Human carbonyl and aldose reductases: New catalytic functions in tetrahydrobiopterin biosynthesis

Park, Young Shik; Heizmann, Claus W.; Wermuth, Bendicht; Levine, Robert A.; Steinerstauch, Petra; Guzman, Jaime; Blau, Nenad

doi:10.1016/0006-291x(91)91628-p

Cited by 75 publications

(57 citation statements)

References 18 publications

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“…In addition to SPR, two other genes are essential and sufficient for BH 4 biosynthesis: GTP cyclohydrolase I (GCH1) and 6-pyruvoyltetrahydropterin synthase (PTS) (Thony et al, 2000). Aldose reductase (AKR1B1) and carbonyl reductase (CBR1 and CBR3) have also been shown to participate in different stages of BH 4 synthesis (Iino et al, 2003;Park et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Sepiapterin reductase expression is increased in Parkinson's disease brain tissue

et al. 2007

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The PARK3 locus on chromosome 2p13 has shown linkage to both the development and age of onset of Parkinson's disease (PD). One candidate gene at this locus is sepiapterin reductase (SPR). Sepiapterin reductase catalyzes the final step in the biosynthetic pathway of tetrahydrobiopterin (BH 4 ), an essential cofactor for aromatic amino acid hydrolases including tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. The expression of SPR was assayed using semiquantitative real-time RT-PCR in human post-mortem cerebellar tissue from neuropathologically confirmed PD cases and neurologically normal controls. The expression of other enzymes involved in BH 4 biosynthesis, including aldose reductase (AKR1B1), carbonyl reductase (CBR1 and CBR3), GTP-cyclohydrolase I (GCH1), and 6-pyruvoyltetrahydrobiopterin (PTS), was also examined. Single-nucleotide polymorphisms around the SPR gene that have been previously reported to show association to PD affection and onset age were genotyped in these samples. Expression of SPR showed a significant 4-fold increase in PD cases relative to controls, while the expression of AKR1B1 and PTS was significantly decreased in PD cases. No difference in expression was detected for CBR1, CBR3, and GCH1. Genetic variants did not show a significant effect on SPR expression, however, this is likely due to the low frequency of rare genotypes in the sample. While the association of SPR to PD is not strong enough to support that this is the PARK3 gene, this study further implicates a role for SPR in idiopathic PD.

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Section: Introductionmentioning

confidence: 99%

Sepiapterin reductase expression is increased in Parkinson's disease brain tissue

et al. 2007

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“…The results demonstrated an alternative synthesis of BH4 and DH4 in Dictyostelium in the absence of SR. The alternative synthesis of BH4 in vivo was suggested to be possible by the activities of CR(s) and AR [6,7] and recently identified in human SR deficient patients [8].…”

Section: Pteridine Production By the Mutant Cellsmentioning

confidence: 99%

“…It was well known that SR specifically reduces C1 0 carbonyl group of PPH4 and catalyzes two successive steps of reduction in situ via isomerization. Animal AR also participates in the process by specifically reducing C2 0 carbonyl group of PPH4 [6,7], providing 1 0 -oxo-2 0 -L L-hydroxypropyl-H4-pterin to SR for a final reduction to BH4. Therefore, it was speculated that in Dictyostelium DH4 synthesis might occur in two steps: C2 0 carbonyl reduction of PPH4 by a putative AR-like enzyme, which in contrast to animal AR would catalyze D D-threo-type reduction, followed by reduction of C1 0 carbonyl group by SR.…”

Section: Pteridine Production By the Mutant Cellsmentioning

confidence: 99%

“…The diketo compound is reduced further to BH4 by SR. SR carries out two consecutive reductions of C1 0 carbonyl group via isomerization reaction [2][3][4][5]. BH4 synthesis is also mediated by aldose reductase (AR; 1.1.1.21) in animals [6,7]. AR specifically reduces C2 0 carbonyl group and generates 1 0 -oxo-2 0 -L L-hydroxypropyl-tetrahydropterin (H4-pterin), which is further reduced to BH4 by SR.…”

Section: Introductionmentioning

confidence: 99%

“…AR specifically reduces C2 0 carbonyl group and generates 1 0 -oxo-2 0 -L L-hydroxypropyl-tetrahydropterin (H4-pterin), which is further reduced to BH4 by SR. In the complete absence of SR activity, an alternative synthesis of BH4 was suggested to be possible by carbonyl reductase (CR) and AR [7] and was recently demonstrated in vivo through finding of human patients deficient in SR [8]. BH4 has two chiral carbons in its C6-side chain and therefore can exist as four different isomers.…”

Section: Introductionmentioning

confidence: 99%

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d‐threo‐tetrahydrobiopterin is synthesized via 1′‐oxo‐2′‐d‐hydroxypropyl‐tetrahydropterin inDictyostelium discoideumAx2

et al. 2005

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Mutations in the BH₄-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase

2006

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Tetrahydrobiopterin (BH(4)) deficiencies are a highly heterogeneous group of disorders with several hundred patients, and so far a total of 193 different mutant alleles or molecular lesions identified in the GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SR), carbinolamine-4a-dehydratase (PCD), or dihydropteridine reductase (DHPR) genes. The spectrum of mutations causing a reduction in one of the three biosynthetic (GTPCH, PTPS, and SR) or the two regenerating enzymes (PCD and DHPR) is tabulated and reviewed. Furthermore, current genomic variations or SNPs are also compiled. Mutations in GCH1 are scattered over the entire gene, and only 5 out of 104 mutant alleles, present in a homozygous state, are reported to cause the autosomal recessive form of inheritable hyperphenylalaninemia (HPA) associated with monoamine neurotransmitter deficiency. Almost all other 99 different mutant alleles in GCH1 are observed together with a wild-type allele and cause Dopa-responsive dystonia (DRD, Segawa disease) in a dominant fashion with reduced penetrance. Compound heterozygous or homozygous mutations are spread over the entire genes for PTS with 44 mutant alleles, for PCBD with nine mutant alleles, and for QDPR with 29 mutant alleles. These mutations cause an autosomal recessive inherited form of HPA, mostly accompanied by a deficiency of the neurotransmitters dopamine and serotonin. Lack of sepiapterin reductase activity, an autosomal recessive variant of BH(4) deficiency presenting without HPA, was diagnosed in patients with seven different mutant alleles in the SPR gene in exons 2 or 3 or in intron 2. Details on all mutations presented here are constantly updated in the BIOMDB database (www.bh4.org).

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Human carbonyl and aldose reductases: New catalytic functions in tetrahydrobiopterin biosynthesis

Cited by 75 publications

References 18 publications

Sepiapterin reductase expression is increased in Parkinson's disease brain tissue

Sepiapterin reductase expression is increased in Parkinson's disease brain tissue

d‐threo‐tetrahydrobiopterin is synthesized via 1′‐oxo‐2′‐d‐hydroxypropyl‐tetrahydropterin inDictyostelium discoideumAx2

Mutations in the BH₄-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase

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Human carbonyl and aldose reductases: New catalytic functions in tetrahydrobiopterin biosynthesis

Cited by 75 publications

References 18 publications

Sepiapterin reductase expression is increased in Parkinson's disease brain tissue

Sepiapterin reductase expression is increased in Parkinson's disease brain tissue

d‐threo‐tetrahydrobiopterin is synthesized via 1′‐oxo‐2′‐d‐hydroxypropyl‐tetrahydropterin inDictyostelium discoideumAx2

Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase

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Mutations in the BH₄-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase