Unexpected assembly machinery for 4(3H)-quinazolinone scaffold synthesis

• Published in: Nature communications Vol. 13; no. 1; p. 6522
• Main Authors: Chen, Xi-Wei, Rao, Li, Chen, Jia-Li, Zou, Yi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.10.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 140/131; 140/58; 38/22; 38/70; 38/77; 38/88; 38/90; 631/45/173; 639/638/92/349; 639/638/92/60; 639/638/92/607; 639/638/92/611; 82/79; 82/80; 82/83; Alkaloids; Alkaloids - chemistry; Amino acids; Ammonium; Assembly; Biosynthesis; Catalysis; Cleavage; Dioxygenase; Dipeptides; Drugs; Fungi; Gene expression; Humanities and Social Sciences; Ketoglutaric acid; Modules; multidisciplinary; Nitrogen atoms; Peptide synthase; Peptide Synthases - metabolism; Peptides; Peptides - chemistry; Pharmaceuticals; Quinazolinone; Quinazolinones; Scaffolds; Science; Science (multidisciplinary); Synthesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34340-3

4(3 H )-quinazolinone is the core scaffold in more than 200 natural alkaloids and numerous drugs. Many chemosynthetic methodologies have been developed to generate it; however, investigation of its native enzymatic formation mechanism in fungi has been largely limited to fumiquinazolines, where the two nitrogen atoms come from anthranilate (N-1) and the α-NH 2 of amino acids (N-3). Here, via biochemical investigation of the chrysogine pathway, unexpected assembly machinery for 4(3 H )-quinazolinone is unveiled, which involves a fungal two-module nonribosomal peptide synthase ftChyA with an unusual terminal condensation domain catalysing tripeptide formation; reveals that N-3 originates from the inorganic ammonium ions or the amide of l -Gln; demonstrates an unusual α-ketoglutarate-dependent dioxygenase ftChyM catalysis of the C-N bond oxidative cleavage of a tripeptide to form a dipeptide. Our study uncovers a unique release and tailoring mechanism for nonribosomal peptides and an alternative route for the synthesis of 4(3 H )-quinazolinone scaffolds. 4(3 H )-quinazolinone is the core scaffold in more than 200 natural alkaloids and numerous drugs. Here, the authors show an alternative assembly machinery for 4(3 H )-quinazolinone mainly includes a two-module NRPS catalysing tripeptide formation, unusual N-3 original sources and an α-KGD catalysing the C-N bond oxidative cleavage of a tripeptide to form a dipeptide.