text: Heptapeptide backbone synthesis The heptapeptide backbone of teicoplanin is assembled by the nonribosomal peptide synthetases (NRPSs) TeiA, TeiB, TeiC and TeiD. Together these comprise seven modules, each containing a number of domains, with each module responsible for the incorporation of a single amino acid. Modules 1, 4, and 5 activate L-4-Hpg as the aminoacyl-AMP, modules 2 and 6 activate L-Tyr, and modules 3 and 7 activate L-3,5-Dpg. The activated amino acids are covalently bound to the NRPS as thioesters by a phosphopantetheine cofactor, which is attached to the peptidyl carrier protein (PCP) domain. The enzyme bound amino acids are then joined by amide bonds by the action of the condensation (C) domain.
  The heptapetide of teicoplanin contains 4 D-amino acids, formed by epimerization of the activated L-amino acids. Modules 2, 4 and 5 each contain an epimerization (E) domain which catalyzes this change. Module 1 does not contain an E domain, and epimerization is proposed to be catalysed by the C domain.  In all, six of the seven total amino acids of the teicoplanin backbone are composed of nonproteinogenic or modified amino acids.  Eleven enzymes are coordinatively induced to produce these six required residues. Teicoplanin contains two chlorinated positions, 2 (3-Cl-Tyr) and 6 (3-Cl-β-Hty). The halogenase Tei8* has been acts to catalyze the halogenation of both tyrosine residues.  Chlorination occurs at the amino acyl-PCP level during the biosynthesis, prior to phenolic oxidative coupling, with the possibility of tyrosine or β-hydroxytyrosine being the substrate of chlorination. Hydroxylation of the tyrosine residue of module 6 also occurs in trans during the assembly of the heptapeptide backbone.