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Chapter 16: Hyperphenylalaninemias: Disorders of Tetrahydrobiopterin Metabolism

Nenad Blau; Beat Thöny

BIOSYNTHESIS AND FUNCTION OF TETRAHYDROBIOPTERIN

Tetrahydrobiopterin (BH4) is essential for diverse processes and is ubiquitously present in all tissues of higher organisms. The best investigated functions of BH4 are as a natural cofactor of the following eight enzymes:1 phenylalanine-4-hydroxylase (PAH), tyrosine-3-hydroxylase (TH), tryptophan-5-hydroxylase (TPH1 and TPH2), nitric oxide synthase (nNOS, iNOS, and eNOS), and glyceryl-ether monooxygenase (GEMO).

BH4 biosynthesis proceeds in the de novo pathway in a manganese-, zinc-, and NADPH-dependent reaction from guanosine triphosphate (GTP) via the two intermediates, 7,8-dihydroneopterin triphosphate (NH2TP) and 6-pyruvoyl-5,6,7,8-tetrahydropterin (PTP) (Figure 16-1). The three enzymes GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase (SR) are required and sufficient to carry out the proper stereospecific reaction to 6R,L-erythro-5,6,7,8-tetrahydrobiopterin (BH4). The committing and rate-limiting step is carried out by GTPCH, a homodecamer containing a single zinc ion in each subunit and consisting of a tightly associated dimer of two pentamers.2 The reaction from NH2TP to PTP is catalyzed by PTPS in a manganese- and zinc-dependent reaction without consuming an external reducing agent. Crystallographic analysis revealed that PTPS is composed of a pair of trimers arranged in a head-to-head fashion to form the functional hexamer.3 The final step is the NADPH-dependent reduction of the two side-chain keto groups of PTP by homodimeric SR.

FIGURE 16-1.

Phenylalanine hydroxylating system (purple), tetrahydrobiopterin (BH4) biosynthesis (orange), and salvage pathway (brown). Enzymes involved in the biosynthesis of BH4: GTP cyclohydrolase I (GTPCH) converts GTP to dihydroneopterin triphosphate (NH2TP), 6-pyruvoly-tetrahydropterin synthase (PTPS) converts NH2TP to 6-pyruvoly-tetrahydropterin (PTP), and sepiapterin reductase (SR) catalyzes the final two steps of reduction of PTP to BH4. PTP can be reduced to BH4 either by alternative reductases, carbonyl reductase (CR), aldose reductase (AR), and 3β-hydroxysteroid dehydrogenase 2 (HSDH2) via 1´-keto-tetrahydropterin (1´-O-PH4) and 2´-keto-tetrahydropterin (2´-O-PH4) or through the salvage pathway via sepiapterin (Sep) and 7,8-dihydrobiopterin (7,8-BH2). This reaction involves dihydrofolate reductase (DHFR). The phenylalanine hydroxylating system consists of the apoenzyme phenylalanine hydroxylases (PAH), cofactor BH4, molecular oxygen (O2), and two regenerating enzymes, pterin-4α-carbinolamine dehydratase (PCD) and dihydropteridine reductase (DHPR). 4α-Hydroxy-tetrahydropterin (HO-BH4), product of the PAH reaction, is dehydrated to the quinonoid dihydrobiopterin (q-BH2) by PCD and subsequently reduced back to BH4 by DHPR. Neopterin (Neo), biopterin (Bio), and primapterin (Pri) are metabolites (in gray) found in different body fluids and used as markers for disorders in BH4 metabolism. In turquoise, regulation of the BH4 biosynthesis at the level of the GTPCH–GFRP complex through cytokines (positive), BH4 (negative), and phenylalanine (Phe) (positive).

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Besides the involvement in the de novo biosynthesis of BH4, SR also may participate in the pterin salvage pathway by catalyzing the ...

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