The Structure of the Phenylalanine-Hydroxylation Cofactor

Kaufman, Seymour

doi:10.1073/pnas.50.6.1085

Cited by 357 publications

(117 citation statements)

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“…presence of higher amounts of Bip in urine, confirming the regulation of pteridine metabolism by Phe, as had been reported previously (3,4,12,13).…”

Section: Discussionsupporting

confidence: 68%

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Measurement of Neopterin and Biopterin in Urine from Phenylketonuria Heterozygotes and Normal Controls

et al. 1991

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SummaryThe effect of an oral load of phenylalanine (100 mg/kg body weight) on the levels of neopterin and biopterin in urine has been determined in 8 heterozygotes for classical phenylketonuria and 25 supposed normal controls. In basal conditions, neopterin and biopterin levels were significantly different between males and females. A significant increase in urinary biopterin was found two hours after the phenylalanine load, both in heterozygotes and in normal homozygotes. This increase was maintained at least until the fourth hour. Neopterin leve ls did not suffer any change during that period.Comparison of urinary pteridines from normal controls and phenylketonuria carriers showed that there were no significant differences between both groups neither before nor after the phenylalanine load. From these data we concluded that measurement of biopterin and neopterin in urine cannot help in the identification of heterozygotes for phenylketonuria.

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“…presence of higher amounts of Bip in urine, confirming the regulation of pteridine metabolism by Phe, as had been reported previously (3,4,12,13).…”

Section: Discussionsupporting

confidence: 68%

“…Hydroxylation of Phe is related to the metabolism of pteridines by the requirement of tetrahydrobiopterin (H4Bip) as the enzymatic cofactor for Phe hydroxylase (4). A defect in the metabolism of the pteridine cofactor leads to a kind of hyperphenylalaninemia (HPA) called HPA due to H4Bip deficiency (5).…”

Section: Introductionmentioning

confidence: 99%

Measurement of Neopterin and Biopterin in Urine from Phenylketonuria Heterozygotes and Normal Controls

et al. 1991

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“…Key Words: Tyrosine hydroxylase [TH; tyrosine 3-monooxygenase; L-tyrosine, tetrahydr0pterin:oxygen oxidoreductase (3-hydroxylating); EC 1.14.16.21, which catalyzes the conversion of L-DOPA from L-tyrosine (Nagatsu et al, 1964), is a rate-limiting enzyme in the biosynthesis of catecholamines (Levitt et al, 1965). The enzyme requires a reduced pterin (Nagatsu et al, 1964), and (6R)-(~-erythro-1 ,2'-dihydroxypropyl)-2-amino-4-hydroxy-5,6,7,8-tebxhydropteridine (6R-tebxhydrobiopteri~ 6RBPH4) is the natural cofactor (Kaufman, 1963;Brenneman and Kaufman, 1964;Matsuura et al, 1985). TH also requires ferrous iron (Nagatsu et al, 1964;Shiman et al, 1971).…”

mentioning

confidence: 99%

“…The enzyme requires a reduced pterin (Nagatsu et al, 1964), and (6R)-(~-erythro-1 ,2'-dihydroxypropyl)-2-amino-4-hydroxy-5,6,7,8-tebxhydropteridine (6R-tebxhydrobiopteri~ 6RBPH4) is the natural cofactor (Kaufman, 1963;Brenneman and Kaufman, 1964;Matsuura et al, 1985). TH also requires ferrous iron (Nagatsu et al, 1964;Shiman et al, 1971).…”

mentioning

confidence: 99%

Dopamine Inhibition of Human Tyrosine Hydroxylase Type 1 Is Controlled by the Specific Portion in the N‐Terminus of the Enzyme

Nakashima¹,

Mori²,

Suzuki³

et al. 1999

Journal of Neurochemistry

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Tyrosine hydroxylase (TH), which converts L-tyrosine to L-DOPA, is a rate-limiting enzyme in the biosynthesis of catecholamines; its activity is regulated by feedback inhibition by catecholamine products including dopamine. To investigate the specific portion of the N-terminus of TH that determines the efficiency of dopamine inhibition, wild-type and N-terminal 3 5 , 38-, and 44-amino acid-deleted mutants (del-35, del-38, and del-44, respectively) of human TH type l were expressed as a maltose binding protein fusion in Escherichia coli and purified as a tetrameric form by affinity and size-exclusion chromatography. The fused-form wild-type enzyme possessed almost the same specific enzymatic activity as the previously reported recombinant nonfused form. Although maximum velocities of all N-terminus-deleted forms were about one-fourth of the wild-type value, there was no difference in Michaelis constants for L-tyrosine or (6R)-(~-erythro-l',2'-dihydroxypropyl)-2-amino-4-hydroxy-5,6,7,8-tetrahydropteridine (GRBPH,) among the four enzymes. The iron contents incorporated into the three N-terminus-deleted mutants were significantly lower than that of wild type. However, there was no substantial difference in incorporated iron contents among the three mutants. The deletion of up to no less than 38 amino acid residues in the N-terminus made the enzyme more resistant to dopamine inhibition than the wild-type or del-35 TH form. Dopamine bound to the del-38 more than to the del-35 TH form. However, when incubation with dopamine was followed by further inhibition with the cofactor GRBPH, dopamine was expelled more readily from the del-38 than from the del-35 TH form. These observations suggest that the amino acid sequence G l~~~-A r g~~-A r g~~ plays a key role in determining the competition between dopamine and GRBPH, and affects the efficiency of dopamine inhibition of the catalytic activity. Key Words: Tyrosine hydroxylase [TH; tyrosine 3-monooxygenase; L-tyrosine, tetrahydr0pterin:oxygen oxidoreductase (3-hydroxylating); EC 1.14.16.21, which catalyzes the conversion of L-DOPA from L-tyrosine (Nagatsu et al., 1964), is a rate-limiting enzyme in the biosynthesis of catecholamines (Levitt et al., 1965). The enzyme requires a reduced pterin (Nagatsu et al., 1964), and (6R)-(~-erythro-1 ,2'-dihydroxypropyl)-2-amino-4-hydroxy-5,6,7,8-tebxhydropteridine (6R-tebxhydrobiopteri~ 6RBPH4) is the natural cofactor (Kaufman, 1963;Brenneman and Kaufman, 1964;Matsuura et al., 1985). TH also requires ferrous iron (Nagatsu et al., 1964;Shiman et al., 1971). TH consists of a catalytic domain (C-domain) and a regulatory domain (R-domain) (Abate and Joh, 1991). The C-domain is located at the C-terminal two-thirds of the molecule and binds the substrates (L-tyrosine and molecular oxygen) and the cofactor (6RBPH,). In contrast, the R-domain has been assigned to the N-terminal end (Hoeldtke and Kaufman, 1977;Abate et al., 1988;Abate and Joh, 1991) and has an important role in substrate specificity and in control of the catalytic activ...

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“…This review will focus on the methods and advances for monitoring pterins in CSF. Current analytical methods are mostly based on earlier BH4 oxidation investigations [10][11][12][13]. They have in common at least one chromatographic separation step.…”

Section: Introductionmentioning

confidence: 99%

Pterin determination in cerebrospinal fluid: state of the art

Guibal

Maître

et al. 2017

Pteridines

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AbstractThe analysis of pterins in the cerebrospinal fluid (CSF) is mandatory for the etiologic diagnosis of inborn errors of dopamine and serotonin metabolism. The success of the available therapeutic strategies for preventing the ongoing brain dysfunction is tightly dependent of the early diagnosis of these neurotransmitter disorders. Previous methods of pterins determination in the CSF have in common at least one reversed phase HPLC step coupled to electrochemical or fluorescence detection (FD). They differ in the oxidation procedure of the reduced forms of pterins into their oxidized fluorescent counterparts. Most of the methods using the FD include at least one offline chemical oxidation procedure and cannot allow the direct quantification of tetrahydrobiopterin (BH4). A recent method proposed a single step simultaneous quantification of all forms of pterins including BH4 by HPLC coupled to FD after post-column coulometric oxidation. Nowadays, recent advances in mass spectrometry (MS), notably in term of sensitivity, allow the direct unambiguous determination of all forms of pterins in the CSF by LC-MS/MS.

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The Structure of the Phenylalanine-Hydroxylation Cofactor

Cited by 357 publications

References 15 publications

Measurement of Neopterin and Biopterin in Urine from Phenylketonuria Heterozygotes and Normal Controls

Measurement of Neopterin and Biopterin in Urine from Phenylketonuria Heterozygotes and Normal Controls

Dopamine Inhibition of Human Tyrosine Hydroxylase Type 1 Is Controlled by the Specific Portion in the N‐Terminus of the Enzyme

Pterin determination in cerebrospinal fluid: state of the art

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