Biosynthesis and Heterologous Production of Argyrins

Pogorevc, Domen; Tang, Ying; Hoffmann, Michael; Zipf, Gregor; Bernauer, Hubert S.; Popoff, Alexander; Steinmetz, Heinrich; Wenzel, Silke C.

doi:10.1021/acssynbio.9b00023

Cited by 33 publications

(59 citation statements)

References 83 publications

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“…However, 4-methoxy-l-Trp is less common in nature, and its biosynthesis has remained obscure. To the best of our knowledge, besides OMSs and ecumicin, only argyrins, macrocyclic peptides produced by marine myxobacterium Cystobacter spp., possess the 4-methoxy-l-Trp moiety [5]. This unusual moiety is essential for the antiproteasomal and antibacterial activities of argyrins [18,19].…”

Section: Identification Of the Oms Biosynthetic Gene Clustermentioning

confidence: 99%

“…To confirm the function of OhmL, the ohmL gene was inactivated by in-frame gene deletion ( Figure S3). Two compounds corresponding to dehydroxy-OMS A (4) and dehydroxy-OMS B (5) were detected in the ohmL deletion mutant strain (∆ohmL strain), with m/z = 1442.90 and m/z = 1456.91, respectively, by UPLC-qTOF-HRMS analysis ( Figure 3B). Compounds 4 and 5 were proposed to be the derivatives of OMS A (1) and OMS B (2), respectively, dehydroxylated at the β-position of the Phe moiety on the basis of the MS/MS fragmentation patterns ( Figure S4A,B).…”

Section: Biosynthesis Of the β-Hydroxy-l-phe Moietymentioning

confidence: 99%

“…Therefore, we could expect that a putative TDO along with an O-MT, respectively encoded by ohmK and ohmJ, may catalyze the desired hydroxylation and methylation. OhmK and OhmJ show high similarity to Arg5 (59%) and Arg4 (72%), respectively, which are involved in the biosynthesis of argyrins [5]. Two genes homologous to ohmK and ohmJ were also found in the gene cluster of ecumicin, which possesses the same 4-methoxy-l-Trp moiety (Figure 2A).To verify the role of OhmK and OhmJ in the formation of the 4-methoxy-l-Trp moiety, ohmK and ohmJ were separately inactivated by in-frame deletion ( Figure S3).…”

Section: Biosynthesis Of the 4-methoxy-l-trp Moietymentioning

confidence: 99%

“…Both OMSs and ecumicin include the same two non-proteinogenic amino acid residues, β-hydroxy-l-phenylalanine (β-hydroxy-l-Phe) and 4-methoxy-l-tryptophan (4-methoxy-l-Trp). Whereas β-hydroxylation of amino acids often occurs in the biosynthesis of several nonribosomal peptides (NRPs), 4-methoxy-l-Trp is rarely found in NRP biosynthesis [4,5].hydroxylated at position 5 of the indole ( Figure S2A). The formation of 5-methoxy-L-Trp has been well characterized: Trp hydroxylase-1 converts L-Trp to 5-hydroxy-L-Trp, which is then methylated to 5-methoxy-L-Trp by hydroxyindole O-methyltransferase [17].…”

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confidence: 99%

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confidence: 99%

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Characterization of the Ohmyungsamycin Biosynthetic Pathway and Generation of Derivatives with Improved Antituberculosis Activity

et al. 2019

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The cyclic depsipeptides ohmyungsamycin (OMS) A (1) and B (2), isolated from the marine-derived Streptomyces sp. SNJ042, contain two non-proteinogenic amino acid residues, β-hydroxy-l-phenylalanine (β-hydroxy-l-Phe) and 4-methoxy-l-tryptophan (4-methoxy-l-Trp). Draft genome sequencing of Streptomyces sp. SNJ042 revealed the OMS biosynthetic gene cluster consisting of a nonribosomal peptide synthetase (NRPS) gene and three genes for amino acid modification. By gene inactivation and analysis of the accumulated products, we found that OhmL, encoding a P450 gene, is an l-Phe β-hydroxylase. Furthermore, OhmK, encoding a Trp 2,3-dioxygenase homolog, and OhmJ, encoding an O-methyltransferase, are suggested to be involved in hydroxylation and O-methylation reactions, respectively, in the biosynthesis of 4-methoxy-l-Trp. In addition, the antiproliferative and antituberculosis activities of the OMS derivatives dehydroxy-OMS A (4) and demethoxy-OMS A (6) obtained from the mutant strains were evaluated in vitro. Interestingly, dehydroxy-OMS A (4) displayed significantly improved antituberculosis activity and decreased cytotoxicity compared to wild-type OMS A.

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Section: Identification Of the Oms Biosynthetic Gene Clustermentioning

confidence: 99%

Section: Biosynthesis Of the β-Hydroxy-l-phe Moietymentioning

confidence: 99%

Section: Biosynthesis Of the 4-methoxy-l-trp Moietymentioning

confidence: 99%

mentioning

confidence: 99%

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Characterization of the Ohmyungsamycin Biosynthetic Pathway and Generation of Derivatives with Improved Antituberculosis Activity

et al. 2019

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Myxococcus xanthus as Host for the Production of Benzoxazoles

et al. 2022

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Benzoxazoles are important structural motifs in pharmaceutical drugs. Here, we present the heterologous production of 3hydroxyanthranilate-derived benzoxazoles in the host bacterium Myxococcus xanthus following the expression of two genes from the nataxazole biosynthetic gene cluster of Streptomyces sp. Tü 6176. The M. xanthus expression strain achieved a benzoxazole titer of 114.6 � 7.4 mg L À 1 upon precursor supplementation, which is superior to other bacterial production systems. Crosstalk between the heterologously expressed benzoxazole pathway and the endogenous myxochelin pathway led to the combinatorial biosynthesis of benzoxazoles featuring a 2,3-dihydroxybenzoic acid (2,3-DHBA) building block. Subsequent in vitro studies confirmed that this crosstalk is not only due to the availability of 2,3-DHBA in M. xanthus, rather, it is promoted by the adenylating enzyme MxcE from the myxochelin pathway, which contributes to the activation of aryl carboxylic acids and delivers them to benzoxazole biosynthesis.

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Natural Products That Contain Higher Homologated Amino Acids

Owens,

Ahmed,

Lang Harman

et al. 2024

ChemBioChem

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This review focuses on discussing natural products (NPs) that contain higher homologs of amino acids (homoAAs) in the structure as well as the proposed and characterized biosynthesis of these non‐proteinogenic amino acids. Homologation of amino acids includes the insertion of a methylene group into its side chain. It is not a very common modification found in NP biosynthesis as approximately 450 homoAA‐containing NPs have been isolated from four bacterial phyla (Cyanobacteria, Actinomycetota, Myxococcota, and Pseudomonadota), two fungal phyla (Ascomycota and Basidiomycota), and one animal phylum (Porifera), except for a few examples. Amino acids that are found to be homologated and incorporated in the NP structures include the following ten amino acids: alanine, arginine, cysteine, isoleucine, glutamic acid, leucine, phenylalanine, proline, serine, and tyrosine, where isoleucine, leucine, phenylalanine, and tyrosine share the comparable enzymatic pathway. Other amino acids have their individual homologation pathway (arginine, proline, and glutamic acid for bacteria), likely utilize the primary metabolic pathway (alanine and glutamic acid for fungi), or have not been reported (cysteine and serine). Despite its possible high potential in the drug discovery field, the biosynthesis of homologated amino acids has a large room to explore for future combinatorial biosynthesis and metabolic engineering purpose.

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Biosynthesis and Heterologous Production of Argyrins

Cited by 33 publications

References 83 publications

Characterization of the Ohmyungsamycin Biosynthetic Pathway and Generation of Derivatives with Improved Antituberculosis Activity

Characterization of the Ohmyungsamycin Biosynthetic Pathway and Generation of Derivatives with Improved Antituberculosis Activity

Myxococcus xanthus as Host for the Production of Benzoxazoles

Natural Products That Contain Higher Homologated Amino Acids

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