Post-translational activation of human phenylalanine 4-monooxygenase from an endobiotic to a xenobiotic enzyme by reactive oxygen and reactive nitrogen species.
An investigation into the post-translational activation of cDNA-expressed human phenylalanine 4-monooxygenase and human hepatic cytosolic fraction phenylalanine 4-monooxygenase activity with respect to both endobiotic metabolism and xenobiotic metabolism revealed that the reactive oxygen species (hydrogen peroxide and hydroxyl radical) and reactive nitrogen species (nitric oxide and peroxynitrite) could elicit the post-translational activation of the enzyme with respect to both of these biotransformation reactions. In virtually all instances, the K(m) values were decreased and the V(max) values were increased; the only exceptions observed being with hydrogen peroxide and L-phenylalanine. These effects were shown to occur at activator concentrations known to exist in physiological situations and, hence, suggest that reactive oxygen and reactive nitrogen species may cause, and may be involved with, the post-translational activation of phenylalanine 4-monooxygenase within the human body. This mechanism, in response to free-radical bursts, may enable the enzyme to expand its substrate range and to process certain xenobiotics as and when required.
Pharmaceutical Science Division, King's College London, London, UK.
A
A
Antypa
C
C
Rebello
A
A
Biernacka
K
K
Krajewski
J
J
Cassam
S C
SC
Mitchell
G B
GB
Steventon
D002233:Carbocysteine / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D018076:DNA, Complementary / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000494:pharmacology; D010651:Phenylalanine Hydroxylase / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D026361:Reactive Nitrogen Species / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D015262:Xenobiotics / Q000378:metabolism*
D018076:DNA, Complementary; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D015262:Xenobiotics; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D017665:Hydroxyl Radical; D026422:S-Nitrosoglutathione; D002233:Carbocysteine; D006861:Hydrogen Peroxide; D010651:Phenylalanine Hydroxylase