Enzyme kinetic and molecular modelling studies of sulphur-containing substrates of phenylalanine 4-monooxygenase.
Previous investigations into the binding of substrates/cofactors to the PAH active site have only concentrated on Phe, thienylalanine and BH(4). This is the first reported investigation to model aliphatic thioether amino acid substrates to PAH. The clearance of the thioether substrates (4.82-79.09% of Phe) in the rat and human (1.19-37.41% of Phe) showed species differences. The xenobiotic thioether substrates (SMC and SCMC) were predicted to be poor substrates for PAH by the molecular modelling investigation and this has now been confirmed by the in vitro enzyme kinetic data. However, reaction phenotyping investigations have found that PAH was the major enzyme involved in the metabolism of SCMC in vitro and in vivo.
Patel
N G
NG
Pharmaceutical Sciences Division, School of Biomedical and Health Sciences, King's College London, London, UK.
Iliadou
C
C
Boonyapiwat
B
B
Barlow
D J
DJ
Forbes
B
B
Mitchell
S C
SC
Steventon
G B
GB
D000818:Animals; D020134:Catalytic Domain; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D010651:Phenylalanine Hydroxylase / Q000378:metabolism*; D051381:Rats; D013379:Substrate Specificity; D013455:Sulfur / Q000032:analysis / Q000378:metabolism*
D013455:Sulfur; D010651:Phenylalanine Hydroxylase