4-Hydroxyphenylglycine (HPG) is a non-proteogenic amino acid found in vancomycin and related glycopeptides. HPG is synthesized from the shikimic acid pathway and requires four enzymes to synthesize:Yim, G., Thaker, M. N., Koteva, K., Wright, G. "Glycopeptide antibiotic biosynthesis." The Journal of Antibiotics, 2014, 67, 31-41. Both L- and D-HPG are used in the vancomycin class of antibiotics. Tyrosine, a similar amino acid, differs by a methylene group (CH2) between the aromatic ring and the alpha carbon.
Biosynthesis
HPG is synthesized from prephenate, an intermediate in the shikimic acid pathway and also a precursor to tyrosine. Prephenate is aromatized by prephenate dehydrogenase (Pdh) using NAD+ as a cofactor to produce 4-hydroxyphenylpyruvate. 4-Hydroxyphenylpyruvate is then oxidized by 4-hydroxymandelate synthase (4HmaS) using oxygen to form 4-hydroxymandelate and hydrogen peroxide. 4HmaS is a non-heme iron-dependent dioxygenase. The reaction mechanism of this unique oxidation was proposed by Choroba et al in 2000Choroba, O. W., Williams, D. H., Spencer, J. B. "Biosynthesis of the Vancomycin Group of Antibiotics: Involvement of an Unusual Dioxygenase in the Pathway to (S)-4-Hydroxyphenylglycine." J. Am. Chem. Soc. 2000, 122, 5389-5390.
4-Hydroxymandelate is subsequently oxidized by hydroxymandelate oxidase (Hmo) to 4-hydroxylbenzoylformate, using FMN as a cofactor.Li, T.-L., Choroba, O. W., Charles, E. H., Sandercock, A. M., Williams, D. H., Spencer, J. B. "Characterisation of a hydroxymandelate oxidase involved in the biosynthesis of two unusual amino acids occurring in the vancomycin group of antibiotics." Chem. Commun., 2001, 1752-1753. Finally, 4-hydroxyphenylglycine transaminase (HpgT) transfers an ammonia moiety from a donor to 4-hydroxylbenzoylformate to form HPG. Several different molecules can serve as the nitrogen donor for the transamination, however, Hubbard et al suspect L-tyrosine to serve as the most efficient donor.Hubbard, B. K., Thomas, M. G., Walsh, C. T. "Biosynthesis of L-p-hydroxyphenylglycine, a non-proteogenic amino acid constituent of peptide antibiotics." Chemistry & Biology, 2000, 7 (12), 931-942. By doing so, the following cycle is constructed:
HPG is also synthesized in Herpetosiphon aurantiacus using enzymes Haur_(1871,1887,1888).Kastner, S., Müller, S., Natesan, L., König, G. M., Guthke, R., Nett, M. "4-Hydroxyphenylglycine biosynthesis in Herpetosiphon aurantiacus: a case of gene duplication and catalytic divergence." Arch. Microbiol. 2012, 194, 557-566.
See also Vancomycin Oritavancin Glycopeptide antibiotics
References