التفاصيل البيبلوغرافية
| العنوان: |
Resistance gene-guided genome mining reveals the roseopurpurins as inhibitors of cyclin-dependent kinases. |
| المؤلفون: |
Dunbar, Kyle L., Perlatti, Bruno, Liu, Nicholas, Cornelius, Amber, Mummau, Daniel, Yi-Ming Chiang, Hon, Lawrence, Nimavat, Monika, Pallas, Jason, Kordes, Sina, Ho Leung Ng, Harvey, Colin J. B. |
| المصدر: |
Proceedings of the National Academy of Sciences of the United States of America; 11/28/2023, Vol. 120 Issue 48, p1-57, 57p |
| مصطلحات موضوعية: |
CYCLIN-dependent kinases, GENOMES, GENE expression, ASPERGILLUS nidulans, MICROBIAL genomes, NATURAL products |
| مستخلص: |
With the significant increase in the availability of microbial genome sequences in recent years, resistance gene-guided genome mining has emerged as a powerful approach for identifying natural products with specific bioactivities. Here, we present the use of this approach to reveal the roseopurpurins as potent inhibitors of cyclin-dependent kinases (CDKs), a class of cell cycle regulators implicated in multiple cancers. We identified a biosynthetic gene cluster (BGC) with a putative resistance gene with homology to human CDK2. Using targeted gene disruption and transcription factor overexpression in Aspergillus uvarum, and heterologous expression of the BGC in Aspergillus nidulans, we demonstrated that roseopurpurin C (1) is produced by this cluster and characterized its biosynthesis. We determined the potency, specificity, and mechanism of action of 1 as well as multiple intermediates and shunt products produced from the BGC. We show that 1 inhibits human CDK2 with a Kiapp of 44 nM, demonstrates selectivity for clinically relevant members of the CDK family, and induces G1 cell cycle arrest in HCT116 cells. Structural analysis of 1 complexed with CDK2 revealed the molecular basis of ATP-competitive inhibition. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
