Structural Insight into the Aromatic Amino Acid Hydroxylases and Their Disease-Related Mutant Forms

Flatmark, Torgeir; Stevens, Raymond C.

doi:10.1021/cr980450y

Cited by 167 publications

(204 citation statements)

References 98 publications

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“…another residue involved in pterin binding (E286A and E286Q), so far not observed in PKU patients, have been made in rat PAH and expressed in E. coli; the corresponding proteins have very low specific activities (0.5 and 0.02% of wild type, respectively), and E286A has a 70-fold increased K m for BH 4 . 23 Other mutations in the active site may affect phenylalanine substrate binding, the overall structure of the active site, or have more indirect effects by affecting protein folding and stability.…”

Section: Ig Jennings Et Almentioning

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%

“…For catalytic activity, the enzyme requires a cofactor tetrahydrobiopterin (BH 4 ), enzyme-bound iron and molecular oxygen. The activity is tightly regulated by a variety of mechanisms, including activation by the substrate phenylalanine, inhibition by the cofactor BH 4 , and additional activation by phosphorylation. Phenylalanine is both an essential amino acid and toxic at pathophysiological levels.…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, defects in PAH result in the disorders hyperpheylalaninaemia (HPA) and phenylketonuria (PKU), characterised by elevated serum concentrations of phenylalanine 5,6 (Online Mendelian Inheritance in Man (OMIM), http:/ /www.ncbi.nlm.nih.gov/omim). Deficiency of PAH enzymatic activity is the most common cause of HPA, with 99% mutant alleles mapping to the PAH gene; the remainder map to the genes coding for other enzymes involved in BH 4 homeostasis. The disorder is transmitted in an autosomal recessive pattern and is the most common inborn error of amino acid metabolism in the Caucasian population, affecting on average one in 10 000 people.…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, structural interpretations of selected mutations in PAH have been reported recently. 4,[12][13][14]22 However, the criteria for selection of mutations analysed in these studies have not been detailed, and the effects have been discussed without the structural knowledge of the entire protein. To gain more general insights into the molecular basis of PAH deficiency, we chose in this study to correlate the metabolic phenotype and expression studies with the structural knowledge for a larger unbiased set of mutations.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Ig Jennings Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Iron Proteins with Mononuclear Active Sites

Emerson¹,

Mehn²,

Que³

2005

Encyclopedia of Inorganic Chemistry

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Metalloenzymes containing a mononuclear nonheme iron center are often involved in dioxygen metabolism. We have divided this superfamily of enzymes into seven subcategories: iron superoxide dismutase and superoxide reductase, lipoxygenase, catechol dioxygenases, α‐keto acid‐dependent enzymes, isopenicillin N synthase, pterin‐dependent hydroxylases, and Rieske dioxygenases. The degree of catalytic versatility and coordination flexibility encompassed by these enzymes is unsurpassed by any other known metalloenzyme superfamily. Herein we discuss the present state of knowledge regarding their active site structures and the critical role the metal center plays in their respective catalytic mechanisms.

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MonoanionicN,N,O-Scorpionate Ligands and their Iron(II) and Zinc(II) Complexes: Models for Mononuclear Active Sites of Non-Heme Iron Oxidases and Zinc Enzymes

Beck

Weibert

Burzlaff

2001

Eur. J. Inorg. Chem.

160

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The chemical behavior of two bis(3,5‐dialkylpyrazol‐1‐yl)acetic acids and their coordination properties towards ZnCl2 and FeCl2 was studied. Reaction of bis(3,5‐dimethylpyrazol‐1‐yl)acetic acid (bdmpza) (1) with ZnCl2 and FeCl2 gave the 2:1 complexes [(bdmpza)2Zn] (4) and [(bdmpza)2Fe] (5). Crystal structures of both complexes were obtained. In contrast, the sterically more hindered ligand bis(3,5‐di‐tert‐butylpyrazol‐1‐yl)acetic acid (bdtbpza) (3) coordinates only once to zinc(II) resulting in the complex [(bdtbpza)ZnCl] (6). This provides a structural model complex for the active sites of zinc enzymes such as thermolysin or carboxypeptidase. The good agreement with these active sites was demonstrated by a crystal structure of 6. To the best of our knowledge, this is the first report of zinc complexes with a monoanionic N,N,O‐tridentate ligand using a carboxylate O‐donor. Substitution of benzylthiolate for the chloride ligand 6 yielded [(bdtbpza)Zn(SCH2Ph)] (8) indicating that the bulky tert‐butyl groups do not prevent access to the zinc atom. Reaction of bdtbpza (3) with FeCl2 led to [(bdtbpza)FeCl] (7), which might serve as a structural model complex for the active sites of mononuclear non‐heme iron oxidases and oxygenases such as IPNS, DAOCS or CAS.

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Structural Insight into the Aromatic Amino Acid Hydroxylases and Their Disease-Related Mutant Forms

Cited by 167 publications

References 98 publications

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

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

Iron Proteins with Mononuclear Active Sites

MonoanionicN,N,O-Scorpionate Ligands and their Iron(II) and Zinc(II) Complexes: Models for Mononuclear Active Sites of Non-Heme Iron Oxidases and Zinc Enzymes

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