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Woncheol Kim Dr. Dongho Lee Dr. Seong Su Hong Dr. Zhu Na Jin Chul Shin Su Heun Roh Cheng‐Zhu Wu Oksik Choi Kyeong Lee Dr. Yue‐Mao Shen Dr. Sang‐Gi Paik Dr. Jung Joon Lee Dr. Young‐Soo Hong Dr. 《Chembiochem : a European journal of chemical biology》2009,10(7):1243-1251
Tailor made : We report the rational biosynthesis of C15 hydroxylated non‐quinone geldanamycin analogues by site‐directed mutagenesis of the geldanamycin polyketide synthase (PKS), together with a combination of post‐PKS tailoring genes. Rational biosynthetic engineering allowed the generation of geldanamycin derivatives, such as DHQ3 illustrated in the figure, which had superior pharmacological properties in comparison to the parent compound.
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Özlem Erol Till F. Schäberle Dr. Alexander Schmitz Shwan Rachid Dr. Cristian Gurgui Dr. Mustafa El Omari Friederike Lohr Stefan Kehraus Dr. Jörn Piel Prof. Dr. Rolf Müller Prof. Dr. Gabriele M. König Prof. Dr. 《Chembiochem : a European journal of chemical biology》2010,11(9):1253-1265
Corallopyronin A is a myxobacterial compound with potent antibacterial activity. Feeding experiments with labelled precursors resulted in the deduction of all biosynthetic building blocks for corallopyronin A and revealed an unusual feature of this metabolite: its biosynthesis from two chains, one solely PKS‐derived and the other NRPS/PKS‐derived. The starter molecule is believed to be carbonic acid or its monomethyl ester. The putative corallopyronin A biosynthetic gene cluster is a trans‐AT‐type mixed PKS/NRPS gene cluster, containing a β‐branching cassette. Striking features of this gene cluster are a NRPS‐like adenylation domain that is part of a PKS‐type module and is believed to be responsible for glycine incorporation, as well as split modules with individual domains occurring on different genes. It is suggested that CorB is a trans‐acting ketosynthase and it is proposed that it catalyses the Claisen condensation responsible for the interconnection of the two chains. Additionally, the stereochemistry of corallopyronin A was deduced by a combination of a modified Mosher's method and ozonolysis with subsequent chiral GC analyses. 相似文献
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Weissman KJ Hong H Oliynyk M Siskos AP Leadlay PF 《Chembiochem : a European journal of chemical biology》2004,5(1):116-125
Phosphopantetheinyl transferases (PPTases) catalyze the essential post-translational activation of carrier proteins (CPs) from fatty acid synthases (FASs) (primary metabolism), polyketide synthases (PKSs), and non-ribosomal polypeptide synthetases (NRPSs) (secondary metabolism). Bacteria typically harbor one PPTase specific for CPs of primary metabolism ("ACPS-type" PPTases) and at least one capable of modifying carrier proteins involved in secondary metabolism ("Sfp-type" PPTases). In order to identify the PPTase(s) associated with erythromycin biosynthesis in Saccharopolyspora erythraea, we have used the genome sequence of this organism to identify, clone, and express (in Escherichia coli) three candidate PPTases: an ACPS-type PPTase (S. erythraea ACPS) and two Sfp-type PPTases (a discrete enzyme (SePptII) and another that is integrated into a modular PKS subunit (SePptI)). In vitro analysis of these recombinant PPTases, with an acyl carrier protein-thioesterase (ACP-TE) didomain from the erythromycin PKS as substrate, revealed that only SePptII is active in phosphopantetheinyl transfer with this substrate. SePptII was also shown to provide complete modification of ACP-TE and of an entire multienzyme subunit from the erythromycin PKS in E. coli. The efficiency of the SePptII in phosphopantetheinyl transfer in E. coli makes it an attractive alternative to other Sfp-type PPTases for co-expression experiments with PKS proteins. 相似文献
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Advanced Mutasynthesis Studies on the Natural α‐Pyrone Antibiotic Myxopyronin from Myxococcus fulvus 下载免费PDF全文
J. Henning Sahner Hilda Sucipto Dr. Silke C. Wenzel Dr. Matthias Groh Prof. Dr. Rolf W. Hartmann Prof. Dr. Rolf Müller 《Chembiochem : a European journal of chemical biology》2015,16(6):946-953
Myxopyronin is a natural α‐pyrone antibiotic from the soil bacterium Myxococcus fulvus Mx f50. Myxopyronin inhibits bacterial RNA polymerase (RNAP) by binding to a part of the enzyme not targeted by the clinically used rifamycins. This mode of action makes myxopyronins promising molecules for the development of novel broad‐spectrum antibacterials. We describe the derivatization of myxopyronins by an advanced mutasynthesis approach as a first step towards this goal. Site‐directed mutagenesis of the biosynthetic machinery was used to block myxopyronin biosynthesis at different stages. The resulting mutants were fed with diverse precursors that mimic the biosynthetic intermediates to restore production. Mutasynthon incorporation and production of novel myxopyronin derivatives were analyzed by HPLC‐MS/MS. This work sets the stage for accessing numerous myxopyronin derivatives, thus significantly expanding the chemical space of f α‐pyrone antibiotics. 相似文献
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Fumitaka Kudo Dr. Atsushi Motegi Kazutoshi Mizoue Dr. Tadashi Eguchi Prof. Dr. 《Chembiochem : a European journal of chemical biology》2010,11(11):1574-1582
FD‐891 is a 16‐membered cytotoxic antibiotic macrolide that is especially active against human leukemia such as HL‐60 and Jurkat cells. We identified the FD‐891 biosynthetic (gfs) gene cluster from the producer Streptomyces graminofaciens A‐8890 by using typical modular type I polyketide synthase (PKS) genes as probes. The gfs gene cluster contained five typical modular type I PKS genes (gfsA, B, C, D, and E), a cytochrome P450 gene (gfsF), a methyltransferase gene (gfsG), and a regulator gene (gfsR). The gene organization of PKSs agreed well with the basic polyketide skeleton of FD‐891 including the oxidation states and α‐alkyl substituent determined by the substrate specificities of the acyltransferase (AT) domains. To clarify the involvement of the gfs genes in the FD‐891 biosynthesis, the P450 gfsF gene was inactivated; this resulted in the loss of FD‐891 production. Instead, the gfsF gene‐disrupted mutant accumulated a novel FD‐891 analogue 25‐O‐methyl‐FD‐892, which lacked the epoxide and the hydroxyl group of FD‐891. Furthermore, the recombinant GfsF enzyme coexpressed with putidaredoxin and putidaredoxin reductase converted 25‐O‐methyl‐FD‐892 into FD‐891. In the course of the GfsF reaction, 10‐deoxy‐FD‐891 was isolated as an enzymatic reaction intermediate, which was also converted into FD‐891 by GfsF. Therefore, it was clearly found that the cytochrome P450 GfsF catalyzes epoxidation and hydroxylation in a stepwise manner in the FD‐891 biosynthesis. These results clearly confirmed that the identified gfs genes are responsible for the biosynthesis of FD‐891 in S. graminofaciens. 相似文献