4-Hydroxyphenylglycine

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:^[1] 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.

4-Hydroxyphenylglycine

4-Hydroxyphenylglycine (HPG). (R)-D-HPG shown on left; (S)-L-HPG shown on right.
Names
IUPAC name Nortyrosine
Systematic IUPAC name Amino(4-hydroxyphenyl)acetic acid
Other names 3-Amino-2,3,6-trideoxy-3-methyl-L-lyxo-hexopyranose
Identifiers
CAS Number	37784-25-1
3D model (JSmol)	Interactive image
Beilstein Reference	513130
ChEBI	CHEBI:50418 CHEBI:15695 D
ChEMBL	ChEMBL130865
ChemSpider	83189
ECHA InfoCard	100.012.139
EC Number	213-353-2
KEGG	C03493 D
PubChem CID	92143
UNII	7UYG7X0F53
CompTox Dashboard (EPA)	DTXSID90860473
InChI Key: LJCWONGJFPCTTL-UHFFFAOYSA-N
SMILES C1=CC(=CC=C1C(C(=O)O)N)O
Properties
Chemical formula	C8H9NO3
Molar mass	167.164 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Biosynthesis

Biosynthesis of HPG

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 2000^[2]

Proposed mechanism by Choroba et al for the oxidation of 4-hydroxymandelate.

4-Hydroxymandelate is subsequently oxidized by hydroxymandelate oxidase (Hmo) to 4-hydroxylbenzoylformate, using FMN as a cofactor.^[3] 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.^[4] By doing so, the following cycle is constructed:

HPG synthetic cycle

HPG is also synthesized in Herpetosiphon aurantiacus using enzymes Haur_(1871,1887,1888).^[5]

See also

• Vancomycin
• Oritavancin
• Glycopeptide antibiotics

References

1. Yim, G., Thaker, M. N., Koteva, K., Wright, G. "Glycopeptide antibiotic biosynthesis." The Journal of Antibiotics, 2014, 67, 31-41.
2. Choroba, 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.
3. 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.
4. 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.
5. 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.