Saframycin A

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Andrew G. Myers - One of the best experts on this subject based on the ideXlab platform.

  • IdentificAtion of GAPDH As A protein tArget of the SAfrAmycin AntiproliferAtive Agents
    Proceedings of the National Academy of Sciences of the United States of America, 2004
    Co-Authors: Chengguo Xing, Jacob R. Laporte, Joseph K. Barbay, Andrew G. Myers
    Abstract:

    SAfrAmycin A (SAfA) is A member of A clAss of nAturAl products with potent AntiproliferAtive effects in leukemiA- And tumor-derived cells. This Activity is frequently conjectured to derive from the Ability of SAfrAmycins to covAlently modify duplex DNA. We used A DNA-linked Affinity purificAtion technique to identify GAPDH As A protein tArget of DNA–smAll molecule Adducts of severAl members of the SAfrAmycin clAss. NucleAr trAnslocAtion of GAPDH occurs upon treAtment of cAncer cells with SAfrAmycins, And depletion of cellulAr GAPDH levels by smAll interfering RNA trAnsfection confers drug resistAnce. Roeder And coworkers hAve recently suggested thAt GAPDH is A key trAnscriptionAl coActivAtor necessAry for entry into S phAse. Our dAtA suggest thAt GAPDH is Also cApAble of forming A ternAry complex with SAfrAmycin-relAted compounds And DNA thAt induces A toxic response in cells. These studies implicAte A previously unknown moleculAr mechAnism of AntiproliferAtive Activity And, given thAt one member of the SAfrAmycin clAss hAs shown efficAcy in cAncer treAtment, suggest thAt GAPDH mAy be A potentiAl tArget for chemotherApeutic intervention.

  • A Solid-Supported, EnAntioselective Synthesis SuitAble for the RApid PrepArAtion of LArge Numbers of Diverse StructurAl AnAlogues of (−)-SAfrAmycin A
    Journal of the American Chemical Society, 2002
    Co-Authors: Andrew G. Myers, Brian A. Lanman
    Abstract:

    A 10-step solid-supported, enAntioselective synthesis suitAble for the rApid prepArAtion of lArge numbers of diverse structurAl AnAlogues of SAfrAmycin A is described. The synthetic route, which beArs AnAlogy to solid-phAse peptide synthesis, involves the directed condensAtion of N-protected α-Amino Aldehyde reActAnts. A novel duAl linker wAs developed for AttAchment of intermediAtes to the solid support viA A C-protective group, A substituted morpholino nitrile derivAtive. The route employs A novel diAstereospecific cycloreleAse mechAnism, supports structurAl vAriAtion At multiple sites in the SAfrAmycin core, And obviAtes the need for chromAtogrAphic purificAtion of the products or Any intermediAte. To demonstrAte the feAsibility of structurAl vAriAtion At multiple sites, A mAtrix of 16 SAfrAmycin A AnAlogues wAs prepAred by pArAllel synthesis with simultAneous vAriAtion of two sites. This work is notAble not only As A preliminAry step towArd lArge-scAle librAry construction but Also As An exAmple of th...

  • A solid supported enAntioselective synthesis suitAble for the rApid prepArAtion of lArge numbers of diverse structurAl AnAlogues of SAfrAmycin A
    Journal of the American Chemical Society, 2002
    Co-Authors: Andrew G. Myers, Brian A. Lanman
    Abstract:

    A 10-step solid-supported, enAntioselective synthesis suitAble for the rApid prepArAtion of lArge numbers of diverse structurAl AnAlogues of SAfrAmycin A is described. The synthetic route, which beArs AnAlogy to solid-phAse peptide synthesis, involves the directed condensAtion of N-protected α-Amino Aldehyde reActAnts. A novel duAl linker wAs developed for AttAchment of intermediAtes to the solid support viA A C-protective group, A substituted morpholino nitrile derivAtive. The route employs A novel diAstereospecific cycloreleAse mechAnism, supports structurAl vAriAtion At multiple sites in the SAfrAmycin core, And obviAtes the need for chromAtogrAphic purificAtion of the products or Any intermediAte. To demonstrAte the feAsibility of structurAl vAriAtion At multiple sites, A mAtrix of 16 SAfrAmycin A AnAlogues wAs prepAred by pArAllel synthesis with simultAneous vAriAtion of two sites. This work is notAble not only As A preliminAry step towArd lArge-scAle librAry construction but Also As An exAmple of th...

  • TrAnscriptionAl Response PAthwAys in A YeAst StrAin Sensitive to SAfrAmycin A And A More Potent AnAlog: Evidence for A Common BAsis of Activity
    Chemistry & biology, 2002
    Co-Authors: Alleyn T. Plowright, Scott E. Schaus, Andrew G. Myers
    Abstract:

    AbstrAct SAfrAmycin A (SAfA) is A nAturAl product thAt inhibits humAn cAncer cell proliferAtion. Its synthetic AnAlog, QAD, is A more potent inhibitor of these cells. SAfA does not Affect wild-type yeAst, but it does inhibit growth of the strAin CCY333 (Δ PDR1/PDR3/ERG6 ) (IC 50 = 0.9 μM). QAD is Also A more effective inhibitor of CCY333 growth (IC 50 = 0.4 μM). TrAnscription profiling of SAfA- And QAD-treAted CCY333 cultures showed thAt both drugs generAted neArly identicAl profiles, with Altered expression levels (≥2-fold) of more thAn 240 genes. Both Agents induced the overexpression of genes involved in glycolysis, oxidAtive stress, And protein degrAdAtion And repressed genes encoding histones, biosynthetic enzymes, And the cellulAr import mAchinery. SignificAntly, neither drug Affected the expression of known DNA-dAmAge repAir genes, As might hAve been expected if their primAry mechAnism of Action involved the covAlent modificAtion of DNA.

  • One-step construction of the pentAcyclic skeleton of SAfrAmycin A from A "Trimer" of AlphA-Amino Aldehydes.
    Organic letters, 2000
    Co-Authors: Andrew G. Myers, Daniel W. Kung
    Abstract:

    The entire skeleton of the SAfrAmycin Antitumor Antibiotics is Assembled in one remArkAble trAnsformAtion (8 --> 9) from An N-linked oligomer of three AlphA-Amino Aldehyde components, A reAction pAthwAy thAt mAy pArAllel the biosynthetic route to the SAfrAmycins.

Brian A. Lanman - One of the best experts on this subject based on the ideXlab platform.

  • A Solid-Supported, EnAntioselective Synthesis SuitAble for the RApid PrepArAtion of LArge Numbers of Diverse StructurAl AnAlogues of (−)-SAfrAmycin A
    Journal of the American Chemical Society, 2002
    Co-Authors: Andrew G. Myers, Brian A. Lanman
    Abstract:

    A 10-step solid-supported, enAntioselective synthesis suitAble for the rApid prepArAtion of lArge numbers of diverse structurAl AnAlogues of SAfrAmycin A is described. The synthetic route, which beArs AnAlogy to solid-phAse peptide synthesis, involves the directed condensAtion of N-protected α-Amino Aldehyde reActAnts. A novel duAl linker wAs developed for AttAchment of intermediAtes to the solid support viA A C-protective group, A substituted morpholino nitrile derivAtive. The route employs A novel diAstereospecific cycloreleAse mechAnism, supports structurAl vAriAtion At multiple sites in the SAfrAmycin core, And obviAtes the need for chromAtogrAphic purificAtion of the products or Any intermediAte. To demonstrAte the feAsibility of structurAl vAriAtion At multiple sites, A mAtrix of 16 SAfrAmycin A AnAlogues wAs prepAred by pArAllel synthesis with simultAneous vAriAtion of two sites. This work is notAble not only As A preliminAry step towArd lArge-scAle librAry construction but Also As An exAmple of th...

  • A solid supported enAntioselective synthesis suitAble for the rApid prepArAtion of lArge numbers of diverse structurAl AnAlogues of SAfrAmycin A
    Journal of the American Chemical Society, 2002
    Co-Authors: Andrew G. Myers, Brian A. Lanman
    Abstract:

    A 10-step solid-supported, enAntioselective synthesis suitAble for the rApid prepArAtion of lArge numbers of diverse structurAl AnAlogues of SAfrAmycin A is described. The synthetic route, which beArs AnAlogy to solid-phAse peptide synthesis, involves the directed condensAtion of N-protected α-Amino Aldehyde reActAnts. A novel duAl linker wAs developed for AttAchment of intermediAtes to the solid support viA A C-protective group, A substituted morpholino nitrile derivAtive. The route employs A novel diAstereospecific cycloreleAse mechAnism, supports structurAl vAriAtion At multiple sites in the SAfrAmycin core, And obviAtes the need for chromAtogrAphic purificAtion of the products or Any intermediAte. To demonstrAte the feAsibility of structurAl vAriAtion At multiple sites, A mAtrix of 16 SAfrAmycin A AnAlogues wAs prepAred by pArAllel synthesis with simultAneous vAriAtion of two sites. This work is notAble not only As A preliminAry step towArd lArge-scAle librAry construction but Also As An exAmple of th...

Hideaki Oikawa - One of the best experts on this subject based on the ideXlab platform.

  • Chemo-enzymAtic TotAl Syntheses of JorunnAmycin A, SAfrAmycin A, And N-Fmoc SAfrAmycin Y3.
    Journal of the American Chemical Society, 2018
    Co-Authors: Ryo Tanifuji, Kento Koketsu, Atsushi Minami, Hideaki Oikawa, Michiko Takakura, Ryutaro Asano, Hiroki Oguri
    Abstract:

    The Antitumor tetrAhydroisoquinoline (THIQ) AlkAloids shAre A common pentAcyclic scAffold thAt is biosynthesized by nonribosomAl peptide synthetAses involving unique enzymAtic Pictet–Spengler cyclizAtions. Herein we report concise And divergent chemo-enzymAtic totAl syntheses of THIQ AlkAloids by merging precise chemicAl synthesis with in vitro engineered biosynthesis. A recombinAnt enzyme SfmC responsible for the biosynthesis of SAfrAmycin A wAs AdApted for the Assembly of these nAturAl products And their derivAtives, by optimizing designer substrAtes compAtible with SfmC through chemicAl synthesis. The AppropriAtely functionAlized pentAcyclic skeleton were efficiently synthesized by streAmlining the linkAge between SfmC-cAtAlyzed multistep enzymAtic conversions And chemicAl mAnipulAtions of the intermediAtes to instAll Aminonitrile And N-methyl groups. This ApproAch Allowed rApid Access to the elAborAted pentAcyclic skeleton in A single dAy stArting from two simple synthetic substrAtes without isolAtion...

  • Chemo-enzymAtic TotAl Syntheses of JorunnAmycin A, SAfrAmycin A, And N‑Fmoc SAfrAmycin Y3
    2018
    Co-Authors: Ryo Tanifuji, Kento Koketsu, Atsushi Minami, Hideaki Oikawa, Michiko Takakura, Ryutaro Asano, Hiroki Oguri
    Abstract:

    The Antitumor tetrAhydroisoquinoline (THIQ) AlkAloids shAre A common pentAcyclic scAffold thAt is biosynthesized by nonribosomAl peptide synthetAses involving unique enzymAtic Pictet–Spengler cyclizAtions. Herein we report concise And divergent chemo-enzymAtic totAl syntheses of THIQ AlkAloids by merging precise chemicAl synthesis with in vitro engineered biosynthesis. A recombinAnt enzyme SfmC responsible for the biosynthesis of SAfrAmycin A wAs AdApted for the Assembly of these nAturAl products And their derivAtives, by optimizing designer substrAtes compAtible with SfmC through chemicAl synthesis. The AppropriAtely functionAlized pentAcyclic skeleton were efficiently synthesized by streAmlining the linkAge between SfmC-cAtAlyzed multistep enzymAtic conversions And chemicAl mAnipulAtions of the intermediAtes to instAll Aminonitrile And N-methyl groups. This ApproAch Allowed rApid Access to the elAborAted pentAcyclic skeleton in A single dAy stArting from two simple synthetic substrAtes without isolAtion of the intermediAtes. Further functionAl group mAnipulAtions Allowed operAtionAlly simple And expeditious syntheses of jorunnAmycin A, SAfrAmycin A, And N-Fmoc SAfrAmycin Y3 thAt could be versAtile And common precursors for the ArtificiAl production of other Antitumor THIQ AlkAloids And their vAriAnts

  • Pictet-SpenglerAse involved in tetrAhydroisoquinoline Antibiotic biosynthesis.
    Current opinion in chemical biology, 2012
    Co-Authors: Kento Koketsu, Atsushi Minami, Kenji Watanabe, Hiroki Oguri, Hideaki Oikawa
    Abstract:

    NonribosomAl peptide synthetAse (NRPS) is A progrAmmAble modulAr mAchinery thAt produces A number of biologicAlly Active smAll-molecule peptides. SAfrAmycin A is A potent Antitumor Antibiotic with A unique pentAcyclic tetrAhydroisoquinoline scAffold. We found thAt the nonribosomAl peptide synthetAse SfmC cAtAlyzes A seven-step trAnsformAtion of reAdily synthesized dipeptidyl substrAtes with long Acyl chAins into A complex SAfrAmycin scAffold. BAsed on A series of enzymAtic reActions, we proposed A detAiled mechAnism involving the reduction of vArious peptidyl thioesters by A single R domAin followed by iterAtive C domAin-mediAted Pictet-Spengler reActions. This shows thAt NRPSs possess A remArkAble cApAbility to Acquire novel function for diversifying structures of peptide nAturAl products.

  • Reconstruction of the SAfrAmycin core scAffold defines duAl Pictet-Spengler mechAnisms
    Nature Chemical Biology, 2010
    Co-Authors: Kento Koketsu, Kenji Watanabe, Hiroki Oguri, Haruna Suda, Hideaki Oikawa
    Abstract:

    SAfrAmycin A is A potent Antitumor Antibiotic with A unique pentAcyclic tetrAhydroisoquinoline scAffold. We found thAt the nonribosomAl peptide synthetAse SfmC cAtAlyzes A seven-step trAnsformAtion of reAdily synthesized dipeptidyl substrAtes with long Acyl chAins into A complex SAfrAmycin scAffold. BAsed on A series of enzymAtic reActions, we propose A detAiled mechAnism involving the reduction of vArious peptidyl thioesters by A single R domAin followed by iterAtive C domAin–mediAted Pictet-Spengler reActions. The chemicAl synthesis of AcylAted dipeptide substrAtes for SfmC, A tetrAdomAin NRPS enzyme, defines the mechAnism of formAtion of two rings in SAfrAmycin And explAins the unusuAl presence of A fAtty Acid loAding system in this biosynthetic gene cluster.

Kento Koketsu - One of the best experts on this subject based on the ideXlab platform.

  • Chemo-enzymAtic TotAl Syntheses of JorunnAmycin A, SAfrAmycin A, And N-Fmoc SAfrAmycin Y3.
    Journal of the American Chemical Society, 2018
    Co-Authors: Ryo Tanifuji, Kento Koketsu, Atsushi Minami, Hideaki Oikawa, Michiko Takakura, Ryutaro Asano, Hiroki Oguri
    Abstract:

    The Antitumor tetrAhydroisoquinoline (THIQ) AlkAloids shAre A common pentAcyclic scAffold thAt is biosynthesized by nonribosomAl peptide synthetAses involving unique enzymAtic Pictet–Spengler cyclizAtions. Herein we report concise And divergent chemo-enzymAtic totAl syntheses of THIQ AlkAloids by merging precise chemicAl synthesis with in vitro engineered biosynthesis. A recombinAnt enzyme SfmC responsible for the biosynthesis of SAfrAmycin A wAs AdApted for the Assembly of these nAturAl products And their derivAtives, by optimizing designer substrAtes compAtible with SfmC through chemicAl synthesis. The AppropriAtely functionAlized pentAcyclic skeleton were efficiently synthesized by streAmlining the linkAge between SfmC-cAtAlyzed multistep enzymAtic conversions And chemicAl mAnipulAtions of the intermediAtes to instAll Aminonitrile And N-methyl groups. This ApproAch Allowed rApid Access to the elAborAted pentAcyclic skeleton in A single dAy stArting from two simple synthetic substrAtes without isolAtion...

  • Chemo-enzymAtic TotAl Syntheses of JorunnAmycin A, SAfrAmycin A, And N‑Fmoc SAfrAmycin Y3
    2018
    Co-Authors: Ryo Tanifuji, Kento Koketsu, Atsushi Minami, Hideaki Oikawa, Michiko Takakura, Ryutaro Asano, Hiroki Oguri
    Abstract:

    The Antitumor tetrAhydroisoquinoline (THIQ) AlkAloids shAre A common pentAcyclic scAffold thAt is biosynthesized by nonribosomAl peptide synthetAses involving unique enzymAtic Pictet–Spengler cyclizAtions. Herein we report concise And divergent chemo-enzymAtic totAl syntheses of THIQ AlkAloids by merging precise chemicAl synthesis with in vitro engineered biosynthesis. A recombinAnt enzyme SfmC responsible for the biosynthesis of SAfrAmycin A wAs AdApted for the Assembly of these nAturAl products And their derivAtives, by optimizing designer substrAtes compAtible with SfmC through chemicAl synthesis. The AppropriAtely functionAlized pentAcyclic skeleton were efficiently synthesized by streAmlining the linkAge between SfmC-cAtAlyzed multistep enzymAtic conversions And chemicAl mAnipulAtions of the intermediAtes to instAll Aminonitrile And N-methyl groups. This ApproAch Allowed rApid Access to the elAborAted pentAcyclic skeleton in A single dAy stArting from two simple synthetic substrAtes without isolAtion of the intermediAtes. Further functionAl group mAnipulAtions Allowed operAtionAlly simple And expeditious syntheses of jorunnAmycin A, SAfrAmycin A, And N-Fmoc SAfrAmycin Y3 thAt could be versAtile And common precursors for the ArtificiAl production of other Antitumor THIQ AlkAloids And their vAriAnts

  • Pictet-SpenglerAse involved in tetrAhydroisoquinoline Antibiotic biosynthesis.
    Current opinion in chemical biology, 2012
    Co-Authors: Kento Koketsu, Atsushi Minami, Kenji Watanabe, Hiroki Oguri, Hideaki Oikawa
    Abstract:

    NonribosomAl peptide synthetAse (NRPS) is A progrAmmAble modulAr mAchinery thAt produces A number of biologicAlly Active smAll-molecule peptides. SAfrAmycin A is A potent Antitumor Antibiotic with A unique pentAcyclic tetrAhydroisoquinoline scAffold. We found thAt the nonribosomAl peptide synthetAse SfmC cAtAlyzes A seven-step trAnsformAtion of reAdily synthesized dipeptidyl substrAtes with long Acyl chAins into A complex SAfrAmycin scAffold. BAsed on A series of enzymAtic reActions, we proposed A detAiled mechAnism involving the reduction of vArious peptidyl thioesters by A single R domAin followed by iterAtive C domAin-mediAted Pictet-Spengler reActions. This shows thAt NRPSs possess A remArkAble cApAbility to Acquire novel function for diversifying structures of peptide nAturAl products.

  • Reconstruction of the SAfrAmycin core scAffold defines duAl Pictet-Spengler mechAnisms
    Nature Chemical Biology, 2010
    Co-Authors: Kento Koketsu, Kenji Watanabe, Hiroki Oguri, Haruna Suda, Hideaki Oikawa
    Abstract:

    SAfrAmycin A is A potent Antitumor Antibiotic with A unique pentAcyclic tetrAhydroisoquinoline scAffold. We found thAt the nonribosomAl peptide synthetAse SfmC cAtAlyzes A seven-step trAnsformAtion of reAdily synthesized dipeptidyl substrAtes with long Acyl chAins into A complex SAfrAmycin scAffold. BAsed on A series of enzymAtic reActions, we propose A detAiled mechAnism involving the reduction of vArious peptidyl thioesters by A single R domAin followed by iterAtive C domAin–mediAted Pictet-Spengler reActions. The chemicAl synthesis of AcylAted dipeptide substrAtes for SfmC, A tetrAdomAin NRPS enzyme, defines the mechAnism of formAtion of two rings in SAfrAmycin And explAins the unusuAl presence of A fAtty Acid loAding system in this biosynthetic gene cluster.

Hiroki Oguri - One of the best experts on this subject based on the ideXlab platform.

  • Chemo-enzymAtic TotAl Syntheses of JorunnAmycin A, SAfrAmycin A, And N-Fmoc SAfrAmycin Y3.
    Journal of the American Chemical Society, 2018
    Co-Authors: Ryo Tanifuji, Kento Koketsu, Atsushi Minami, Hideaki Oikawa, Michiko Takakura, Ryutaro Asano, Hiroki Oguri
    Abstract:

    The Antitumor tetrAhydroisoquinoline (THIQ) AlkAloids shAre A common pentAcyclic scAffold thAt is biosynthesized by nonribosomAl peptide synthetAses involving unique enzymAtic Pictet–Spengler cyclizAtions. Herein we report concise And divergent chemo-enzymAtic totAl syntheses of THIQ AlkAloids by merging precise chemicAl synthesis with in vitro engineered biosynthesis. A recombinAnt enzyme SfmC responsible for the biosynthesis of SAfrAmycin A wAs AdApted for the Assembly of these nAturAl products And their derivAtives, by optimizing designer substrAtes compAtible with SfmC through chemicAl synthesis. The AppropriAtely functionAlized pentAcyclic skeleton were efficiently synthesized by streAmlining the linkAge between SfmC-cAtAlyzed multistep enzymAtic conversions And chemicAl mAnipulAtions of the intermediAtes to instAll Aminonitrile And N-methyl groups. This ApproAch Allowed rApid Access to the elAborAted pentAcyclic skeleton in A single dAy stArting from two simple synthetic substrAtes without isolAtion...

  • Chemo-enzymAtic TotAl Syntheses of JorunnAmycin A, SAfrAmycin A, And N‑Fmoc SAfrAmycin Y3
    2018
    Co-Authors: Ryo Tanifuji, Kento Koketsu, Atsushi Minami, Hideaki Oikawa, Michiko Takakura, Ryutaro Asano, Hiroki Oguri
    Abstract:

    The Antitumor tetrAhydroisoquinoline (THIQ) AlkAloids shAre A common pentAcyclic scAffold thAt is biosynthesized by nonribosomAl peptide synthetAses involving unique enzymAtic Pictet–Spengler cyclizAtions. Herein we report concise And divergent chemo-enzymAtic totAl syntheses of THIQ AlkAloids by merging precise chemicAl synthesis with in vitro engineered biosynthesis. A recombinAnt enzyme SfmC responsible for the biosynthesis of SAfrAmycin A wAs AdApted for the Assembly of these nAturAl products And their derivAtives, by optimizing designer substrAtes compAtible with SfmC through chemicAl synthesis. The AppropriAtely functionAlized pentAcyclic skeleton were efficiently synthesized by streAmlining the linkAge between SfmC-cAtAlyzed multistep enzymAtic conversions And chemicAl mAnipulAtions of the intermediAtes to instAll Aminonitrile And N-methyl groups. This ApproAch Allowed rApid Access to the elAborAted pentAcyclic skeleton in A single dAy stArting from two simple synthetic substrAtes without isolAtion of the intermediAtes. Further functionAl group mAnipulAtions Allowed operAtionAlly simple And expeditious syntheses of jorunnAmycin A, SAfrAmycin A, And N-Fmoc SAfrAmycin Y3 thAt could be versAtile And common precursors for the ArtificiAl production of other Antitumor THIQ AlkAloids And their vAriAnts

  • Pictet-SpenglerAse involved in tetrAhydroisoquinoline Antibiotic biosynthesis.
    Current opinion in chemical biology, 2012
    Co-Authors: Kento Koketsu, Atsushi Minami, Kenji Watanabe, Hiroki Oguri, Hideaki Oikawa
    Abstract:

    NonribosomAl peptide synthetAse (NRPS) is A progrAmmAble modulAr mAchinery thAt produces A number of biologicAlly Active smAll-molecule peptides. SAfrAmycin A is A potent Antitumor Antibiotic with A unique pentAcyclic tetrAhydroisoquinoline scAffold. We found thAt the nonribosomAl peptide synthetAse SfmC cAtAlyzes A seven-step trAnsformAtion of reAdily synthesized dipeptidyl substrAtes with long Acyl chAins into A complex SAfrAmycin scAffold. BAsed on A series of enzymAtic reActions, we proposed A detAiled mechAnism involving the reduction of vArious peptidyl thioesters by A single R domAin followed by iterAtive C domAin-mediAted Pictet-Spengler reActions. This shows thAt NRPSs possess A remArkAble cApAbility to Acquire novel function for diversifying structures of peptide nAturAl products.

  • Reconstruction of the SAfrAmycin core scAffold defines duAl Pictet-Spengler mechAnisms
    Nature Chemical Biology, 2010
    Co-Authors: Kento Koketsu, Kenji Watanabe, Hiroki Oguri, Haruna Suda, Hideaki Oikawa
    Abstract:

    SAfrAmycin A is A potent Antitumor Antibiotic with A unique pentAcyclic tetrAhydroisoquinoline scAffold. We found thAt the nonribosomAl peptide synthetAse SfmC cAtAlyzes A seven-step trAnsformAtion of reAdily synthesized dipeptidyl substrAtes with long Acyl chAins into A complex SAfrAmycin scAffold. BAsed on A series of enzymAtic reActions, we propose A detAiled mechAnism involving the reduction of vArious peptidyl thioesters by A single R domAin followed by iterAtive C domAin–mediAted Pictet-Spengler reActions. The chemicAl synthesis of AcylAted dipeptide substrAtes for SfmC, A tetrAdomAin NRPS enzyme, defines the mechAnism of formAtion of two rings in SAfrAmycin And explAins the unusuAl presence of A fAtty Acid loAding system in this biosynthetic gene cluster.