Biosynthesis of Chloro-β-Hydroxytyrosine, a Nonproteinogenic Amino Acid of the Peptidic Backbone of Glycopeptide Antibiotics

Puk, Oliver; Bischoff, Daniel; Kittel, Claudia; Pelzer, Stefan; Weist, Stefan; Stegmann, Efthimia; Süssmuth, Roderich D.; Wohlleben, Wolfgang

doi:10.1128/jb.186.18.6093-6100.2004

Cited by 93 publications

(91 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…7, the chlorination event is arbitrarily shown to occur at the end. Previous studies have shown that chlorination takes place sometime during peptide synthesis (32).…”

Section: Vol 77 2011 Map Of Occidiofungin Of B Contaminans Ms14 6195mentioning

confidence: 99%

See 1 more Smart Citation

Genetic and Biochemical Map for the Biosynthesis of Occidiofungin, an Antifungal Produced by Burkholderia contaminans Strain MS14

Smith

Liu

et al. 2011

Appl Environ Microbiol

View full text Add to dashboard Cite

A striking feature of Burkholderia contaminans strain MS14 is the production of a glycolipopeptide named occidiofungin. Occidiofungin has a broad range of antifungal activities against plant and animal pathogens. In this study, a complete covalent structure characterization and identification of the whole genomic DNA region for the occidiofungin gene (ocf) cluster are described. Discovery of the presence of 2,4-diaminobutyric acid and 3-chloro-␤-hydroxytyrosine and elucidation of the structure of a novel C 18 fatty amino acid residue have been achieved. In addition, seven additional putative open reading frames (the genes from ocfI to ocfN [ocfI-N] and ORF16) were identified. Transcription of all the putative genes ocfI-N identified in the region except ORF16 was regulated by both ambR1 and ambR2. Elucidation of the structure and the ocf gene cluster provides insight into the biosynthesis of occidiofungin and promotes future aims at understanding the biosynthetic machinery. This work provides new avenues for optimizing the production and synthesis of structural analogs of occidiofungin.

show abstract

“…7, the chlorination event is arbitrarily shown to occur at the end. Previous studies have shown that chlorination takes place sometime during peptide synthesis (32).…”

Section: Vol 77 2011 Map Of Occidiofungin Of B Contaminans Ms14 6195mentioning

confidence: 99%

“…The biosynthesis of polyketides shares striking architectural and organizational similarities with nonribosomal peptide biosynthesis, and their modules can be integrated to produce the hybrid NRPS-PKS products. Some pharmaceutical antimicrobial agents, such as the precursor of penicillin and erythromycin, are synthesized through these mechanisms (6,7,32,40).…”

mentioning

confidence: 99%

Genetic and Biochemical Map for the Biosynthesis of Occidiofungin, an Antifungal Produced by Burkholderia contaminans Strain MS14

Smith

Liu

et al. 2011

Appl Environ Microbiol

View full text Add to dashboard Cite

show abstract

“…The role of the fourth P450 in the vancomycin gene cluster, OxyD, has been investigated in vivo, where it has been shown to be involved in the biosynthesis of L-␤-R-hydroxytyrosine (L-3-R-hydroxytyrosine), an essential precursor in the biosynthesis of the vancomycin aglycone (19,20). OxyD has been shown to be transcribed along with two other genes, the first a non-ribosomal peptide synthase (BpsD), composed of single adenylation (A) and carrier protein (PCP) domains (21), whereas the second (Bhp) was originally annotated as a perhydrolase (20) but was recently shown to be a thioesterase (22).…”

mentioning

confidence: 99%

Structural Characterization of OxyD, a Cytochrome P450 Involved in β-Hydroxytyrosine Formation in Vancomycin Biosynthesis

Cryle

Meinhart

Schlichting

2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

The cytochrome P450 OxyD from the balhimycin glycopeptide antibiotic biosynthetic operon of Amycolatopsis mediterranei is involved in the biosynthesis of the modified amino acid ␤-R-hydroxytyrosine, an essential precursor for biosynthesis of the vancomycin-type aglycone. OxyD binds the substrate tyrosine not free in solution, but rather covalently linked to the carrier protein (CP) domain of the non-ribosomal peptide synthase BpsD, exhibiting micromolar binding affinity to a tyrosineloaded carrier protein construct. The crystal structure of OxyD was determined to 2.1-Å resolution, revealing a potential binding site for the carrier protein-bound substrate in a different orientation to that seen with the acyl carrier protein-bound P450 BioI Hydroxylated amino acid residues are widely utilized in nature as precursors for complex natural products (see Fig. 1). The oxidative modification of amino acids at the ␤-position is a process that occurs in many different classes of medicinally important biomolecules, including the vancomycin-type antibiotics (reviewed in Refs. 2, 3). These glycopeptide antibiotics have had great clinical success in treating Gram-positive bacterial infections that are resistant to other classes of antibiotics and function through blocking cell wall biosynthesis via complex formation with the cell wall precursor peptidoglycan peptidyl units terminating in -Lys-D-Ala-D-Ala (2, 3). The biosynthesis of the vancomycin peptide requires the incorporation of two amino acid residues derived from ␤-R-hydroxytyrosine. Another group of medicinally important molecules that contain hydroxylated amino acid residues is the aminocoumarincontaining angucycline family of antibiotic compounds, which include coumermycin A, clorobiocin, and simocyclinone and act upon bacterial DNA gyrase. ␤-R-Hydroxytyrosine is an essential precursor in the biosynthesis of these types of antibiotics, where it is needed for the formation of both the A (Fig. 1, blue) and B (Fig. 1, red) rings in the aminocoumarin core. Further examples of the incorporation of hydroxylated amino acids into the biosyntheses of medicinally important compounds can be found in the biosyntheses of the nikkomycin-type antibiotics, zorbamycin and echinomycin ( Fig. 1) (4 -7).Despite the large structural difference in the compounds highlighted above and the difference in the biosyntheses of the compounds overall, the formation of the ␤-hydroxyamino acid precursors follows a conserved route. This involves the oxidation of the amino acid by a member of the cytochrome P450 (P450) 2 superfamily. P450s form a superfamily of heme containing monoxygenases that catalyze a vast array of biologically important transformations (8). The archetypical P450 reaction is the hydroxylation of unactivated C-H bonds, a difficult oxidation made more impressive by the ability of P450s to utilize their oxidative power both regio-and stereoselectively. Many P450s play important roles in natural product biosyntheses, where such selectivity is channeled toward the synthesis of comp...

show abstract

“…However, the natural substrate of BhaA and, therefore, the timing of the two halogenation reactions have remained elusive. Feeding studies with nonchlorinated ␤-OH-Tyr indicated the biosynthesis of completely chlorinated balhimycin by a mutant strain, which is blocked in ␤-OH-Tyr synthesis (97). This fact clearly points to a chlorination time point later than the stage of free ␤-OH-Tyr.…”

Section: Halogenation Of Electron-rich Aromatic Rings and Unactivatedmentioning

confidence: 99%

“…The respective genes encoding halogenases are embedded in many NRPS and PKS biosynthetic gene clusters (33,36,78,93,98). Studies with chlorination-deficient mutants of the balhimycin producer Amycolatopsis mediterranei demonstrated that a single halogenase BhaA is responsible for the chlorination of the two ␤-OH-Tyr residues of the glycopeptide (97). BhaA is a representative of the FADH 2 -dependent halogenases, which mainly carry out halogenation of electronrich aromatic rings (61,146).…”

Section: Halogenation Of Electron-rich Aromatic Rings and Unactivatedmentioning

confidence: 99%

Chemoenzymatic and Template-Directed Synthesis of Bioactive Macrocyclic Peptides

Grünewald

Marahiel

2006

Microbiol Mol Biol Rev

202

134

View full text Add to dashboard Cite

SUMMARY Non-ribosomally synthesized peptides have compelling biological activities ranging from antimicrobial to immunosuppressive and from cytostatic to antitumor. The broad spectrum of applications in modern medicine is reflected in the great structural diversity of these natural products. They contain unique building blocks, such as d-amino acids, fatty acids, sugar moieties, and heterocyclic elements, as well as halogenated, methylated, and formylated residues. In the past decades, significant progress has been made toward the understanding of the biosynthesis of these secondary metabolites by nonribosomal peptide synthetases (NRPSs) and their associated tailoring enzymes. Guided by this knowledge, researchers genetically redesigned the NRPS template to synthesize new peptide products. Moreover, chemoenzymatic strategies were developed to rationally engineer nonribosomal peptides products in order to increase or alter their bioactivities. Specifically, chemical synthesis combined with peptide cyclization mediated by nonribosomal thioesterase domains enabled the synthesis of glycosylated cyclopeptides, inhibitors of integrin receptors, peptide/polyketide hybrids, lipopeptide antibiotics, and streptogramin B antibiotics. In addition to the synthetic potential of these cyclization catalysts, which is the main focus of this review, different enzymes for tailoring of peptide scaffolds as well as the manipulation of carrier proteins with reporter-labeled coenzyme A analogs are discussed.

show abstract

Biosynthesis of Chloro-β-Hydroxytyrosine, a Nonproteinogenic Amino Acid of the Peptidic Backbone of Glycopeptide Antibiotics

Cited by 93 publications

References 33 publications

Genetic and Biochemical Map for the Biosynthesis of Occidiofungin, an Antifungal Produced by Burkholderia contaminans Strain MS14

Genetic and Biochemical Map for the Biosynthesis of Occidiofungin, an Antifungal Produced by Burkholderia contaminans Strain MS14

Structural Characterization of OxyD, a Cytochrome P450 Involved in β-Hydroxytyrosine Formation in Vancomycin Biosynthesis

Chemoenzymatic and Template-Directed Synthesis of Bioactive Macrocyclic Peptides

Contact Info

Product

Resources

About