Human liver 6-pyruvoyl tetrahydropterin reductase is biochemically and immunologically indistinguishable from aldose reductase

Steinerstauch, Petra; Wermuth, Bendicht; Leimbacher, Walter; Curtius, Hans−Christoph

doi:10.1016/0006-291x(89)91786-5

Cited by 26 publications

(6 citation statements)

References 19 publications

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“…In addition we obtained polyclonal antiserum against this enzyme, and used it as a tool for the study of the role of PPH 4 reductase in the biosynthesis of BH 4 • A preliminary account of this work has been presented (20). In a most recent communication we have shown, that PPH 4 reductase is biochemically and immunologically indistinguishable from aldose reductase from human brain (25). Similar conclusions were reached by Milstien and Kaufman using rat brain enzymes (26).…”

Section: Introductionsupporting

confidence: 59%

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Purification and Characterization of a Carbonyl Reductase from Human Liver, which is Competent in the Reduction of 6-Pyruvoyl-Tetrahydropterin

Steinerstauch

Sawada²,

Leimbacher

et al. 1989

Pteridines

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SummaryAn enzyme which reduces 6-pyruvoyl-tetrahydropterin has been purified to apparent homogeneity from human liver. It consists of a single polypeptide chain with a molecular weight of 35 kDa, has an isoelectric point of 5.9 ± 0.1 and contains no glycosyl residues. The pure enzyme has a specific activity of 450 mU/mg protein at pH 7.0 in 10 mM potassium phosphate buffer. It converts 6-pyruvoyl-tetrahydropterin to 6-lactoyltetrahydropterin by transfer of the pro 4R-hydrogen of NADPH to form the side chain -OH at position C(2') of the substrate. Km values are 1.8 IlM for 6-pyruvoyl-tetrahydropterin and 5.5 IlM for NADPH. Polyclonal antibodies raised against the purified enzyme recognize 6-pyruvoyl-tetrahydropterin reductase in Western blot and ELISA but do not cross-react with human sepiapterin reductase. The enzyme appears to be identical with aldose reductase.

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Section: Introductionsupporting

confidence: 59%

“…Unless otherwise specified, the enzyme activity was assayed in 0.1 M potassium phosphate buffer, pH 7.0, containing 0. 25 …”

Section: Pph 4 Reductase Activity Assaysmentioning

confidence: 99%

Purification and Characterization of a Carbonyl Reductase from Human Liver, which is Competent in the Reduction of 6-Pyruvoyl-Tetrahydropterin

Steinerstauch

Sawada²,

Leimbacher

et al. 1989

Pteridines

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“…Although SR is sufficient for completion of BH 4 biosynthesis, other enzymes share the same substrates with SR and are able to catalyse the same reactions: AR (aldose reductase; AKR1B1) [13,14] and CR (carbonyl reductase; CBR1) [15] both participate in the di-keto reduction of the carbonyl side chain of 6-pyruvoyltetrahydropterin in vivo (Figure 3). Previously, it was proposed that, in the absence of SR activity, a salvage pathway may alternatively synthesize BH 4 [15]: AR and CR convert 6-pyruvoyltetrahydropterin into 1 -oxo-2 -hydroxypropyl-tetrahydropterin, which is non-enzymatically converted into sepiapterin; CR then reduces sepiapterin to 7,8dihydrobiopterin, which is reduced to BH 4 by DHFR [16] ( Figure 3).…”

Section: Salvage and Alternative Pathwaysmentioning

confidence: 99%

Tetrahydrobiopterin: biochemistry and pathophysiology

Werner

Blau

Thöny

2011

Biochemical Journal

412

393

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BH4 (6R-L-erythro-5,6,7,8-tetrahydrobiopterin) is an essential cofactor of a set of enzymes that are of central metabolic importance, including four aromatic amino acid hydroxylases, alkylglycerol mono-oxygenase and three NOS (NO synthase) isoenzymes. Consequently, BH4 is present in probably every cell or tissue of higher organisms and plays a key role in a number of biological processes and pathological states associated with monoamine neurotransmitter formation, cardiovascular and endothelial dysfunction, the immune response and pain sensitivity. BH4 is formed de novo from GTP via a sequence of three enzymatic steps carried out by GTP cyclohydrolase I, 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. An alternative or salvage pathway involves dihydrofolate reductase and may play an essential role in peripheral tissues. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase, except for NOSs, in which the BH4 cofactor undergoes a one-electron redox cycle without the need for additional regeneration enzymes. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I. BH4 biosynthesis is controlled in mammals by hormones and cytokines. BH4 deficiency due to autosomal recessive mutations in all enzymes, except for sepiapterin reductase, has been described as a cause of hyperphenylalaninaemia. A major contributor to vascular dysfunction associated with hypertension, ischaemic reperfusion injury, diabetes and others, appears to be an effect of oxidized BH4, which leads to an increased formation of oxygen-derived radicals instead of NO by decoupled NOS. Furthermore, several neurological diseases have been suggested to be a consequence of restricted cofactor availability, and oral cofactor replacement therapy to stabilize mutant phenylalanine hydroxylase in the BH4-responsive type of hyperphenylalaninaemia has an advantageous effect on pathological phenylalanine levels in patients.

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“…H2‐NTP is converted to 6‐pyruvoyltetrahydropterin (PPH4) by PTPS and then to BH4 by sepiapterin reductase (SR, EC 1.1.1.153). In addition, aldose reductase (EC 1.1.1.21) catalyzes the reduction of the C2′‐oxo group in PPH4 to yield 6‐lactoyltetrahydropterin (LPH4) [5–7]. LPH4 is reduced further to BH4 by SR or is oxidized non‐enzymatically to sepiapterin.…”

Section: Introductionmentioning

confidence: 99%

Escherichia coli 6‐pyruvoyltetrahydropterin synthase ortholog encoded by ygcM has a new catalytic activity for conversion of sepiapterin to 7,8‐dihydropterin

Woo¹,

Hwang²,

Kim³

et al. 2002

FEBS Letters

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The putative gene (ygcM) of Escherichia coli was veri¢ed in vitro to encode the ortholog of 6-pyruvoyltetrahydropterin synthase (PTPS). Unexpectedly, the enzyme was found to convert sepiapterin to 7,8-dihydropterin without any cofactors. The enzymatic product 7,8-dihydropterin was identi¢ed by HPLC and mass spectrometry analyses, suggesting a novel activity of the enzyme to cleave the C6 side chain of sepiapterin. The optimal activity occurred at pH 6.5^7.0. The reaction rate increased up to 3.2-fold at 60^80 ‡C, re£ecting the thermal stability of the enzyme. The reaction required no metal ion and was activated slightly by low concentrations (1^5 mM) of EDTA. The apparent K m value for sepiapterin was determined as 0.92 mM and the V max value was 151.3 nmol/min/ mg. The new catalytic function of E. coli PTPS does not imply any physiological role, because sepiapterin is not an endogenous substrate of the organism. The same activity, however, was also detected in a PTPS ortholog of Synechocystis sp. PCC 6803 but not signi¢cant in Drosophila and human enzymes, suggesting that the activity may be prevalent in bacterial PTPS orthologs. ß

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Human liver 6-pyruvoyl tetrahydropterin reductase is biochemically and immunologically indistinguishable from aldose reductase

Cited by 26 publications

References 19 publications

Purification and Characterization of a Carbonyl Reductase from Human Liver, which is Competent in the Reduction of 6-Pyruvoyl-Tetrahydropterin

Purification and Characterization of a Carbonyl Reductase from Human Liver, which is Competent in the Reduction of 6-Pyruvoyl-Tetrahydropterin

Tetrahydrobiopterin: biochemistry and pathophysiology

Escherichia coli 6‐pyruvoyltetrahydropterin synthase ortholog encoded by ygcM has a new catalytic activity for conversion of sepiapterin to 7,8‐dihydropterin

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