Saad Alrashdi, Federica Casolari, K. Kyeremeh, Hai Deng
{"title":"生物活性咔唑衍生物的化学酶法合成","authors":"Saad Alrashdi, Federica Casolari, K. Kyeremeh, Hai Deng","doi":"10.3390/synbio2010002","DOIUrl":null,"url":null,"abstract":"Carbazoles are key scaffolds of either antimicrobial/antiviral alkaloid natural products or therapeutics. As such, access to structurally diverse indole-containing carbazoles has attracted considerable attention. In this report, a pilot study is described using biotransformation to provide carbazoles that contain various acyl substituents. The biotransformation system contains the thiamine-diphosphate (ThDP)-dependent enzyme NzsH, the FabH-like 3-ketoacyl-ACP synthase NzsJ, and the aromatase/cyclase NzsI, encoded in the biosynthetic gene cluster (nzs) of the bacterial carbazole alkaloid natural product named neocarazostatin A. The utilization of a range of acyl-SNACs (synthetic acyl-thioester analogues of the native substrate) together with indole-3-pyruvate and pyruvate in the designed biotransformation system allows production of carbazole derivatives. Our results demonstrate that this three-enzyme system displays a considerable substrate profile toward acyl donors for production of carbazoles with different acyl substituents. Finally, two more enzymes were included in the biotransformation system: the tryptophan synthase stand-alone β-subunit variant, PfTrpB, generated from directed evolution in the literature, and a commercially available L-amino acid oxidase (LAAO). The addition of these two enzymes allows the transformation to start with indole building blocks to provide carbazoles with modifications in the indole ring system.","PeriodicalId":507619,"journal":{"name":"SynBio","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Chemo-Enzymatic Synthesis of Bioactive Carbazole Derivatives\",\"authors\":\"Saad Alrashdi, Federica Casolari, K. Kyeremeh, Hai Deng\",\"doi\":\"10.3390/synbio2010002\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Carbazoles are key scaffolds of either antimicrobial/antiviral alkaloid natural products or therapeutics. As such, access to structurally diverse indole-containing carbazoles has attracted considerable attention. In this report, a pilot study is described using biotransformation to provide carbazoles that contain various acyl substituents. The biotransformation system contains the thiamine-diphosphate (ThDP)-dependent enzyme NzsH, the FabH-like 3-ketoacyl-ACP synthase NzsJ, and the aromatase/cyclase NzsI, encoded in the biosynthetic gene cluster (nzs) of the bacterial carbazole alkaloid natural product named neocarazostatin A. The utilization of a range of acyl-SNACs (synthetic acyl-thioester analogues of the native substrate) together with indole-3-pyruvate and pyruvate in the designed biotransformation system allows production of carbazole derivatives. Our results demonstrate that this three-enzyme system displays a considerable substrate profile toward acyl donors for production of carbazoles with different acyl substituents. Finally, two more enzymes were included in the biotransformation system: the tryptophan synthase stand-alone β-subunit variant, PfTrpB, generated from directed evolution in the literature, and a commercially available L-amino acid oxidase (LAAO). The addition of these two enzymes allows the transformation to start with indole building blocks to provide carbazoles with modifications in the indole ring system.\",\"PeriodicalId\":507619,\"journal\":{\"name\":\"SynBio\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-01-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"SynBio\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.3390/synbio2010002\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"SynBio","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3390/synbio2010002","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Chemo-Enzymatic Synthesis of Bioactive Carbazole Derivatives
Carbazoles are key scaffolds of either antimicrobial/antiviral alkaloid natural products or therapeutics. As such, access to structurally diverse indole-containing carbazoles has attracted considerable attention. In this report, a pilot study is described using biotransformation to provide carbazoles that contain various acyl substituents. The biotransformation system contains the thiamine-diphosphate (ThDP)-dependent enzyme NzsH, the FabH-like 3-ketoacyl-ACP synthase NzsJ, and the aromatase/cyclase NzsI, encoded in the biosynthetic gene cluster (nzs) of the bacterial carbazole alkaloid natural product named neocarazostatin A. The utilization of a range of acyl-SNACs (synthetic acyl-thioester analogues of the native substrate) together with indole-3-pyruvate and pyruvate in the designed biotransformation system allows production of carbazole derivatives. Our results demonstrate that this three-enzyme system displays a considerable substrate profile toward acyl donors for production of carbazoles with different acyl substituents. Finally, two more enzymes were included in the biotransformation system: the tryptophan synthase stand-alone β-subunit variant, PfTrpB, generated from directed evolution in the literature, and a commercially available L-amino acid oxidase (LAAO). The addition of these two enzymes allows the transformation to start with indole building blocks to provide carbazoles with modifications in the indole ring system.