page_title: Vancomycin
section_title: Biosynthesis
hierarchical_section_title: Vancomycin / Biosynthesis
caption_attribution_description: English: Linear heptapeptide which consists of modified aromatic rings
context_page_description: Vancomycin is an antibiotic used to treat a number of bacterial infections. It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant Staphylococcus aureus. Blood levels may be measured to determine the correct dose. Vancomycin is also recommended by mouth as a treatment for severe Clostridium difficile colitis. When taken by mouth it is very poorly absorbed.
  Common side effects include pain in the area of injection and allergic reactions. Occasionally, hearing loss, low blood pressure, or bone marrow suppression occur. Safety in pregnancy is not clear, but no evidence of harm has been found, and it is likely safe for use when breastfeeding. It is a type of glycopeptide antibiotic and works by blocking the construction of a cell wall.
  Vancomycin was first sold in 1954. It is on the World Health Organization's List of Essential Medicines. The World Health Organization classifies vancomycin as critically important for human medicine. It is available as a generic medication. Vancomycin is made by the soil bacterium Amycolatopsis orientalis.
context_section_description: Vancomycin is made by the soil bacterium Amycolatopsis orientalis.
  Vancomycin biosynthesis occurs primarily via three nonribosomal protein syntheses (NRPSs) VpsA, VpsB, and VpsC. The enzymes determine the amino acid sequence during its assembly through its 7 modules. Before vancomycin is assembled through NRPS, the non-proteinogenic amino acids are first synthesized. L-tyrosine is modified to become the β-hydroxytyrosine (β-HT) and 4-hydroxyphenylglycine (4-Hpg) residues. 3,5 dihydroxyphenylglycine ring (3,5-DPG) is derived from acetate.
  Nonribosomal peptide synthesis occurs through distinct modules that can load and extend the protein by one amino acid per module through the amide bond formation at the contact sites of the activating domains. Each module typically consists of an adenylation (A) domain, a peptidyl carrier protein (PCP) domain, and a condensation (C) domain. In the A domain, the specific amino acid is activated by converting into an aminoacyl adenylate enzyme complex attached to a 4'phosphopantetheine cofactor by thioesterification The complex is then transferred to the PCP domain with the expulsion of AMP. The PCP domain uses the attached 4'-phosphopantethein prosthetic group to load the growing peptide chain and their precursors. The organization of the modules necessary to biosynthesize Vancomycin is shown in Figure 1. In the biosynthesis of Vancomycin, additional modification domains are present, such as the epimerization (E) domain, which isomerizes the amino acid from one stereochemistry to another, and a thioesterase domain (TE) is used as a catalyst for cyclization and releases of the molecule via a thioesterase scission.
  A set of NRPS enzymes (peptide synthase VpsA, VpsB, and VpsC) are responsible for assembling the heptapeptide. (Figure 2). VpsA codes for modules 1, 2, and 3. VpsB codes for modules 4, 5, and 6, and VpsC codes for module 7. The vancomycin aglycone contains 4 D-amino acids, although the NRPSs only contain 3 epimerization domains. The origin of D-Leu at residue 1 is not known. The three peptide syntheses are located at the start of the region of the bacterial genome linked with antibiotic biosynthesis, and span 27 kb.
  β-hydroxytyrosine (β-HT) is synthesized prior to incorporation into the heptapeptide backbone. L-tyrosine is activated and loaded on the NRPS VpsD, hydroxylated by OxyD, and released by the thioesterase Vhp. The timing of the chlorination by halogenase VhaA during biosynthesis is currently undetermined, but is proposed to occur before the complete assembly of the heptapeptide.
  After the linear heptapeptide molecule is synthesized, vancomycin has to undergo further modifications, such as oxidative cross-linking and glycosylation, in trans by distinct enzymes, referred to as tailoring enzymes, to become biologically active (Figure 3). To convert the linear heptapeptide to cross-linked, glycosylated vancomycin, six enzymes, are required. The enzymes OxyA, OxyB, OxyC, and OxyD are cytochrome P450 enzymes. OxyB catalyzes oxidative cross-linking between residues 4 and 6, OxyA between residues 2 and 4, and OxyC between residues 5 and 7. This cross-linking occurs while the heptapeptide is covalently bound to the PCP domain of the 7th NRPS module. These P450s are recruited by the X domain present in the 7th NRPS module, which is unqiue to glycopeptide antibiotic biosynthesis. The cross-linked heptapeptide is then released by the action of the TE domain, and methyltransferase Vmt then N-methylates the terminal leucine residue. GtfE then joins D-glucose to the phenolic oxygen of residue 4, followed by the addition of vancosamine catalyzed by GtfD.
  Some of the glycosyltransferases capable of glycosylating vancomycin and related nonribosomal peptides display notable permissivity and have been employed for generating libraries of differentially glycosylated analogs through a process known as glycorandomization.
caption: Figure 2: Linear heptapeptide, which consists of modified aromatic rings
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