text: Thiopeptide biosynthesis involves particularly extensive modification of the core peptide scaffold. Indeed, due to the highly complex structures of thiopeptides, it was commonly thought that these natural products were nonribosomal peptides. Recognition of the ribosomal origin of these molecules came in 2009 with the independent discovery of the gene clusters for several thiopeptides.
  The standard nomenclature for thiopeptide biosynthetic proteins follows that of the thiomuracin gene cluster. In addition to the precursor peptide, referred to as the A peptide, thiopeptide biosynthesis requires at least six genes. These include lanthipeptide-like dehydratases, designated the B and C proteins, which install dehydroalanine and dehydrobutyrine moieties by dehydrating Ser/Thr precursor residues. Azole and azoline synthesis is effected by the E protein, the dehydrogenase, and the G protein, the cyclodehydratase. The nitrogen-containing heterocycle is installed by the D protein cyclase via a putative [4+2] cycloaddition of dehydroalanine moieties to form the characteristic macrocycle. The F protein is responsible for binding of the leader peptide.
  Thiopeptide biosynthesis is biochemically similar to that of cyanobactins, lanthipeptides, and linear azol(in)e-containing peptides (LAPs). As with cyanobactins and LAPs, azole and azoline synthesis occurs via the action of an ATP-dependent YcaO-domain cyclodehydratase. In contrast to LAPs, where cyclodehydration occurs via the action of two distinct proteins responsible for leader peptide binding and cyclodehydrative catalysis, these are fused into a single protein (G protein) in cyanobactin and thiopeptide biosynthesis. However, in thiopeptides, an additional protein, designated the Ocin-ThiF-like protein (F protein) is necessary for leader peptide recognition and potentially recruiting other biosynthetic enzymes.