Pterin-Dependent Amino Acid Hydroxylases

Tj, Kappock; Jp, Caradonna

doi:10.1021/cr9402034

Cited by 313 publications

(401 citation statements)

References 772 publications

(2,302 reference statements)

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“…A nonspecific role for the cofactor in protecting not only PAH protein integrity, but also the activity of essentially all mutants, by preventing a chemical inactivation has recently been put forward (20). Thus, the binding of BH 4 at saturating concentrations might additionally prevent peroxide formation due to uncoupled reactions [hydrogen peroxide is known to inactivate PAH (37,38)] and protect the right configuration of the active site in PKU mutants, independent of the location of the mutation.…”

Section: Discussionmentioning

confidence: 99%

Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations

Erlandsen

Pey

Gámez

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

152

162

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Phenylketonuria patients harboring a subset of phenylalanine hydroxylase (PAH) mutations have recently shown normalization of blood phenylalanine levels upon oral administration of the PAH cofactor tetrahydrobiopterin [(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4)]. Several hypotheses have been put forward to explain BH 4 responsiveness, but the molecular basis for the corrective effect(s) of BH4 has not been understood. We have investigated the biochemical, kinetic, and structural changes associated with BH4-responsive mutations (F39L, I65T, R68S, H170D, E178G, V190A, R261Q, A300S, L308F, A313T, A373T, V388M, E390G, P407S, and Y414C). The biochemical and kinetic characterization of the 15 mutants studied points toward a multifactorial basis for the BH4 responsiveness; the mutants show residual activity (>30% of WT) and display various kinetic defects, including increased Km (BH4) and reduced cooperativity of substrate binding, but no decoupling of cofactor (BH4) oxidation. For some, BH4 seems to function through stabilization and protection of the enzyme from inactivation and proteolytic degradation. In the crystal structures of a phenylketonuria mutant, A313T, minor changes were seen when compared with the WT PAH structures, consistent with the mild effects the mutant has upon activity of the enzyme both in vitro and in vivo. Truncations made in the A313T mutant PAH form revealed that the N and C termini of the enzyme influence active site binding. Of fundamental importance is the observation that BH4 appears to increase Phe catabolism if at least one of the two heterozygous mutations has any residual activity remaining.

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Section: Discussionmentioning

confidence: 99%

Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations

Erlandsen

Pey

Gámez

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

152

162

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“…The only known missense mutation in the N-terminal autoregulatory sequence known is S16P. Phosphorylation at S16 reduces the concentration of phenylalanine required for activation, [1][2][3] and the S16P mutation would be expected to affect the delicate balance of phenylalanine concentration and PAH activity in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Phenylalanine hydroxylase (PAH) is the enzyme that catalyses the conversion of phenylalanine to tyrosine, a ratelimiting step in phenylalanine catabolism and protein and neurotransmitter biosynthesis (see recent reviews [1][2][3][4] ). For catalytic activity, the enzyme requires a cofactor tetrahydrobiopterin (BH 4 ), enzyme-bound iron and molecular oxygen.…”

Section: Introductionmentioning

confidence: 99%

Structural interpretation of mutations in phenylalanine hydroxylase protein aids in identifying genotype–phenotype correlations in phenylketonuria

Jennings

Cotton²,

Kobe

2000

Eur J Hum Genet

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Phenylalanine hydroxylase (PAH) is the enzyme that converts phenylalanine to tyrosine as a rate-limiting step in phenylalanine catabolism and protein and neurotransmitter biosynthesis. Over 300 mutations have been identified in the gene encoding PAH that result in a deficient enzyme activity and lead to the disorders hyperphenylalaninaemia and phenylketonuria. The determination of the crystal structure of PAH now allows the determination of the structural basis of mutations resulting in PAH deficiency. We present an analysis of the structural basis of 120 mutations with a 'classified' biochemical phenotype and/or available in vitro expression data. We find that the mutations can be grouped into five structural categories, based on the distinct expected structural and functional effects of the mutations in each category. Missense mutations and small amino acid deletions are found in three categories: 'active site mutations', 'dimer interface mutations', and 'domain structure mutations'. Nonsense mutations and splicing mutations form the category of 'proteins with truncations and large deletions'. The final category, 'fusion proteins', is caused by frameshift mutations. We show that the structural information helps formulate some rules that will help predict the likely effects of unclassified and newly discovered mutations: proteins with truncations and large deletions, fusion proteins and active site mutations generally cause severe phenotypes; domain structure mutations and dimer interface mutations spread over a range of phenotypes, but domain structure mutations in the catalytic domain are more likely to be severe than domain structure mutations in the regulatory domain or dimer interface mutations. European Journal of Human Genetics (2000) 8, 683-696.

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“…Studies on TH from several species suggest that Ser40 is the main site involved in direct activation of TH (Sutherland et al 1993;Lew et al 1999;Salvatore et al 2000). This serine residue is phosphorylated in vitro by cAMP-dependent kinase (PKA), protein kinase C (PKC), mitogen-activated protein kinase-activated protein kinase 1 (MAPKAP-K1) and Ca 2+ /calmodulin-dependent protein kinase II (CaM-KII; Kappock and Caradonna 1996). CaM-KII also phosphorylates TH on Ser19 (Campbell et al 1986;Isobe et al 1991).…”

mentioning

confidence: 99%

Regulation of tyrosine hydroxylase by stress‐activated protein kinases

Toska

Kleppe

Armstrong

et al. 2002

Journal of Neurochemistry

110

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Recombinant human tyrosine hydroxylase (hTH1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (MSK1) at Ser40 and by p38 regulated/activated kinase (PRAK) on Ser19. Phosphorylation by MSK1 induced an increase in V max and a decrease in K m for 6-(R)-5,6,7,8-tetrahydrobiopterin (BH 4 ), while these kinetic parameters were unaffected as a result of phosphorylation by PRAK. Phosphorylation of both Ser40 and Ser19 induced a high-affinity binding of 14-3-3 proteins, but only the interaction of 14-3-3 with Ser19 increased the hTH1 activity. The 14-3-3 proteins also inhibited the rate of dephosphorylation of Ser19 and Ser40 by 82 and 36%, respectively. The phosphorylation of hTH1 on Ser19 caused a threefold increase in the rate of phosphorylation of Ser40. These studies provide new insights into the possible roles of stress-activated protein kinases in the regulation of catecholamine biosynthesis.

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Pterin-Dependent Amino Acid Hydroxylases

Cited by 313 publications

References 772 publications

Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations

Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations

Structural interpretation of mutations in phenylalanine hydroxylase protein aids in identifying genotype–phenotype correlations in phenylketonuria

Regulation of tyrosine hydroxylase by stress‐activated protein kinases

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