Measurement of Biopterin and the Use of Inhibitors of Biopterin Biosynthesis
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Tetrahydrobiopterin (BH 4 ) and related pteridines have received much attention since BH 4 was found to be an essential cofactor for nitric oxide synthases (NOS) ( 1 – 3 ). As shown in Fig. 1 , BH 4 is produced from guanosine 5′-triphosphate (GTP) by three enzymes. GTP cyclohydrolase I converts GTP to dihydroneopterin triphosphate, which is then converted to 6-pyruvoyltetrahydropterin by 6-pyruvoyltetrahydropterin synthase. This second unstable intermediate compound is converted to BH 4 through a two-step reduction of its side-chain carbonyl groups by sepiapterin reductase.
Fig. 1. Proposed scheme for BH 4 metabolism. The reactions of tyrosine hydroxylase, tryptophan hydroxylase, and NOS are not shown. The route for the conversion of 6-pyruvoyl-tetrahydropterin to BH 4 is controversial ( 5 , 45 ). Recent best-fit analysis of kinetic data for sepiapterin reductase (EC 1.1.1.153) ( 46 ) suggests that the following route is predominant: 6-pyruvoyl-tetrahydropterin is reduced at the 2′-oxo group to form 6-(1′-oxo-2′-hydroxypropyl)-tetrahydropterin (also called 6-lactoyl-tetrahydropterin) by sepiapterin reductase. Then, 6-(1′-oxo-2′-hydroxypropyl)-tetrahydropterin is isomerized by sepiapterin reductase to 6-(1′-hydroxy-2′-oxopropyl)-tetrahydropterin, which is reduced again at the 2′-oxo group by sepiapterin reductase. The conversion of 6-pyruvoyltetrahydropterin to 6-(1′-oxo-2′-hydroxypropyl)-tetrahydropterin is also catalyzed by aldose reductase (EC 1.1.1.21) ( 47 , 48 ). Regarding the salvage pathway from sepiapterin to BH 4 , see the text.
