Premithramycinone G, an Early Shunt Product of the Mithramycin Biosynthetic Pathway Accumulated upon Inactivation of Oxygenase MtmOII

Abdelfattah, Mohamed S.; Rohr, Juergen

doi:10.1002/anie.200600511

Cited by 26 publications

(16 citation statements)

References 43 publications

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“…DMSP was shown to be degraded by several bacterial types from salt marsh sediments 80,81 . Also, metabolic clades 2 and 7 possess a few antibiotic biosynthesis pathways e.g., Kanamycin biosynthesis in clade 2, and Paromomycin and Mithramycin biosynthesis in clade 7 82 . There are also some interesting reactions involved in detoxification, such as furfural degradation in clade 2 83 , and a reaction related to mercury detoxification pathways in clade 3 84 .…”

Section: Resultsmentioning

confidence: 99%

Comparative genomics study reveals Red Sea Bacillus with characteristics associated with potential microbial cell factories (MCFs)

Othoum

Prigent

Derouiche

et al. 2019

Sci Rep

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Recent advancements in the use of microbial cells for scalable production of industrial enzymes encourage exploring new environments for efficient microbial cell factories (MCFs). Here, through a comparison study, ten newly sequenced Bacillus species, isolated from the Rabigh Harbor Lagoon on the Red Sea shoreline, were evaluated for their potential use as MCFs. Phylogenetic analysis of 40 representative genomes with phylogenetic relevance, including the ten Red Sea species, showed that the Red Sea species come from several colonization events and are not the result of a single colonization followed by speciation. Moreover, clustering reactions in reconstruct metabolic networks of these Bacillus species revealed that three metabolic clades do not fit the phylogenetic tree, a sign of convergent evolution of the metabolism of these species in response to special environmental adaptation. We further showed Red Sea strains Bacillus paralicheniformis (Bac48) and B. halosaccharovorans (Bac94) had twice as much secreted proteins than the model strain B. subtilis 168. Also, Bac94 was enriched with genes associated with the Tat and Sec protein secretion system and Bac48 has a hybrid PKS/NRPS cluster that is part of a horizontally transferred genomic region. These properties collectively hint towards the potential use of Red Sea Bacillus as efficient protein secreting microbial hosts, and that this characteristic of these strains may be a consequence of the unique ecological features of the isolation environment.

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Section: Resultsmentioning

confidence: 99%

Comparative genomics study reveals Red Sea Bacillus with characteristics associated with potential microbial cell factories (MCFs)

Othoum

Prigent

Derouiche

et al. 2019

Sci Rep

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“…Instead, an epoxidation of the double bond, followed by hydrolysis, would install two hydroxyl groups to give two tertiary alcohols. Indeed, other characterized homologs to ClaX1 are MtmOII [22] (30% identity) and TcmG [23] (26% identity). While the precise mechanisms of these latter enzymes are still under investigation, it is thought that both act as flavin-dependent epoxidases.…”

Section: Resultsmentioning

confidence: 99%

Biosynthetic Gene Cluster for the Cladoniamides, Bis-Indoles with a Rearranged Scaffold

Ryan

2011

PLoS ONE

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The cladoniamides are bis-indole alkaloids isolated from Streptomyces uncialis, a lichen-associated actinomycete strain. The cladoniamides have an unusual, indenotryptoline structure rarely observed among bis-indole alkaloids. I report here the isolation, sequencing, and annotation of the cladoniamide biosynthetic gene cluster and compare it to the recently published gene cluster for BE-54017, a closely related indenotryptoline natural product. The cladoniamide gene cluster differs from the BE-54017 gene cluster in gene organization and in the absence of one N-methyltransferase gene but otherwise contains close homologs to all genes in the BE-54017 cluster. Both gene clusters encode enzymes needed for the construction of an indolocarbazole core, as well as flavin-dependent enzymes putatively involved in generating the indenotryptoline scaffold from an indolocarbazole. These two bis-indolic gene clusters exemplify the diversity of biosynthetic routes that begin from the oxidative dimerization of two molecules of l-tryptophan, highlight enzymes for further study, and provide new opportunities for combinatorial engineering.

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“…The pathway for MTM (l " Fig. 1 B) starts by the condensation of ten malonyl-CoA units by the type II polyketide synthase MtmPKS to render a 20-carbon chain that undergoes regioselective cyclizations by aromatase MtmQ and cyclases MtmX and MtmY, oxygenation by MtmOII, and reductions to form the first isolable intermediate 2 [10][11][12][13]. Then, 2 is converted into 3 by O-methylase MtmMI [14], and in turn is sequentially glycosylated by glycosyltransferases MtmGIV, MtmGIII, and MtmGIV to render 6, which contains a trisaccharide of D-olivose-D-oliose-D-mycarose incorporated at position C12a-O [15,16].…”

Section: Mithramycin Gene Cluster and Biosynthesis Pathway In Streptomentioning

confidence: 99%

Expanding the Chemical Diversity of the Antitumoral Compound Mithramycin by Combinatorial Biosynthesis and Biocatalysis: The Quest for Mithralogs with Improved Therapeutic Window

et al. 2015

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Mithramycin is an antitumor compound of the aureolic acid family produced by Streptomyces argillaceus. It has been used to treat several types of cancer including testicular carcinoma, chronic and acute myeloid leukemia as well as hypercalcemias and Paget's disease. Although the use of mithramycin in humans has been limited because its side effects, in recent years a renewed interest has arisen since new uses and activities have been ascribed to it. Chemically, mithramycin is characterized by a tricyclic aglycone bearing two aliphatic side chains attached at C3 and C7, and disaccharide and trisaccharide units attached at positions 2 and 6, respectively. The mithramycin gene cluster has been characterized. This has allowed for the development of several mithramycin analogs ("mithralogs") by combinatorial biosynthesis and/or biocatalysis. The combinatorial biosynthesis strategies include gene inactivation and/or the use of sugar biosynthesis plasmids for sugar modification. In addition, lipase-based biocatalysis enabled selective modifications of the hydroxyl groups, providing further mithramycin analogs. As a result, new mithramycin analogs with higher antitumor activity and/or less toxicity have been generated. One, demycarosyl-3D-β-D-digitoxosyl-mithramycin SK (EC-8042), is being tested in regulatory preclinical assays, representing an opportunity to open the therapeutic window of this promising molecular scaffold.

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Premithramycinone G, an Early Shunt Product of the Mithramycin Biosynthetic Pathway Accumulated upon Inactivation of Oxygenase MtmOII

Cited by 26 publications

References 43 publications

Comparative genomics study reveals Red Sea Bacillus with characteristics associated with potential microbial cell factories (MCFs)

Comparative genomics study reveals Red Sea Bacillus with characteristics associated with potential microbial cell factories (MCFs)

Biosynthetic Gene Cluster for the Cladoniamides, Bis-Indoles with a Rearranged Scaffold

Expanding the Chemical Diversity of the Antitumoral Compound Mithramycin by Combinatorial Biosynthesis and Biocatalysis: The Quest for Mithralogs with Improved Therapeutic Window

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