page_title: Nosiheptide
section_title: Biosynthesis
hierarchical_section_title: Nosiheptide / Biosynthesis
caption_attribution_description: English: Nosiheptide intermediate cyclization
context_page_description: Nosiheptide is a thiopeptide antibiotic produced by the bacterium Streptomyces actuosus.
context_section_description: All moieties of the peptidyl backbone of nosiheptide were shown to originate exclusively from proteinogenic amino acids. The structural motifs include dehydroamino acids from the serine or threonine residues undergoing anti elimination of water, thiazoles from cysteine residues with cyclodehydration followed by deoxygenation, and the central hydroxypyridine produced by cyclization between two dehydroalanine acids with incorporation of an adjacent carbonyl group.
  Nosiheptide biosynthesis begins with the translation of a 50 amino acid precursor peptide consisting of a 37 amino acid leader peptide fused to a 13 amino acid structural peptide (SCTTCECCCSCSS), matching the nosiheptide backbone aside from the C-terminal serine residue that is partially cleaved in maturation of the final product. Next, cyclizations occur between 5 of the cysteine residues in the structural sequence and the previous carbonyl on the adjacent amino acid to form thiazole rings after oxidation. Several amino acid residues then undergo elimination of water to produce dehydroamino acids, and the first macrocycle is constructed by cyclization of two of these dehydroamino acid residues. This cyclization includes a Diels-Alder type reaction, dehydration, and elimination of the leader peptide. An indolic acid moiety modified from L-tryptophan is then ligated to the unmodified cysteine residue through a thioester linkage. After methylation and oxidation of the indole, the second macrocycle is formed by reaction of the indole hydroxyl group with the free carboxyl group of the nearby glutamate residue. The now fused bicyclic peptide undergoes several oxidations and partial cleavage of the C-terminal dehydroalanine residue to give the mature nosiheptide.
  The translation and modification of the precursor peptide is undertaken by several enzymes encoded in a localized gene cluster containing 14 structural genes and 1 regulatory gene. One of these genes encodes the peptide, and the others are responsible for the posttranslational modifications.
caption: Nosiheptide intermediate diels-alder type cyclization and aromatization
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