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Ben Shen - One of the best experts on this subject based on the ideXlab platform.
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comparative studies of the biosynthetic gene clusters for anthraquinone fused Enediynes shedding light into the tailoring steps of tiancimycin biosynthesis
Organic Letters, 2018Co-Authors: Xiaohui Yan, Chin-yuan Chang, Dong Yang, Jianjun Chen, Ajeeth Adhikari, Ivana Crnovcic, Christoph Rader, Christiana N Teijaro, Thibault Annaval, Ben ShenAbstract:Comparative analyses of the four known anthraquinone-fused Enediynes biosynthetic gene clusters identified four genes, tnmE6, tnmH, tnmL, and tnmQ, unique to the tnm gene cluster. Larger scale fermentation of both the S. sp. CB03234 wild-type and the ΔtnmH and ΔtnmL mutant strains resulted in the characterization of 20 new tiancimycin (TNM) congeners, including five Enediynes. These findings enabled a proposal for the late stage of TNM biosynthesis featuring an intermediate possibly common for all anthraquinone-fused Enediynes.
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genome mining of micromonospora yangpuensis dsm 45577 as a producer of an anthraquinone fused enediyne
Organic Letters, 2017Co-Authors: Xiaohui Yan, Chin-yuan Chang, Dong Yang, Jianjun Chen, Ajeeth Adhikari, Ivana Crnovcic, Nan Wang, Christoph Rader, Ben ShenAbstract:A new anthraquinone-fused enediyne, yangpumicin A (YPM A, 1), along with four Bergman cyclization congeners (YPM B–E, 2–5), was isolated from Micromonospora yangpuensis DSM 45577 after mining enediyne biosynthetic gene clusters from public actinobacterial genome databases and prioritizing the hits by an enediyne genome neighborhood network analysis for discovery. YPM A is potent against a broad spectrum of human cancer cell lines. The discovery of 1 provides new opportunities for the functionalization of Enediynes to develop new conjugation chemistries for antibody–drug conjugates.
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Predictive Model for Epoxide Hydrolase-Generated Stereochemistry in the Biosynthesis of Nine-Membered Enediyne Antitumor Antibiotics
2016Co-Authors: Geoffrey P. Horsman, Anna Lechner, Yasuo Ohnishi, Bradley S. Moore, Ben ShenAbstract:Nine-membered enediyne antitumor antibiotics C-1027, neocarzinostatin (NCS), and kedarcidin (KED) possess enediyne cores to which activity-modulating peripheral moieties are attached via (R)- or (S)-vicinal diols. We have previously shown that this stereochemical difference arises from hydrolysis of epoxide precursors by epoxide hydrolases (EHs) with different regioselectivities. The inverting EHs, such as SgcF, hydrolyze an (S)-epoxide substrate to yield an (R)-diol in C-1027 biosynthesis, whereas the retaining EHs, such as NcsF2 and KedF, hydrolyze an (S)-epoxide substrate to yield an (S)-diol in NCS and KED biosynthesis. We now report the characterization of a series of EH mutants and provide a predictive model for EH regioselectivity in the biosynthesis of the nine-membered enediyne antitumor antibiotics. A W236Y mutation in SgcF increased the retaining activity toward (S)-styrene oxide by 3-fold, and a W236Y/Q237M double mutation in SgcF, mimicking NcsF2 and KedF, resulted in a 20-fold increase in the retaining activity. To test the predictive utility of these mutations, two putative enediyne biosynthesis-associated EHs were identified by genome mining and confirmed as inverting enzymes, SpoF from Salinospora tropica CNB-440 and SgrF (SGR_625) from Streptomyces griseus IFO 13350. Finally, phylogenetic analysis of EHs revealed a familial classification according to inverting versus retaining activity. Taken together, these results provide a predictive model for vicinal diol stereochemistry in enediyne biosynthesis and set the stage for further elucidating the origins of EH regioselectivity
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Enediynes exploration of microbial genomics to discover new anticancer drug leads
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: Ben Shen, Tingting Huang, Jeffrey D. Rudolf, Xiaohui Yan, Dong Yang, Qihui Teng, Jeremy R LohmanAbstract:The enediyne natural products have been explored for their phenomenal cytotoxicity. The development of Enediynes into anticancer drugs has been successfully achieved through the utilization of polymer- and antibody–drug conjugates (ADCs) as drug delivery systems. An increasing inventory of Enediynes would benefit current application of ADCs in many oncology programs. Innovations in expanding the enediyne inventory should take advantage of the current knowledge of enediyne biosynthesis and post-genomics technologies. Bioinformatics analysis of microbial genomes reveals that Enediynes are underexplored, in particular from Actinomycetales. This digest highlights the emerging opportunities to explore microbial genomics for the discovery of novel enediyne natural products.
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cloning and sequencing of the kedarcidin biosynthetic gene cluster from streptoalloteichus sp atcc 53650 revealing new insights into biosynthesis of the enediyne family of antitumor antibiotics
Molecular BioSystems, 2013Co-Authors: Jeremy R Lohman, Shengxiong Huang, Geoffrey P Horsman, Paul E Dilfer, Yihua Chen, Tingting Huang, Evelyn Wendtpienkowski, Ben ShenAbstract:Enediyne natural product biosynthesis is characterized by a convergence of multiple pathways, generating unique peripheral moieties that are appended onto the distinctive enediyne core. Kedarcidin (KED) possesses two unique peripheral moieties, a (R)-2-aza-3-chloro-β-tyrosine and an iso-propoxy-bearing 2-naphthonate moiety, as well as two deoxysugars. The appendage pattern of these peripheral moieties to the enediyne core in KED differs from the other Enediynes studied to date with respect to stereochemical configuration. To investigate the biosynthesis of these moieties and expand our understanding of enediyne core formation, the biosynthetic gene cluster for KED was cloned from Streptoalloteichus sp. ATCC 53650 and sequenced. Bioinformatics analysis of the ked cluster revealed the presence of the conserved genes encoding for enediyne core biosynthesis, type I and type II polyketide synthase loci likely responsible for 2-aza-L-tyrosine and 3,6,8-trihydroxy-2-naphthonate formation, and enzymes known for deoxysugar biosynthesis. Genes homologous to those responsible for the biosynthesis, activation, and coupling of the L-tyrosine-derived moieties from C-1027 and maduropeptin and of the naphthonate moiety from neocarzinostatin are present in the ked cluster, supporting 2-aza-L-tyrosine and 3,6,8-trihydroxy-2-naphthoic acid as precursors, respectively, for the (R)-2-aza-3-chloro-β-tyrosine and the 2-naphthonate moieties in KED biosynthesis.
Ivanka Jeric - One of the best experts on this subject based on the ideXlab platform.
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bergman cyclization of acyclic amino acid derived Enediynes leads to the formation of 2 3 dihydrobenzo f isoindoles
ChemInform, 2011Co-Authors: Matija Gredicak, Ivana Matanovic, Boris Zimmermann, Ivanka JericAbstract:Heating of the Enediynes (Ia)—(Ic) in the presence of cyclohexadiene renders possible the new access to dihydrobenzoisoindoles via Bergmann cyclization and subsequent intramolecular nucleophilic substitution.
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bergman cyclization of acyclic amino acid derived Enediynes leads to the formation of 2 3 dihydrobenzo f isoindoles
Journal of Organic Chemistry, 2010Co-Authors: Matija Gredicak, Ivana Matanovic, Boris Zimmermann, Ivanka JericAbstract:Enediyne−peptide conjugates are recently recognized as useful tools in targeting various proteins, while the mechanism underlying the observed activity remains somewhat unclear. Addressing these issues, we have prepared acyclic amino acid derived Enediynes and disclosed a novel thermally induced cyclization−elimination pathway. Initial formation of 1,4-benzene diradical and H-atom abstraction from an external donor is followed by SN2 substitution leading to 2,3-dihydrobenzo[f]isoindoles. The proposed mechanism is supported by experimental and computational data. Additionally, we showed that amino acid side chains, although placed three bonds away from acetylene terminuses, have an appreciable influence on the reactivity of studied Enediynes. These results demonstrate that amino acid or peptide parts of enediyne−peptide conjugates cannot be considered as recognition elements exclusively but may also participate in various reactions through amine functionality.
Xiaohui Yan - One of the best experts on this subject based on the ideXlab platform.
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comparative studies of the biosynthetic gene clusters for anthraquinone fused Enediynes shedding light into the tailoring steps of tiancimycin biosynthesis
Organic Letters, 2018Co-Authors: Xiaohui Yan, Chin-yuan Chang, Dong Yang, Jianjun Chen, Ajeeth Adhikari, Ivana Crnovcic, Christoph Rader, Christiana N Teijaro, Thibault Annaval, Ben ShenAbstract:Comparative analyses of the four known anthraquinone-fused Enediynes biosynthetic gene clusters identified four genes, tnmE6, tnmH, tnmL, and tnmQ, unique to the tnm gene cluster. Larger scale fermentation of both the S. sp. CB03234 wild-type and the ΔtnmH and ΔtnmL mutant strains resulted in the characterization of 20 new tiancimycin (TNM) congeners, including five Enediynes. These findings enabled a proposal for the late stage of TNM biosynthesis featuring an intermediate possibly common for all anthraquinone-fused Enediynes.
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Structural Insights into the Free-Standing Condensation Enzyme SgcC5 Catalyzing Ester-Bond Formation in the Biosynthesis of the Enediyne Antitumor Antibiotic C-1027.
Biochemistry, 2018Co-Authors: Chin-yuan Chang, Jeremy R Lohman, Tingting Huang, Karolina Michalska, Lance Bigelow, Jeffrey D. Rudolf, Robert Jedrzejczak, Xiaohui Yan, Gyorgy BabniggAbstract:C-1027 is a chromoprotein enediyne antitumor antibiotic, consisting of the CagA apoprotein and the C-1027 chromophore. The C-1027 chromophore features a nine-membered enediyne core appended with three peripheral moieties, including an (S)-3-chloro-5-hydroxy-β-tyrosine. In a convergent biosynthesis of the C-1027 chromophore, the (S)-3-chloro-5-hydroxy-β-tyrosine moiety is appended to the enediyne core by the free-standing condensation enzyme SgcC5. Unlike canonical condensation domains from the modular nonribosomal peptide synthetases that catalyze amide-bond formation, SgcC5 catalyzes ester-bond formation, as demonstrated in vitro, between SgcC2-tethered (S)-3-chloro-5-hydroxy-β-tyrosine and (R)-1-phenyl-1,2-ethanediol, a mimic of the enediyne core as an acceptor substrate. Here, we report that (i) genes encoding SgcC5 homologues are widespread among both experimentally confirmed and bioinformatically predicted enediyne biosynthetic gene clusters, forming a new clade of condensation enzymes, (ii) SgcC5 sh...
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Structural Insights into the Free-Standing Condensation Enzyme SgcC5 Catalyzing Ester-Bond Formation in the Biosynthesis of the Enediyne Antitumor Antibiotic C‑1027
2018Co-Authors: Chin-yuan Chang, Jeremy R Lohman, Tingting Huang, Karolina Michalska, Lance Bigelow, Jeffrey D. Rudolf, Robert Jedrzejczak, Xiaohui Yan, Gyorgy BabniggAbstract:C-1027 is a chromoprotein enediyne antitumor antibiotic, consisting of the CagA apoprotein and the C-1027 chromophore. The C-1027 chromophore features a nine-membered enediyne core appended with three peripheral moieties, including an (S)-3-chloro-5-hydroxy-β-tyrosine. In a convergent biosynthesis of the C-1027 chromophore, the (S)-3-chloro-5-hydroxy-β-tyrosine moiety is appended to the enediyne core by the free-standing condensation enzyme SgcC5. Unlike canonical condensation domains from the modular nonribosomal peptide synthetases that catalyze amide-bond formation, SgcC5 catalyzes ester-bond formation, as demonstrated in vitro, between SgcC2-tethered (S)-3-chloro-5-hydroxy-β-tyrosine and (R)-1-phenyl-1,2-ethanediol, a mimic of the enediyne core as an acceptor substrate. Here, we report that (i) genes encoding SgcC5 homologues are widespread among both experimentally confirmed and bioinformatically predicted enediyne biosynthetic gene clusters, forming a new clade of condensation enzymes, (ii) SgcC5 shares a similar overall structure with the canonical condensation domains but forms a homodimer in solution, the active site of which is located in a cavity rather than a tunnel typically seen in condensation domains, and (iii) the catalytic histidine of SgcC5 activates the 2-hydroxyl group, while a hydrogen-bond network in SgcC5 prefers the R-enantiomer of the acceptor substrate, accounting for the regio- and stereospecific ester-bond formation between SgcC2-tethered (S)-3-chloro-5-hydroxy-β-tyrosine and (R)-1-phenyl-1,2-ethanediol upon acid–base catalysis. These findings expand the catalytic repertoire and reveal new insights into the structure and mechanism of condensation enzymes
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genome mining of micromonospora yangpuensis dsm 45577 as a producer of an anthraquinone fused enediyne
Organic Letters, 2017Co-Authors: Xiaohui Yan, Chin-yuan Chang, Dong Yang, Jianjun Chen, Ajeeth Adhikari, Ivana Crnovcic, Nan Wang, Christoph Rader, Ben ShenAbstract:A new anthraquinone-fused enediyne, yangpumicin A (YPM A, 1), along with four Bergman cyclization congeners (YPM B–E, 2–5), was isolated from Micromonospora yangpuensis DSM 45577 after mining enediyne biosynthetic gene clusters from public actinobacterial genome databases and prioritizing the hits by an enediyne genome neighborhood network analysis for discovery. YPM A is potent against a broad spectrum of human cancer cell lines. The discovery of 1 provides new opportunities for the functionalization of Enediynes to develop new conjugation chemistries for antibody–drug conjugates.
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Enediynes exploration of microbial genomics to discover new anticancer drug leads
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: Ben Shen, Tingting Huang, Jeffrey D. Rudolf, Xiaohui Yan, Dong Yang, Qihui Teng, Jeremy R LohmanAbstract:The enediyne natural products have been explored for their phenomenal cytotoxicity. The development of Enediynes into anticancer drugs has been successfully achieved through the utilization of polymer- and antibody–drug conjugates (ADCs) as drug delivery systems. An increasing inventory of Enediynes would benefit current application of ADCs in many oncology programs. Innovations in expanding the enediyne inventory should take advantage of the current knowledge of enediyne biosynthesis and post-genomics technologies. Bioinformatics analysis of microbial genomes reveals that Enediynes are underexplored, in particular from Actinomycetales. This digest highlights the emerging opportunities to explore microbial genomics for the discovery of novel enediyne natural products.
Irina A Balova - One of the best experts on this subject based on the ideXlab platform.
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Intramolecular Nicholas Reactions in the Synthesis of HeteroEnediynes Fused to Indole, Triazole, and Isocoumarin.
The Journal of organic chemistry, 2020Co-Authors: Natalia A Danilkina, Alexander F Khlebnikov, Anastasia I Govdi, Stefan Brase, Alexander S. D’yachenko, Ilya V. Kornyakov, Irina A BalovaAbstract:The applicability of an intramolecular Nicholas reaction for the preparation of 10-membered O- and N-Enediynes fused to indole, 1,2,3-triazole, and isocoumarin was investigated. The general approach to acyclic enediyne precursors fused to heterocycles includes inter- and intramolecular buta-1,3-diyne cyclizations with the formation of iodoethynylheterocycles, followed by Sonogashira coupling. The nature of both a heterocycle and a nucleophilic group affects the possibility of a 10-membered ring closure by the Nicholas reaction. Among oxacycles, an isocoumarin-fused enediyne was obtained. In the case of O-enediyne annulated with indole, instead of the formation of a 10-membered cycle, BF3-promoted addition of an OH-group to the proximal triple bond at the C3 position afforded dihydrofuryl-substituted indole. For 1,2,3-triazole-fused analogues, using NH-Ts as a nucleophilic functional group allowed obtaining 10-membered azaenediyne, while the substrate with a hydroxyl group gave only traces of the desired 10-membered oxacycle. An improved method for the deprotection of Co-complexes of cyclic Enediynes using tetrabutylammonium fluoride in an acetone/water mixture and the investigation of the 10-membered Enediynes' reactivity in the Bergman cyclization are also reported. In the solid state, all synthesized iodoethynylheterocycles were found to be involved in halogen bond (XB) formation with either O or N atoms as XB acceptors.
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relative reactivity of benzothiophene fused Enediynes in the bergman cyclization
Journal of Organic Chemistry, 2018Co-Authors: Anna G Lyapunova, Natalia A Danilkina, Andrey M Rumyantsev, Alexander F Khlebnikov, M V Chislov, Galina L Starova, E V Sambuk, Anastasia I Govdi, Stefan Brase, Irina A BalovaAbstract:To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative Enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothiophene, benzene, and cinnoline annulated 9- and 10-membered Enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic Enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholas-type macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropyl-substituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin.
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Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization
2018Co-Authors: Anna G Lyapunova, A.f. Khlebnikov, Natalia A Danilkina, Andrey M Rumyantsev, M V Chislov, Galina L Starova, E V Sambuk, Anastasia I Govdi, Stefan Bräse, Irina A BalovaAbstract:To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative Enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothiophene, benzene, and cinnoline annulated 9- and 10-membered Enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic Enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholas-type macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropyl-substituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin
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towards isocoumarin fused enediyne systems through the electrophilic cyclization of methyl o buta 1 3 diynyl benzoates
ChemInform, 2016Co-Authors: Natalia A Danilkina, Larisa Yu Gurskaya, Aleksander V Vasilyev, Irina A BalovaAbstract:The synthesis of Enediynes fused to an isocoumarin core was achieved through the electrophilic cyclization of o-(buta-1,3-diynyl)benzoates as a key step, followed by the Sonogashira coupling of the resulting 3-ethynyl-4-iodoisocoumarins with acetylenes. This approach allowed different substituents to be introduced to both ethynyl moieties with complete regiocontrol. The ability of the isocoumarin-fused Enediynes to undergo Bergman cyclization was studied by differential scanning calorimetry.
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electrophilic cyclization of aryldiacetylenes in the synthesis of functionalized Enediynes fused to a heterocyclic core
Journal of Organic Chemistry, 2014Co-Authors: Natalia A Danilkina, A.e. Kulyashova, Alexander F Khlebnikov, Stefan Brase, Irina A BalovaAbstract:An efficient strategy for the synthesis of asymmetrically substituted Enediynes fused to benzothiophene, benzofuran, and indole was developed. The proposed approach is based on the electrophilic cyclization of diacetylenes and Sonogashira coupling. Thus, iodocyclization of readily available ortho-functionalized (buta-1,3-diynyl)arenes was used as a direct way for the synthesis of 2-ethynyl-3-iodoheteroindenes. These substrates and their modified derivatives were easily converted by Sonogashira coupling with acetylenes to a variety of asymmetrically substituted acyclic Enediynes fused to heterocycles. The tolerance of the developed methodology to a variety of functional groups is a great advantage in the synthesis of macrocyclic enediyne systems fused to a heterocyclic core. Synthesis of indole-fused 12-membered macrocyclic dienediyne was achieved using ring-closing metathesis as a key step.
Chin-yuan Chang - One of the best experts on this subject based on the ideXlab platform.
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comparative studies of the biosynthetic gene clusters for anthraquinone fused Enediynes shedding light into the tailoring steps of tiancimycin biosynthesis
Organic Letters, 2018Co-Authors: Xiaohui Yan, Chin-yuan Chang, Dong Yang, Jianjun Chen, Ajeeth Adhikari, Ivana Crnovcic, Christoph Rader, Christiana N Teijaro, Thibault Annaval, Ben ShenAbstract:Comparative analyses of the four known anthraquinone-fused Enediynes biosynthetic gene clusters identified four genes, tnmE6, tnmH, tnmL, and tnmQ, unique to the tnm gene cluster. Larger scale fermentation of both the S. sp. CB03234 wild-type and the ΔtnmH and ΔtnmL mutant strains resulted in the characterization of 20 new tiancimycin (TNM) congeners, including five Enediynes. These findings enabled a proposal for the late stage of TNM biosynthesis featuring an intermediate possibly common for all anthraquinone-fused Enediynes.
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Structural Insights into the Free-Standing Condensation Enzyme SgcC5 Catalyzing Ester-Bond Formation in the Biosynthesis of the Enediyne Antitumor Antibiotic C-1027.
Biochemistry, 2018Co-Authors: Chin-yuan Chang, Jeremy R Lohman, Tingting Huang, Karolina Michalska, Lance Bigelow, Jeffrey D. Rudolf, Robert Jedrzejczak, Xiaohui Yan, Gyorgy BabniggAbstract:C-1027 is a chromoprotein enediyne antitumor antibiotic, consisting of the CagA apoprotein and the C-1027 chromophore. The C-1027 chromophore features a nine-membered enediyne core appended with three peripheral moieties, including an (S)-3-chloro-5-hydroxy-β-tyrosine. In a convergent biosynthesis of the C-1027 chromophore, the (S)-3-chloro-5-hydroxy-β-tyrosine moiety is appended to the enediyne core by the free-standing condensation enzyme SgcC5. Unlike canonical condensation domains from the modular nonribosomal peptide synthetases that catalyze amide-bond formation, SgcC5 catalyzes ester-bond formation, as demonstrated in vitro, between SgcC2-tethered (S)-3-chloro-5-hydroxy-β-tyrosine and (R)-1-phenyl-1,2-ethanediol, a mimic of the enediyne core as an acceptor substrate. Here, we report that (i) genes encoding SgcC5 homologues are widespread among both experimentally confirmed and bioinformatically predicted enediyne biosynthetic gene clusters, forming a new clade of condensation enzymes, (ii) SgcC5 sh...
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Structural Insights into the Free-Standing Condensation Enzyme SgcC5 Catalyzing Ester-Bond Formation in the Biosynthesis of the Enediyne Antitumor Antibiotic C‑1027
2018Co-Authors: Chin-yuan Chang, Jeremy R Lohman, Tingting Huang, Karolina Michalska, Lance Bigelow, Jeffrey D. Rudolf, Robert Jedrzejczak, Xiaohui Yan, Gyorgy BabniggAbstract:C-1027 is a chromoprotein enediyne antitumor antibiotic, consisting of the CagA apoprotein and the C-1027 chromophore. The C-1027 chromophore features a nine-membered enediyne core appended with three peripheral moieties, including an (S)-3-chloro-5-hydroxy-β-tyrosine. In a convergent biosynthesis of the C-1027 chromophore, the (S)-3-chloro-5-hydroxy-β-tyrosine moiety is appended to the enediyne core by the free-standing condensation enzyme SgcC5. Unlike canonical condensation domains from the modular nonribosomal peptide synthetases that catalyze amide-bond formation, SgcC5 catalyzes ester-bond formation, as demonstrated in vitro, between SgcC2-tethered (S)-3-chloro-5-hydroxy-β-tyrosine and (R)-1-phenyl-1,2-ethanediol, a mimic of the enediyne core as an acceptor substrate. Here, we report that (i) genes encoding SgcC5 homologues are widespread among both experimentally confirmed and bioinformatically predicted enediyne biosynthetic gene clusters, forming a new clade of condensation enzymes, (ii) SgcC5 shares a similar overall structure with the canonical condensation domains but forms a homodimer in solution, the active site of which is located in a cavity rather than a tunnel typically seen in condensation domains, and (iii) the catalytic histidine of SgcC5 activates the 2-hydroxyl group, while a hydrogen-bond network in SgcC5 prefers the R-enantiomer of the acceptor substrate, accounting for the regio- and stereospecific ester-bond formation between SgcC2-tethered (S)-3-chloro-5-hydroxy-β-tyrosine and (R)-1-phenyl-1,2-ethanediol upon acid–base catalysis. These findings expand the catalytic repertoire and reveal new insights into the structure and mechanism of condensation enzymes
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genome mining of micromonospora yangpuensis dsm 45577 as a producer of an anthraquinone fused enediyne
Organic Letters, 2017Co-Authors: Xiaohui Yan, Chin-yuan Chang, Dong Yang, Jianjun Chen, Ajeeth Adhikari, Ivana Crnovcic, Nan Wang, Christoph Rader, Ben ShenAbstract:A new anthraquinone-fused enediyne, yangpumicin A (YPM A, 1), along with four Bergman cyclization congeners (YPM B–E, 2–5), was isolated from Micromonospora yangpuensis DSM 45577 after mining enediyne biosynthetic gene clusters from public actinobacterial genome databases and prioritizing the hits by an enediyne genome neighborhood network analysis for discovery. YPM A is potent against a broad spectrum of human cancer cell lines. The discovery of 1 provides new opportunities for the functionalization of Enediynes to develop new conjugation chemistries for antibody–drug conjugates.