“…429,431 Based on this work, it is currently hypothesized that fosfazinomycin is assembled via a convergent process involving the incorporation of phosphonate and amino acid building blocks (Scheme 39). In the phosphonate side of the pathway, the enzymes FzmBCDG, which consist of an O- methyltranferase, phosphoenolpyruvate (PEP) phosphomutase, phosphonopyruvate (PnPy) decarboxylase, and α-ketoglutarate diooxygenase, respectively, convert PEP ( 188 ) to the intermediate ( S )-2-hydroxy-2-phosphono-acetate ( 189 ).…”
Natural products that contain functional groups with heteroatom-heteroatom linkages (X–X, where X = N, O, S, and P) are a small yet intriguing group of metabolites. The reactivity and diversity of these structural motifs has captured the interest of synthetic and biological chemists alike. Functional groups containing X–X bonds are found in all major classes of natural products and often impart significant biological activity. This review presents our current understanding of the biosynthetic logic and enzymatic chemistry involved in the construction of X–X bond containing functional groups within natural products. Elucidating and characterizing biosynthetic pathways that generate X–X bonds could both provide tools for biocatalysis and synthetic biology, as well as guide efforts to uncover new natural products containing these structural features.
“…429,431 Based on this work, it is currently hypothesized that fosfazinomycin is assembled via a convergent process involving the incorporation of phosphonate and amino acid building blocks (Scheme 39). In the phosphonate side of the pathway, the enzymes FzmBCDG, which consist of an O- methyltranferase, phosphoenolpyruvate (PEP) phosphomutase, phosphonopyruvate (PnPy) decarboxylase, and α-ketoglutarate diooxygenase, respectively, convert PEP ( 188 ) to the intermediate ( S )-2-hydroxy-2-phosphono-acetate ( 189 ).…”
Natural products that contain functional groups with heteroatom-heteroatom linkages (X–X, where X = N, O, S, and P) are a small yet intriguing group of metabolites. The reactivity and diversity of these structural motifs has captured the interest of synthetic and biological chemists alike. Functional groups containing X–X bonds are found in all major classes of natural products and often impart significant biological activity. This review presents our current understanding of the biosynthetic logic and enzymatic chemistry involved in the construction of X–X bond containing functional groups within natural products. Elucidating and characterizing biosynthetic pathways that generate X–X bonds could both provide tools for biocatalysis and synthetic biology, as well as guide efforts to uncover new natural products containing these structural features.
“…The GNAT fold was recently identified in many more tRNA-dependent transferases in Streptomyces species, which utilize specific aa-tRNAs for synthesis of broad-spectrum antibiotics. For instance, the protein VlmA utilizes Ser-tRNA Ser for synthesis of the antibiotic valanimycin 45 ; DhpH and DhpK utilize Gly-tRNA Gly and Leu-tRNA Leu for biosynthesis of tripeptide phosphonate 46 ; the protein PacB utilizes Ala-tRNA Ala in the biosynthetic pathway for pacidamycin 47 ; FzmI uses Val-tRNA Val for synthesis of fosfazinomycin 48 ; Orf11 uses Gly-tRNA Gly for the synthesis of a streptothricin-related antibiotic. 49
10.1080/15476286.2017.1356980-f0003Figure 3.Role of aa-tRNA transferases exhibiting a GNAT fold.…”
Section: The Cytosolic Domain Of Aapgs Exhibits a Gcn5-like Acetyltramentioning
ABSTRACTtRNA-dependent addition of amino acids to lipids on the outer surface of the bacterial membrane results in decreased effectiveness of antimicrobials such as cationic antimicrobial peptides (CAMPs) that target the membrane, and increased virulence of several pathogenic species. After a brief introduction to CAMPs and the various bacterial resistance mechanisms used to counteract these compounds, this review focuses on recent advances in tRNA-dependent pathways for lipid modification in bacteria. Phenotypes associated with amino acid lipid modifications and regulation of their expression will also be discussed.
“…The lack of kinamyin D enrichment upon feeding 15 N-labeled L-cysteine suggests that 3 arises from off-pathway reactions of a shunt product generated in mutants blocked in kinamycin synthesis. Significantly, this finding, along with recent investigations of hydrazide assembly in fosfazinomycin biosynthesis, 18 raises serious doubts about the long-assumed intermediacy of stealthin C in this pathway and will reshape future efforts to decipher the enzymatic chemistry of diazo formation.…”
mentioning
confidence: 99%
“…18 In natural product biosynthesis, aromatic C–N bonds have been generated by cytochrome P450s. 19a,b Aminotransferases are hypothesized to be involved in aromatic C–N bond formation in azamerone 20a and streptonigrin 20b biosynthesis, respectively.…”
The kinamycin family of aromatic polyketide natural products contains an atypical angucycline ring system substituted with a diazo group. The enzymatic chemistry involved in constructing both of these structural features has been largely unexplored. Here we report the in vivo and in vitro production of seongomycin, a shunt product from this pathway, and stealthin C, a proposed biosynthetic precursor to the kinamycins. We show that a single enzyme, the flavin-dependent monooxygenase AlpJ, can generate these metabolites from N-acetyl-L-cysteine and L-cysteine, respectively, and that the synthesis of stealthin C likely proceeds via a non-enzymatic S–N-type Smiles rearrangement. This unexpected route to stealthin C reveals a distinct approach to install aromatic amino groups in metabolites and raises questions about the intermediacy of this species in kinamycin production.
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