of original substrates by organisms such as microbes is a valuable tool in improving pharmacokinetics or physicochemical properties of the base compounds. The fungal metabolite AS1387392 is a histone deacetylase inhibitor with potential as a therapeutic immunosuppressant. However, its paucity of functional groups, essential to synthesizing derivatives, is a drawback. Amycolatopsis azurea JCM-3275 catalyzed hydroxylation of AS1387392 to AS1429716, which may facilitate the synthesis of more derivatives by the additional hydroxyl moiety present in AS1429716. This reaction was inhibited by cytochrome P450 inhibitor metyrapone, indicating that cytochrome P450 may be responsible for the transformation. Degenerate PCR primers were subsequently constructed and used to clone genes encoding cytochrome P450 from the genomic DNA of A. azurea JCM-3275. We cloned an entire novel P450 gene (1209 bp) and named it P450Um-1. Its deduced amino acid sequence was homologous with that of the CYP105 subfamily. Further cloning of the upstream region, which may contain the native promoter site, was followed by insertion of the open reading frame with the upstream area into Streptomycetes high copy vector pIJ702, giving the expression plasmid pNUm-1. P450Um-1 was specifically expressed in Streptomyces lividans TK24, and this recombinant strain converted AS1387392 to AS1429716 without any redox partners. These results show that P450Um-1, a novel bacterial P450, catalyzed hydroxylation of AS1387392 to AS1429716. This resultant recombinant strain is expected to be an efficient biocatalyst with application to more suitable redox systems than those tested here.

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Section: Introductionmentioning

confidence: 99%

Cloning and heterologous expression of P450Um-1, a novel bacterial P450 gene, for hydroxylation of immunosuppressive agent AS1387392

et al. 2010

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“…Changes of the code name of the reportedly novel immunosuppressive cyclic tetra-peptide published in The Journal of Antibiotics, November issue, 63, 633-636 (2010), and the following three articles [1][2][3] were not clearly explained. In addition, citations to the synthetic preparation and testing of those compounds were not included.…”

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AS1387392, a novel immunosuppressive cyclic tetrapeptide compound with inhibitory activity against mammalian histone deacetylase

Sasamura¹,

Sakamoto²,

Takagaki³

et al. 2012

J Antibiot

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The Comprehensive Peptaibiotics Database

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Neumann

Burgstaller

et al. 2013

Chemistry & Biodiversity

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Peptaibiotics are nonribosomally biosynthesized peptides, which - according to definition - contain the marker amino acid α-aminoisobutyric acid (Aib) and possess antibiotic properties. Being known since 1958, a constantly increasing number of peptaibiotics have been described and investigated with a particular emphasis on hypocrealean fungi. Starting from the existing online 'Peptaibol Database', first published in 1997, an exhaustive literature survey of all known peptaibiotics was carried out and resulted in a list of 1043 peptaibiotics. The gathered information was compiled and used to create the new 'The Comprehensive Peptaibiotics Database', which is presented here. The database was devised as a software tool based on Microsoft (MS) Access. It is freely available from the internet at http://peptaibiotics-database.boku.ac.at and can easily be installed and operated on any computer offering a Windows XP/7 environment. It provides useful information on characteristic properties of the peptaibiotics included such as peptide category, group name of the microheterogeneous mixture to which the peptide belongs, amino acid sequence, sequence length, producing fungus, peptide subfamily, molecular formula, and monoisotopic mass. All these characteristics can be used and combined for automated search within the database, which makes The Comprehensive Peptaibiotics Database a versatile tool for the retrieval of valuable information about peptaibiotics. Sequence data have been considered as to December 14, 2012.

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Bioconversion of AS1387392: bioconversion studies involving Amycolatopsis azurea JCM 3275

Cited by 4 publications

References 11 publications

Cloning and heterologous expression of P450Um-1, a novel bacterial P450 gene, for hydroxylation of immunosuppressive agent AS1387392

Cloning and heterologous expression of P450Um-1, a novel bacterial P450 gene, for hydroxylation of immunosuppressive agent AS1387392

AS1387392, a novel immunosuppressive cyclic tetrapeptide compound with inhibitory activity against mammalian histone deacetylase

The Comprehensive Peptaibiotics Database

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