==Biosynthesis==

Vancomycin biosynthesis occurs via different nonribosomal protein synthases (NRPSs). [1]  The enzymes determine the amino acid sequence during its assembly through its 7 modules.  Before Vancomycin is assembled through NRPS, the amino acids are first modified.  L-tyrosine is modified to become the β-hydroxychlorotyrosine (β-hTyr) and 4-hydroxyphenylglycine (HPG) residues.  On the other hand, acetate is used to derive the  3,5 dihydroxyphenylglycine ring (3,5-DPG). [2]

Non-ribosomal peptide synthesis occurs through distinct modules that can load and extend the protein by one amino acid through the amide bond formation at the contact sites of the activating domains.  [4]  Each module typically consists of an adenylation (A) domain, a peptidyl carrier protein (PCP) domain, and a condensation (C) or elongation 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 [7, 8].  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. [3] 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 is used 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 multienzymes (peptide synthase CepA, CepB, and CepC) are responsible for assembling the heptapeptide. (Figure 2). The organization of CepA, CepB, and Cep C closely resembles orther peptide synthases such as those for surfactin  (SrfA1, SrfA2 and SrfA3) and gramicidin (GrsA and GrsB. [4] Each peptide synthase activates codes for various amino acids in order to activate each domain.  CepA codes for modules 1, 2 and 3, CepB codes for modules 4,5,and 6, and CepC codes for module 7 codes.  The three peptide synthases are located at the start of the region of the bacterial genome linked with antibiotic biosynthesis and spans 27kb. [4]

After the linear heptapeptide molecule is synthesized, Vancomycin has to further undergo post-translational modifications, such as oxidative cross-linking and glycosylation, in trans by distinct enzymes, referred to as tailoring enzymes, in order to become biologically active (Figure 3).  To convert the linear heptapeptide, eight enzymes, Open Reading Frames (ORF) 7, 8, 9, 10, 11, 14, 18, 20, and 21 are used. The enzymes ORF 7, 8,9 and 20 are P450 enzymes, ORF 10 and 18 show to nonheme haloperoxidases and ORF 9 and 14 are identified as putative hydroxylation enzymes. [5]  With the help of these enzymes, β-hydroxyl groups are  introduced onto tyrosine residues 2 and 6 and coupling occurs for rings 5 and 7, rings 4 and 6, and rings 4 and 2.  In addition, a haloperoxidase is used to attach the chlorine atoms onto rings 2 and 6 via an oxidative process. [4]

Figure 1:  Modules and Domains of Vancomycin assembly. [Modules consist of an adenylation (A) domain, a peptidyl carrier protein (PCP) domain, a condensation (C) domain, a epimerization (E) domain, and a thioesterase (TE) domain]

Figure 2: Linear heptapeptide which consists of modified aromatic rings

Figure 3:  Modifications that are necessary for Vancomycin to become biologically active. 

==References==

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