FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2897713497> ?p ?o ?g. }

• W2897713497 endingPage "19995" @default.
• W2897713497 startingPage "19982" @default.
• W2897713497 abstract "Actinobacteria possess a great wealth of pathways for production of bioactive compounds. Following advances in genome mining, dozens of natural product (NP) gene clusters are routinely found in each actinobacterial genome; however, the modus operandi of this large arsenal is poorly understood. During investigations of the secondary metabolome of Streptomyces rapamycinicus, the producer of rapamycin, we observed accumulation of two compounds never before reported from this organism. Structural elucidation revealed actinoplanic acid A and its demethyl analogue. Actinoplanic acids (APLs) are potent inhibitors of Ras farnesyltransferase and therefore represent bioactive compounds of medicinal interest. Supported with the unique structure of these polyketides and using genome mining, we identified a gene cluster responsible for their biosynthesis in S. rapamycinicus. Based on experimental evidence and genetic organization of the cluster, we propose a stepwise biosynthesis of APL, the first bacterial example of a pathway incorporating the rare tricarballylic moiety into an NP. Although phylogenetically distant, the pathway shares some of the biosynthetic principles with the mycotoxins fumonisins. Namely, the core polyketide is acylated with the tricarballylate by an atypical nonribosomal peptide synthetase–catalyzed ester formation. Finally, motivated by the conserved colocalization of the rapamycin and APL pathway clusters in S. rapamycinicus and all other rapamycin-producing actinobacteria, we confirmed a strong synergism of these compounds in antifungal assays. Mining for such evolutionarily conserved coharboring of pathways would likely reveal further examples of NP sets, attacking multiple targets on the same foe. These could then serve as a guide for development of new combination therapies. Actinobacteria possess a great wealth of pathways for production of bioactive compounds. Following advances in genome mining, dozens of natural product (NP) gene clusters are routinely found in each actinobacterial genome; however, the modus operandi of this large arsenal is poorly understood. During investigations of the secondary metabolome of Streptomyces rapamycinicus, the producer of rapamycin, we observed accumulation of two compounds never before reported from this organism. Structural elucidation revealed actinoplanic acid A and its demethyl analogue. Actinoplanic acids (APLs) are potent inhibitors of Ras farnesyltransferase and therefore represent bioactive compounds of medicinal interest. Supported with the unique structure of these polyketides and using genome mining, we identified a gene cluster responsible for their biosynthesis in S. rapamycinicus. Based on experimental evidence and genetic organization of the cluster, we propose a stepwise biosynthesis of APL, the first bacterial example of a pathway incorporating the rare tricarballylic moiety into an NP. Although phylogenetically distant, the pathway shares some of the biosynthetic principles with the mycotoxins fumonisins. Namely, the core polyketide is acylated with the tricarballylate by an atypical nonribosomal peptide synthetase–catalyzed ester formation. Finally, motivated by the conserved colocalization of the rapamycin and APL pathway clusters in S. rapamycinicus and all other rapamycin-producing actinobacteria, we confirmed a strong synergism of these compounds in antifungal assays. Mining for such evolutionarily conserved coharboring of pathways would likely reveal further examples of NP sets, attacking multiple targets on the same foe. These could then serve as a guide for development of new combination therapies." @default.
• W2897713497 created "2018-10-26" @default.
• W2897713497 creator A5008747896 @default.
• W2897713497 creator A5013392201 @default.
• W2897713497 creator A5017562980 @default.
• W2897713497 creator A5025557216 @default.
• W2897713497 creator A5035648383 @default.
• W2897713497 creator A5042214180 @default.
• W2897713497 date "2018-12-01" @default.
• W2897713497 modified "2023-10-17" @default.
• W2897713497 title "Discovery of the actinoplanic acid pathway in Streptomyces rapamycinicus reveals a genetically conserved synergism with rapamycin" @default.
• W2897713497 cites W1496011245 @default.
• W2897713497 cites W1538571351 @default.
• W2897713497 cites W1908709110 @default.
• W2897713497 cites W1925846115 @default.
• W2897713497 cites W1948568063 @default.
• W2897713497 cites W1969555177 @default.
• W2897713497 cites W1970192765 @default.
• W2897713497 cites W1974491169 @default.
• W2897713497 cites W1977709885 @default.
• W2897713497 cites W1979351994 @default.
• W2897713497 cites W1990622316 @default.
• W2897713497 cites W1991412566 @default.
• W2897713497 cites W1992969636 @default.
• W2897713497 cites W1995995599 @default.
• W2897713497 cites W1996873343 @default.
• W2897713497 cites W2000990355 @default.
• W2897713497 cites W2008343440 @default.
• W2897713497 cites W2014734955 @default.
• W2897713497 cites W2021196811 @default.
• W2897713497 cites W2022819817 @default.
• W2897713497 cites W2031611770 @default.
• W2897713497 cites W2033317994 @default.
• W2897713497 cites W2033591223 @default.
• W2897713497 cites W2047161107 @default.
• W2897713497 cites W2048172017 @default.
• W2897713497 cites W2053783176 @default.
• W2897713497 cites W2055043387 @default.
• W2897713497 cites W2058382321 @default.
• W2897713497 cites W2060215372 @default.
• W2897713497 cites W2060518424 @default.
• W2897713497 cites W2063013559 @default.
• W2897713497 cites W2074462548 @default.
• W2897713497 cites W2074978097 @default.
• W2897713497 cites W2080621968 @default.
• W2897713497 cites W2083795747 @default.
• W2897713497 cites W2088639083 @default.
• W2897713497 cites W2094395518 @default.
• W2897713497 cites W2096238248 @default.
• W2897713497 cites W2100266438 @default.
• W2897713497 cites W2107881585 @default.
• W2897713497 cites W2112887820 @default.
• W2897713497 cites W2117334916 @default.
• W2897713497 cites W2120503144 @default.
• W2897713497 cites W2123960043 @default.
• W2897713497 cites W2127322768 @default.
• W2897713497 cites W2132926880 @default.
• W2897713497 cites W2136391678 @default.
• W2897713497 cites W2143485490 @default.
• W2897713497 cites W2143640800 @default.
• W2897713497 cites W2160355621 @default.
• W2897713497 cites W2167991274 @default.
• W2897713497 cites W2181646642 @default.
• W2897713497 cites W2217028767 @default.
• W2897713497 cites W2224175912 @default.
• W2897713497 cites W2320844767 @default.
• W2897713497 cites W2345013256 @default.
• W2897713497 cites W2345462336 @default.
• W2897713497 cites W2387584962 @default.
• W2897713497 cites W2410975458 @default.
• W2897713497 cites W2518401183 @default.
• W2897713497 cites W2558088991 @default.
• W2897713497 cites W2589005863 @default.
• W2897713497 cites W2611021352 @default.
• W2897713497 cites W2616593173 @default.
• W2897713497 cites W2622291317 @default.
• W2897713497 cites W2637550166 @default.
• W2897713497 cites W2766177580 @default.
• W2897713497 cites W2770627510 @default.
• W2897713497 cites W2790947586 @default.
• W2897713497 cites W2794839960 @default.
• W2897713497 cites W2116688320 @default.
• W2897713497 doi "https://doi.org/10.1074/jbc.ra118.005314" @default.
• W2897713497 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6311506" @default.
• W2897713497 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30327433" @default.
• W2897713497 hasPublicationYear "2018" @default.
• W2897713497 type Work @default.
• W2897713497 sameAs 2897713497 @default.
• W2897713497 citedByCount "10" @default.
• W2897713497 countsByYear W28977134972018 @default.
• W2897713497 countsByYear W28977134972019 @default.
• W2897713497 countsByYear W28977134972021 @default.
• W2897713497 countsByYear W28977134972022 @default.
• W2897713497 crossrefType "journal-article" @default.
• W2897713497 hasAuthorship W2897713497A5008747896 @default.
• W2897713497 hasAuthorship W2897713497A5013392201 @default.
• W2897713497 hasAuthorship W2897713497A5017562980 @default.
• W2897713497 hasAuthorship W2897713497A5025557216 @default.

• next