Genetic and Biochemical Characterization of Halogenation and Drug Transportation Genes Encoded in the Albofungin Biosynthetic Gene Cluster

Abstract

Albofungin, a natural product produced from Streptomycetes, exhibits bioactivities against bacteria, fungi, and tumor cells. The biosynthetic logic, regulations, and resistance of albofungin remain yet to be addressed.

Discovery of a Bacterial Hydrazine Transferase That Constructs the N-Aminolactam Pharmacophore in Albofungin Biosynthesis

“…The mutant strain of afn12 (a halogenase) abolished the production of chloroalbofungin (2), confirming that Afn12 converts 1 to 2. 23 Taken together, these in vivo results established the tailoring steps (from 6 to 2) in the biosynthesis of 1 (Figure 3).…”

Carrier Protein Mediated Formation of the Dihydropyridazinone Ring in Actinopyridazinone Biosynthesis

“…These hydrazines serve as key precursors of N−N bonds to form various N−N bond‐containing functional groups with different oxidation degrees and substituents, including α‐keto hydrazone (s56‐p1, 1 ), [15] N ‐hydroxytriazene (triacsin A, 2 ), [16] pyrazole (formycin A, 3 and pyrazomycin, 4 ), [17–20] and dihydropyridazinone (actinopyridazinone, 5 and 6 ) [21] (Figure 1b, c). Recent reports suggested that a hydrazine synthetase is also involved in the biosynthesis of hydrazine‐containing aromatic polyketides [22, 23] . Bioinformatic surveys revealed the high divergence in the genomic contexts surrounding hydrazine synthetase genes, [12, 21] suggesting that the variety of N−N functional groups biosynthesized via the hydrazine intermediates is even greater than currently known.…”

“…Recent reports suggested that a hydrazine synthetase is also involved in the biosynthesis of hydrazine-containing aromatic polyketides. [22,23] Bioinformatic surveys revealed the high divergence in the genomic contexts surrounding hydrazine synthetase genes, [12,21] suggesting that the variety of NÀ N functional groups biosynthesized via the hydrazine intermediates is even greater than currently known. However, the mechanisms to convert the hydrazine intermediates into diverse NÀ N functional groups have remained poorly understood.…”

Bacterial Hydrazine Biosynthetic Pathways Featuring Cupin/Methionyl tRNA Synthetase‐like Enzymes

“…Although not experimentally validated, a putative hydrazine synthetase is also encoded in the biosynthetic gene cluster (BGC) of the NÀ N bond-containing xanthone-type polycyclic polyketide albofungin. [31,32] These examples highlight the diversity of biosynthetic pathways utilizing hydrazine synthetases.…”

“…These include a non‐ribosomal peptide (s56‐p1), amino acid derivatives (azaserine and actinopyridazinone), a fatty acid derivative (triacsin), and a C ‐nucleoside (formycin/pyrazomycin). Although not experimentally validated, a putative hydrazine synthetase is also encoded in the biosynthetic gene cluster (BGC) of the N−N bond‐containing xanthone‐type polycyclic polyketide albofungin [31,32] . These examples highlight the diversity of biosynthetic pathways utilizing hydrazine synthetases.…”