Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.
CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.
Mar Drugs. 2024 Jan 2;22(1):32. doi: 10.3390/md22010032.
Recently, we re-isolated the glycosylated angucycline antibiotics P-1894B () and grincamycin () from the marine-derived SCSIO LR32 as potent antitumor agents and identified their biosynthesis gene cluster . Both P-1894B () and grincamycin () possess a trisaccharide and a disaccharide moiety comprised of five deoxysugars. In this work, three genes encoding glycosyltransferases (GcnG1, GcnG2, and GcnG3) responsible for the assembly of deoxysugars into angucycline aglycone were identified from the biosynthesis gene cluster . Gene inactivations of , , , and by lambda-RED-mediated gene replacements led to the construction of four mutants, in which the glycosyltransferase genes were disrupted, respectively. The metabolites from the mutants were purified and identified, including two new analogues designated as grincamycin U () and V (). The sequential glycosylation steps in the biosynthesis of P-1894B () and grincamycin () catalyzed by GcnG3, GcnG1, and GcnG2 were elucidated.
最近，我们从海洋来源的 SCSIO LR32 中重新分离到了糖基化安格律素抗生素 P-1894B（）和格兰霉素（），它们是具有潜力的抗肿瘤药物，并鉴定了它们的生物合成基因簇。P-1894B（）和格兰霉素（）都含有由五个去氧糖组成的三糖和二糖部分。在这项工作中，我们从生物合成基因簇中鉴定出了三个编码糖基转移酶（GcnG1、GcnG2 和 GcnG3）的基因，这些基因负责将去氧糖组装到安格律素糖苷上。通过 lambda-RED 介导的基因替换，对、、和进行基因失活，分别构建了四个突变体，其中糖苷转移酶基因被破坏。从突变体中纯化并鉴定了代谢产物，包括两种新的类似物，分别命名为格兰霉素 U（）和 V（）。阐明了 GcnG3、GcnG1 和 GcnG2 催化 P-1894B（）和格兰霉素（）生物合成中顺序糖基化步骤。
