Phenylalanine Hydroxylase from Human Kidney

Je, Ayling; Gd, Helfand; Wd, Pirson

doi:10.1159/000458915

Cited by 24 publications

(7 citation statements)

References 6 publications

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“…While glucagon treatment of rats did not cause phosphorylation of kidney PAH, parathyroid hormone did increase the phosphate content . With the use of rat and human sources, no difference in K m values was identified between the liver and kidney forms, leading to an early assertion that they were identical, excepting the lower specific activity and greater lability of the kidney enzyme . A later study using purified, higher activity enzyme showed that the kidney enzyme had several of the characteristics of allosterically activated PAH, including increased hydrophobicity in the absence of activator and a hyperbolic, high BH 4 -dependent activity (which these investigators use to quantitate the extent of l -Phe activation).…”

Section: Molecular Propertiesmentioning

confidence: 99%

Pterin-Dependent Amino Acid Hydroxylases

1996

Chem. Rev.

313

385

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Section: Molecular Propertiesmentioning

confidence: 99%

Pterin-Dependent Amino Acid Hydroxylases

1996

Chem. Rev.

313

385

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“…(H4pterin), and several substituted pyrimidines all cause varying degrees of uncoupling in the PAH system (Storm & Kaufman, 1968; Ayling & Helfand, 1975;Bailey & Aylin, 1978;Kaufman, 1979). Because differences in their aqueous solution conformations may contribute to their markedly different cofactor activities, we chose to study 6-CH3-H4pterin, 7-CH3-H4pterin, and the cis and trans isomers of 6,7-(CH3)2-H4pterin by 'H NMR techniques to determine whether or not such conformational differences do indeed exist.…”

mentioning

confidence: 99%

Tetrahydrobiopterin analogs: the solution conformations of 6-methyltetrahydropterin, 7-methyltetrahydropterin, and cis- and trans-6,7-dimethyltetrahydropterins as determined by proton nuclear magnetic resonance

Williams¹,

Storm²

1985

Biochemistry

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The conformation of tetrahydrobiopterin analogues in aqueous solution at 23 degrees C has been determined by analyzing the 200-MHz 1H NMR spectral parameters of the enzymatically active 6-methyltetrahydropterin, 7-methyltetrahydropterin, and cis- and trans-6,7-dimethyl-5,6,7,8-tetrahydropterins. Each of these cofactors, with the exception of the cis-6,7-dimethyl isomer, exhibited an unusually small trans 6H-7H spin-spin coupling (8.5-9.1 Hz). An empirical equation that accounts for the effects of substituent electronegativity and orientation on vicinal couplings [Haasnoot, C. A. G., deLeeuw, F. A. A. M., & Altona, C. (1980) Tetrahedron 36, 2783-2792] predicted this coupling to be 11.3-11.6 Hz. We attribute the discrepancy between the calculated and experimentally observed values of this coupling to hyperconjugation of the axially oriented C7-H bond with the pi orbital of the vinylogous amide protein of the pterin ring (N8-C8a = C4a-C4 = O) rather than conformational averaging. The trans 6H-7H interproton distance in the 6-methyl analogue is calculated to be 3.0 A from the measured decrease in the spin-lattice relaxation rate of the axially oriented C7 proton after specific deuteration at C6. This is consistent with the single-conformer interpretation. Chemical shift comparisons of the methyl resonances of these analogues, NOE measurements from selectively deuterated analogues, and the differential sensitivities of axially vs. equatorially disposed ring protons to protonation at N5 all indicate that (i) the methyl substituents at both the C6 and C7 positions markedly prefer equatorial-like orientations and (ii) the tetrahydropterin ring is, with the exception of a pronounced pucker at C6, nearly planar.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…The saturation kinetics observed for both tissues and comparable Km values and Ki values for competitors with similar structure such as f-2-thienyl-DL-alanine supported findings obtained under different conditions on the identity of proteins with phenylalanine hydroxylase activity from different organs of man and experimental animals (Berry et al, 1972;McGee etal., 1972;Murthy&Berry, 1974;Ayling et al, 1974Ayling et al, , 1975).…”

Section: Discussionmentioning

confidence: 99%

β-2-Thienyl-dl-alanine as an inhibitor of phenylalanine hydroxylase and phenylalanine intestinal transport

Wapnir

Moak

1979

Biochemical Journal

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The inhibitory properties of beta-2-thienyl-dl-alanine on rat phenylalanine hydroxylase from crude liver and kidney homogenates were assessed in vitro and in vivo, as well as its effects on the intestinal transport of phenylalanine, by using a perfusion procedure in vivo. The apparent K(m) for liver phenylalanine hydroxylase changed from 0.61mm in the absence of the inhibitor to 2.70mm in the presence of 24mm-beta-2-thienyl-dl-alanine, with no significant change in the V(max.). For kidney the corresponding values were 0.50 and 1.60mm respectively. A single dose of beta-2-thienyl-dl-alanine (2mmol/kg) failed to inhibit phenylalanine hydroxylase in either organ. Repeated injections during a 4-day period caused a decline of the enzymic activity to about 40% of controls. Intestinal absorption of phenylalanine when perfused at 0.2-2.0mm concentration was also competitively inhibited by beta-2-thienyl-dl-alanine. Its K(i) value was estimated at 81mm. The limited inhibitory effects of beta-2-thienyl-dl-alanine towards hepatic phenylalanine hydroxylase and phenylalanine intestinal transport, and its rapid metabolism, as suggested by the small elimination of this compound in the urine and its virtual absence from animal tissues, are factors that restrict its potential usefulness as an inducer of phenylketonuria in rats or as an effective blocker of phenylalanine absorption by the gut.

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Phenylalanine Hydroxylase from Human Kidney

Cited by 24 publications

References 6 publications

Pterin-Dependent Amino Acid Hydroxylases

Pterin-Dependent Amino Acid Hydroxylases

Tetrahydrobiopterin analogs: the solution conformations of 6-methyltetrahydropterin, 7-methyltetrahydropterin, and cis- and trans-6,7-dimethyltetrahydropterins as determined by proton nuclear magnetic resonance

β-2-Thienyl-dl-alanine as an inhibitor of phenylalanine hydroxylase and phenylalanine intestinal transport

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