A glutamic acid 3‐methyltransferase encoded by an accessory gene locus important for daptomycin biosynthesis in Streptomyces roseosporus

  title={A glutamic acid 3‐methyltransferase encoded by an accessory gene locus important for daptomycin biosynthesis in Streptomyces roseosporus},
  author={Kien trung Nguyen and David A. Kau and Jian-Qiao Gu and P. Dilkes Brian and Stephen K. Wrigley and Richard H. Baltz and Vivian P. W. Miao},
  journal={Molecular Microbiology},
In many peptide antibiotics, modified amino acids are important for biological activity. The amino acid 3‐methyl‐glutamic acid (3mGlu) has been found only in three cyclic lipopeptide antibiotics: daptomycin and the A21978C family produced by Streptomyces roseosporus, calcium‐dependent antibiotic produced by Streptomyces coelicolor and A54145 produced by Streptomyces fradiae. We studied the non‐ribosomal peptide synthetase genes involved in A21978C biosynthesis and the downstream genes, dptG… 

Development of a Genetic System for Combinatorial Biosynthesis of Lipopeptides in Streptomyces fradiae and Heterologous Expression of the A54145 Biosynthesis Gene Cluster

A suite of mutant strains and plasmids was created for combinatorial biosynthesis efforts focused on modifying the A54145 peptide backbone to generate a compound with daptomycin antibacterial activity and activity in Streptococcus pneumoniae pulmonary infections.

Genomics and the ancient origins of the daptomycin biosynthetic gene cluster

  • R. H. Baltz
  • Biology, Chemistry
    The Journal of Antibiotics
  • 2010
Daptomycin is a clinically useful lipopeptide antibiotic produced by Streptomyces roseosporus, and the cyclized tridecapeptide contains three non-proteinogenic -amino acids: ornithine, 3-methyl-glutamic acid (3mGlu) and kynurinine (Kyn).

Non-ribosomal peptide synthetase module fusions to produce derivatives of daptomycin in Streptomyces roseosporus.

This work explored module exchanges at nucleotide sequences encoding interpeptide linkers in dptD, a gene encoding a di-modular NRPS subunit that incorporates 3-methylglutamic acid and kynurenine into daptomycin, and found mutations causing amino acid substitutions, deletions or insertions in the inter-module linker had no negative effects on lipopeptide yields.

Combinatorial biosynthesis of novel antibiotics related to daptomycin

This study established a robust combinatorial biosynthesis platform to produce novel peptide antibiotics in sufficient quantities for antimicrobial screening and drug development.

Identification of novel mureidomycin analogues via rational activation of a cryptic gene cluster in Streptomyces roseosporus NRRL 15998

This study provides a new way to activate cryptic gene cluster for the acquisition of novel antibiotics and will accelerate the exploitation of prodigious natural products in Streptomyces.

In silico aided metabolic engineering of Streptomyces roseosporus for daptomycin yield improvement

The results demonstrated that the metabolic network based on in silico prediction would be accurate, reasonable, and practical for target gene identification and strain improvement in Streptomyces roseosporus.

Improvement of Daptomycin Production in Streptomyces roseosporus through the Acquisition of Pleuromutilin Resistance

Daptomycin, a cyclic lipopeptide antibiotic produced by Streptomyces roseosporus, displays potent activity against a variety of gram-positive pathogens. There is a demand for generating

Function of MbtH homologs in nonribosomal peptide biosynthesis and applications in secondary metabolite discovery

  • R. H. Baltz
  • Biology
    Journal of Industrial Microbiology & Biotechnology
  • 2011
Expression of MbtH-like proteins is important for a number of applications, including optimal production of native and genetically engineered secondary metabolites produced by mechanisms that employ NRPS enzymes and may serve as beacons to identify gifted actinomycetes and possibly other bacteria that encode multiple functional NRPS pathways for discovery of novel secondary metabolites by genome mining.



Daptomycin biosynthesis in Streptomyces roseosporus: cloning and analysis of the gene cluster and revision of peptide stereochemistry.

The unexpected E-domain suggested that daptomycin would have d-Asn, rather than l- asn, as originally assigned, and this was confirmed by comparing stereospecific synthetic peptides and the natural product both chemically and microbiologically.

Identification and Analysis of the Balhimycin Biosynthetic Gene Cluster and Its Use for Manipulating Glycopeptide Biosynthesis in Amycolatopsis mediterranei DSM5908

Structural analysis by high-performance liquid chromatography–mass spectrometry, fragmentation studies, and amino acid analysis demonstrated that these oxygenases are involved in the coupling of the aromatic side chains of the unusual heptapeptide.

The lipopeptide antibiotic A54145 biosynthetic gene cluster from Streptomyces fradiae

A comparison of the structure and the biosynthetic gene cluster of A54145 with those of the related peptides showed many similarities, which may contribute to the design of experiments to address both fundamental and applied questions in lipopeptide biosynthesis, engineering and drug development.

Genetic evidence for a role of thioesterase domains, integrated in or associated with peptide synthetases, in non-ribosomal peptide biosynthesis in Bacillus subtilis

It is demonstrated for the first time that the C-terminal thioesterase domains and the SrfA-TE protein are directly involved in nonribosomal peptide biosynthesis.

Molecular cloning and sequence analysis of the complestatin biosynthetic gene cluster

  • H. ChiuB. Hubbard C. Khosla
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2001
Heterologous expression and biochemical analysis of 4-hydroxyphenylglycine transaminon confirmed its role as an aminotransferase responsible for formation of all three precursors and presents a unique opportunity for the construction of hybrid vancomycin-type antibiotics.

A C-methyltransferase involved in both ubiquinone and menaquinone biosynthesis: isolation and identification of the Escherichia coli ubiE gene

The transformation of a strain harboring the ubiE401 mutation with o251 on an expression plasmid restored both the growth of this strain on succinate and its ability to synthesize both ubiquinone and menaquinone.

A21978C, a complex of new acidic peptide antibiotics: isolation, chemistry, and mass spectral structure elucidation.

The amino acid sequence was determined using a combination of the Edman degradation and gas chromatography mass spectrum (GC-MS) analysis of appropriately derivatized peptides obtained from partial hydrolysis and a structure for A21978C was assigned.

Characterization of the COQ5 Gene from Saccharomyces cerevisiae EVIDENCE FOR A C-METHYLTRANSFERASE IN UBIQUINONE BIOSYNTHESIS*

These studies show that Coq5p is required for the C-methyltransferase step that converts 2-methoxy-6-polyprenyl-1,4-benzoquinone to 2- meth oxygen-5-methyl- 6- polyprenol-1-4- Benzosquinone.