{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Zhang S"],"funding":["MOST | National Key Research and Development Program of China","National Natural Science Foundation of China","Natural Science Foundation of Liaoning Province"],"pagination":["e0324722"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9769936"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["10(6)"],"pubmed_abstract":["Phosphopantetheinyl transferases (PPTases) play important roles in activating <i>apo</i>-acyl carrier proteins (<i>apo</i>-ACPs) and <i>apo</i>-peptidyl carrier proteins (<i>apo</i>-PCPs) in both primary and secondary metabolism. PPTases catalyze the posttranslational modifications of those carrier proteins by covalent attachment of the 4'-phosphopantetheine group to a conserved serine residue. The protein-protein interactions between a PPTase and a cognate acyl or peptidyl carrier protein have important regulatory functions in microbial biosynthesis, but the molecular mechanism underlying their specific recognition remains elusive. In this study, we identified a new rishirilide biosynthetic gene cluster with a rare in-cluster PPTase from Streptomyces xanthophaeus no2. The function of this Sfp-type PPTase, SxrX, in rishirilide production was confirmed using genetic mutagenesis and biochemical characterization. We applied molecular modeling and site-directed mutagenesis to identify key residues mediating the protein-protein interaction between SxrX and its cognate ACP. In addition, six natural products were isolated from wild-type <i>S. xanthophaeus</i> no2 and the Δ<i>sxrX</i> mutant, including rishirilide A and lupinacidin A, that exhibited antimicrobial and anticancer activities, respectively. SxrX is the first Sfp-type PPTase identified from an aromatic polyketide biosynthetic gene cluster and shown to be responsible for high-level production of rishirilide derivatives. <b>IMPORTANCE</b> Genome mining has been a vital means for natural product drug discovery in the postgenomic era. The rishirilide-type polyketides have attracted attention due to their potent bioactivity, but the poor robustness of production hosts has limited further research and development. This study not only identifies a hyperproducer of rishirilides but also reveals a rare, in-cluster PPTase SxrX that plays an important role in boosting rishirilide biosynthesis. Experimental and computational investigations revealed new insights on the protein-protein interaction between SxrX and its cognate ACP with wide implications for understanding polyketide biosynthesis."],"journal":["Microbiology spectrum"],"pubmed_title":["Enhanced Rishirilide Biosynthesis by a Rare In-Cluster Phosphopantetheinyl Transferase in Streptomyces xanthophaeus."],"pmcid":["PMC9769936"],"funding_grant_id":["2020YEA0908500","32071428","82104044","2021-MS-170"],"pubmed_authors":["Zhou L","Yang Z","Zhu J","Zhang S","Liu T","Yan X","Si T","Fan S"],"additional_accession":[]},"is_claimable":false,"name":"Enhanced Rishirilide Biosynthesis by a Rare In-Cluster Phosphopantetheinyl Transferase in Streptomyces xanthophaeus.","description":"Phosphopantetheinyl transferases (PPTases) play important roles in activating <i>apo</i>-acyl carrier proteins (<i>apo</i>-ACPs) and <i>apo</i>-peptidyl carrier proteins (<i>apo</i>-PCPs) in both primary and secondary metabolism. PPTases catalyze the posttranslational modifications of those carrier proteins by covalent attachment of the 4'-phosphopantetheine group to a conserved serine residue. The protein-protein interactions between a PPTase and a cognate acyl or peptidyl carrier protein have important regulatory functions in microbial biosynthesis, but the molecular mechanism underlying their specific recognition remains elusive. In this study, we identified a new rishirilide biosynthetic gene cluster with a rare in-cluster PPTase from Streptomyces xanthophaeus no2. The function of this Sfp-type PPTase, SxrX, in rishirilide production was confirmed using genetic mutagenesis and biochemical characterization. We applied molecular modeling and site-directed mutagenesis to identify key residues mediating the protein-protein interaction between SxrX and its cognate ACP. In addition, six natural products were isolated from wild-type <i>S. xanthophaeus</i> no2 and the Δ<i>sxrX</i> mutant, including rishirilide A and lupinacidin A, that exhibited antimicrobial and anticancer activities, respectively. SxrX is the first Sfp-type PPTase identified from an aromatic polyketide biosynthetic gene cluster and shown to be responsible for high-level production of rishirilide derivatives. <b>IMPORTANCE</b> Genome mining has been a vital means for natural product drug discovery in the postgenomic era. The rishirilide-type polyketides have attracted attention due to their potent bioactivity, but the poor robustness of production hosts has limited further research and development. This study not only identifies a hyperproducer of rishirilides but also reveals a rare, in-cluster PPTase SxrX that plays an important role in boosting rishirilide biosynthesis. Experimental and computational investigations revealed new insights on the protein-protein interaction between SxrX and its cognate ACP with wide implications for understanding polyketide biosynthesis.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Dec","modification":"2026-06-12T09:50:53.372Z","creation":"2025-04-05T14:54:53.931Z"},"accession":"S-EPMC9769936","cross_references":{"pubmed":["36326495"],"doi":["10.1128/spectrum.03247-22"]}}