The biosyntheticgene cluster of zorbamycin, a member of the bleomycin family of antitumor antibiotics, from Streptomyces flavoviridis ATCC 21892

Galm, Ute; Wendt-Pienkowski, Evelyn; Wu, Liyan; George, Nicholas P.; Oh, Tae‐Jin; Yi, Fan; Tao, Meifeng; Coughlin, Jane M.; Shen, Ben

doi:10.1039/b814075h

Cited by 52 publications

(80 citation statements)

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“…Trp), 222,223 zorbamycin (Val) 224 and nikkomycin (His). 225,226 Common to all these pathways is an NRPS/P450 dependant process for generating these b-hydroxy amino acids for incorporation into the nal natural product.…”

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confidence: 99%

Unrivalled diversity: the many roles and reactions of bacterial cytochromes P450 in secondary metabolism

et al. 2018

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The cytochromes P450 (P450s) are a superfamily of heme-containing monooxygenases that perform diverse catalytic roles in many species, including bacteria. The P450 superfamily is widely known for the hydroxylation of unactivated C-H bonds, but the diversity of reactions that P450s can perform vastly exceeds this undoubtedly impressive chemical transformation. Within bacteria, P450s play important roles in many biosynthetic and biodegradative processes that span a wide range of secondary metabolite pathways and present diverse chemical transformations. In this review, we aim to provide an overview of the range of chemical transformations that P450 enzymes can catalyse within bacterial secondary metabolism, with the intention to provide an important resource to aid in understanding of the potential roles of P450 enzymes within newly identified bacterial biosynthetic pathways. 1.Introduction to P450s 2.Chemistry of P450 enzymes 3.Bacterial biosynthesis pathways involving P450s 3.1Terpene metabolism 3.1. Battersby (1925Battersby ( -2018 to the molecular understanding of biosynthesis over the course of their careers.

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confidence: 99%

Unrivalled diversity: the many roles and reactions of bacterial cytochromes P450 in secondary metabolism

et al. 2018

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“…Stand-alone A-domains have been identified in other nonlinear NRPS pathways, e.g. myxochelin (36) and yersiniabactin (37), whereas free-standing A-PCP didomains are found in the zorbamycin and syringomycin gene clusters (38,39). According to bioinformatic analysis, all NRPS domains are predicted to be functional (supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, GetA could act as an aminoacyltransferase, shuttling the PCP-bound modified histidine from GetM to GetJ. There are several examples of such PCP-to-PCP shuttling reactions (38,55), and the aminoacyltransferases identified to date have been assigned into two groups (38); one group, comprising SyrC, CmaE, and ZmbVIId, contains a GXCXG motif at the active site, and these enzymes are predicted to act as acyltransferases, with the active-site cysteine shown to be directly involved in aminoacyl transfer (52); the second group includes the acyltransferases BarC (53) and CouN7 (54), with an active site serine in the GXSXG motif, and are predicted to function as ordinary thioesterases. GetA and GetN both contain active site serines, which suggest that they both function as normal thioesterases and not as aminoacyltransferases (supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Insights into an Unusual Nonribosomal Peptide Synthetase Biosynthesis

Binz¹,

Maffioli²,

Sosio³

et al. 2010

Journal of Biological Chemistry

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“…Inspired by these findings, we sought to generate new analogs of the BLM family using combinatorial biosynthesis strategies. During our ongoing research on hybrid peptide-polyketide natural product biosynthesis, we have cloned and sequenced the gene clusters for BLM from S. verticillus ATCC15003 (7), TLM from S. hindustanus E465-94 ATCC31158 (8), and zorbamycin from S. flavoviridis ATCC21892 (9). This enabled us to find the differences in BLM, TLM, and zorbamycin biosynthesis and to formulate hypothesis for generating new BLM analogs by genetic manipulation of the BLM, TLM, and zorbamycin biosynthetic machineries.…”

Section: Discussionmentioning

confidence: 99%

“…Upon final removal of MeOH by concentration in vacuo, the residues were lyophilized to afford the final pure metabolites TLM K-1 (as copper complex, 4.1 mg), TLM K-2 (1.4 mg), TLM K-3 (0.5 mg), and TLM K-5 (0.3 mg), respectively. Final treatment of the TLM K-1 copper complex with 0.5 M EDTA-Na (pH 7.3) solution followed by a HPLC purification step afforded copper-free TLM K-1 (3.2 mg) (8,9).…”

Section: Methodsmentioning

confidence: 99%

Functional Characterization of tlmK Unveiling Unstable Carbinolamide Intermediates in the Tallysomycin Biosynthetic Pathway

Wang

Tao

Wendt-Pienkoski

et al. 2009

Journal of Biological Chemistry

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Tallysomycins (TLMs) belong to the bleomycin family of anticancer antibiotics. TLMs differ from bleomycins primarily by the presence of a 4-amino-4,6-dideoxy-L-talose sugar attached to C-41 as part of a glycosylcarbinolamide. We previously proposed, on the basis of bioinformatics analysis of the tlm biosynthetic gene cluster from Streptoalloteichus hindustanus E465-94 ATCC 31158, that the tlmK gene is responsible for the attachment of this sugar moiety. We now report that inactivation of tlmK in S. hindustanus abolished TLM A and TLM B production, the resultant ⌬tlmK mutant instead accumulated five new metabolites, and introduction of a functional copy of tlmK to the ⌬tlmK mutant restored TLM A and TLM B production. Two major metabolites, TLM K-1 and TLM K-2, together with three minor metabolites, TLM K-3, TLM K-4, and TLM K-5, were isolated from the ⌬tlmK mutant, and their structures were elucidated. These findings provide experimental evidence supporting the previous functional assignment of tlmK to encode a glycosyltransferase and unveil two carbinolamide pseudoaglycones as key intermediates in the TLM biosynthetic pathway. TlmK stabilizes the carbinolamide intermediates by glycosylating their hemiaminal hydroxyl groups, thereby protecting them from hydrolysis during TLM biosynthesis. In the absence of TlmK, the carbinolamide intermediates fragment to produce an amide TLM K-1 and aldehyde intermediates, which undergo further oxidative fragmentation to afford carboxylic acids TLM K-2, TLM K-3, TLM K-4, and TLM K-5. Tallysomycins (TLMs)3 belong to the bleomycin (BLM) family of glycopeptide antitumor antibiotics (1, 2) (Fig. 1). The BLMs are currently used clinically under the trade name Blenoxane in combination with a number of other agents for the treatment of Hodgkin lymphoma, carcinomas of the skin, head, and neck, and testicular cancers. Early development of drug resistance and dose-dependent pulmonary toxicity are major limitations of BLMs in chemotherapy (3, 4). Structural modifications to this family of natural products are necessary for improvement in efficacy and reduction of toxicity. Although numerous BLM analogs have been synthesized (5, 6), total synthesis remains of limited practical value because of the complex scaffold of this entire family of natural products. Recent cloning and characterization of the BLM, TLM, and zorbamycin biosynthetic gene clusters from Streptomyces verticillus ATCC15003 (7), Streptoalloteichus hindustanus E465-94 (ATCC 31158) (8), and Streptomyces flavoviridis ATCC21892 (9) opened the possibility toward the production of novel BLM analogs via genetic metabolic engineering approaches.TLMs are structurally related to BLMs but differ from BLMs in three ways; (i) the presence of two hydroxyl groups within the aminoethylbithiazole moiety, one of which is conjugated to a 4-amino-4,6-dideoxy-L-talose sugar as part of a glycosylcarbinolamide, (ii) the presence of two series of C-terminal amine moieties with (A series) or without (B series) a ␤-lysine moiety in the subterminal pos...

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The biosyntheticgene cluster of zorbamycin, a member of the bleomycin family of antitumor antibiotics, from Streptomyces flavoviridis ATCC 21892

Cited by 52 publications

References 50 publications

Unrivalled diversity: the many roles and reactions of bacterial cytochromes P450 in secondary metabolism

Unrivalled diversity: the many roles and reactions of bacterial cytochromes P450 in secondary metabolism

Insights into an Unusual Nonribosomal Peptide Synthetase Biosynthesis

Functional Characterization of tlmK Unveiling Unstable Carbinolamide Intermediates in the Tallysomycin Biosynthetic Pathway

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