We two alone will sing: the two-substrate alpha-keto acid-dependent oxygenases.

Area of Science:

• Biochemistry
• Enzymology
• Structural Biology

Background:

• 4-Hydroxyphenylpyruvate dioxygenase (HPPD) and hydroxymandelate synthase (HMS) are the sole known alpha-keto acid-dependent oxygenases with a vicinal oxygen chelate superfamily fold.
• Conversely, other enzymes in this class exhibit a jellyroll fold, suggesting distinct evolutionary origins.

Purpose of the Study:

• To review recent structural and mechanistic data for HPPD and HMS.
• To contextualize these enzymes within their natural roles and broader enzyme superfamilies.

Main Methods:

• Structural analysis of HPPD and HMS.
• Mechanistic studies of alpha-keto acid-dependent oxygenases.
• Comparative analysis of enzyme superfamilies.

Main Results:

• HPPD and HMS share catalytic mechanisms with other alpha-keto acid-dependent oxygenases, despite differing folds.
• Enzymes utilize alpha-keto acids for reducing equivalents and iron-mediated dioxygen reduction.
• Formation of a high-valence iron-oxo species facilitates substrate hydroxylation.

Conclusions:

• HPPD and HMS represent a unique structural subclass within alpha-keto acid-dependent oxygenases.
• Their conserved catalytic strategies highlight convergent evolution or deep homology.
• Understanding these enzymes provides insights into oxygenase function and evolution.