4-hydroxymandelate synthase (HMS)

4-hydroxymandelate synthase is an Fe(II)-dependent oxygenase enzyme (EC 1.13.11.46) that catalyzes the conversion of 4-hydroxyphenylpyruvate and molecular oxygen to (S)-4-hydroxymandelate and carbon dioxide[2][3][7]. It is a member of the oxidoreductase family, specifically those acting on single donors with incorporation of two oxygen atoms (dioxygenases), and exhibits significant sequence and structural similarity to 4-hydroxyphenylpyruvate dioxygenase (HPPD)[6][7]. The enzyme is functionally critical as it catalyzes the committed step in the biosynthesis of para-hydroxyphenylglycine, a component in several non-ribosomal peptide antibiotics including glycopeptides such as vancomycin[5][2]. The active site contains a facial triad (His/His/carboxylate motif) for iron coordination. The reaction mechanism involves the formation of an Fe(IV)=O intermediate that performs regioselective hydroxylation at the benzylic position of the substrate[1][6][7]. HMS shows substrate specificity for aromatic α-keto acids and displays high regio- and enantioselectivity[7]. While HMS itself is not a direct therapeutic target in humans, it is of biotechnological interest for chiral syntheses and is an important node in antibiotic biosynthetic pathways, making it relevant in the context of infection resistance and natural product biosynthesis[2][5][7]. The enzyme can bind the drug NTBC (nitisinone), a known HPPD inhibitor, although the physiological relevance of this interaction remains primarily of biochemical interest[5]. No significant disease associations, biomarkers, or safety concerns have been described for HMS itself, but its pathway context in antibiotic production makes it significant in fighting resistant bacterial infections[2][5].

Other names

4-hydroxyphenylpyruvate dioxygenase II(S)-4-hydroxyphenylpyruvate:oxygen oxidoreductase (decarboxylating)hydroxymandelate synthase

Competitive inhibition of substrate binding (for inhibitors like NTBC)[5]