7-substituted pterins in humans with suspected pterin-4a-carbinolamine dehydratase deficiency. Mechanism of formation via non-enzymatic transformation from 6-substituted pterins.
A recently described new form of hyperphenylalaninemia is characterized by the excretion of 7-substituted isomers of biopterin and neopterin and 7-oxo-biopterin in the urine of patients. It has been shown that the 7-substituted isomers of biopterin and neopterin derive from L-tetrahydrobiopterin and D-tetrahydroneopterin and are formed during hydroxylation of phenylalanine to tyrosine with rat liver dehydratase-free phenylalanine hydroxylase. We have now obtained identical results using human phenylalanine hydroxylase. The identity of the pterin formed in vitro and derived from L-tetrahydrobiopterin as 7-(1',2'-dihydroxypropyl)pterin was proven by gas-chromatography mass spectrometry. Tetrahydroneopterin and 6-hydroxymethyltetrahydropterin also are converted to their corresponding 7-substituted isomers and serve as cofactors in the phenylalanine hydroxylase reaction. Dihydroneopterin is converted by dihydrofolate reductase to the tetrahydro form which is biologically active as a cofactor for the aromatic amino acid monooxygenases. The 6-substituted pterin to 7-substituted pterin conversion occurs in the absence of pterin-4a-carbinolamine dehydratase and is shown to be a nonenzymatic process. 7-Tetrahydrobiopterin is both a substrate (cofactor) and a competitive inhibitor with 6-tetrahydrobiopterin (Ki approximately 8 microM) in the phenylalanine hydroxylase reaction. For the first time, the formation of 7-substituted pterins from their 6-substituted isomers has been demonstrated with tyrosine hydroxylase, another important mammalian enzyme which functions in the hydroxylation of phenylalanine and tyrosine.
Department of Pediatrics, University of Zurich, Switzerland.
C
C
Adler
S
S
Ghisla
I
I
Rebrin
J
J
Haavik
C W
CW
Heizmann
N
N
Blau
T
T
Kuster
H C
HC
Curtius
D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004093:Dihydropteridine Reductase / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006836:Hydro-Lyases / Q000172:deficiency*; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D011622:Pterins / Q000032:analysis / Q000652:urine*; D011994:Recombinant Proteins / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D007527:Isoenzymes; D011622:Pterins; D011994:Recombinant Proteins; D014446:Tyrosine 3-Monooxygenase; D013762:Tetrahydrofolate Dehydrogenase; D004093:Dihydropteridine Reductase; D006836:Hydro-Lyases; C076392:pterin-4a-carbinolamine dehydratase