Premium
Hydroxylation and Ring‐Opening Mechanism of an Unusual Flavoprotein Monooxygenase, 2‐Methyl‐3‐hydroxypyridine‐5‐carboxylic Acid Oxygenase: A Theoretical Study
Author(s) -
Tian Boxue,
Tu Yaoquan,
Strid Åke,
Eriksson Leif A.
Publication year - 2010
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200902253
Subject(s) - chemistry , hydroxylation , monooxygenase , ring (chemistry) , stereochemistry , carboxylic acid , oxygenase , flavoprotein , dioxygenase , enzyme , flavin group , organic chemistry , cytochrome p450
Hybrid meta‐GGA density functional theory (the MPWB1K functional) was used to study the hydroxylation and ring‐opening mechanism of 2‐methyl‐3‐hydroxypyridine‐5‐carboxylic acid oxygenase (MHPCO). This enzyme catalyses the conversion of 2‐methyl‐3‐hydroxypyridine‐5‐carboxylic acid (MHPC) to α‐( N ‐acetylaminomethylene)succinic acid (AAMS), which is the essential ring‐opening step in the bacterial degradation of vitamin B 6 . MHPCO belongs to the flavin‐containing aromatic hydroxylases family. However, MHPCO is capable of catalysing a subsequent aromatic ring‐cleavage reaction to give acyclic products rather than hydroxylated aromatic ones. Our calculations show that the re‐aromatisation of the hydroxylated intermediate occurs spontaneously in aqueous solution; this implies that the ring‐opening process occurs inside the enzyme’s active site, in which limited water is available. The instability of the hydroxylated intermediate of MHPCO is the main reason why acyclic products are formed. Previously proposed mechanisms for the ring‐opening step were studied, and were shown to be less likely to occur (ΔΔ G ≠298 >35 kcal mol −1 ). Two new pathways with reasonable barrier heights (ΔΔ G ≠298 <15 kcal mol −1 ) are reported herein, which are in accordance with all experimental information present to date.