Simulations of the regulatory ACT domain of human phenylalanine hydroxylase (PAH) unveil its mechanism of phenylalanine binding
نویسندگان
چکیده
منابع مشابه
Structural Features of the Regulatory ACT Domain of Phenylalanine Hydroxylase
Phenylalanine hydroxylase (PAH) catalyzes the conversion of L-Phe to L-Tyr. Defects in PAH activity, caused by mutations in the human gene, result in the autosomal recessively inherited disease hyperphenylalaninemia. PAH activity is regulated by multiple factors, including phosphorylation and ligand binding. In particular, PAH displays positive cooperativity for L-Phe, which is proposed to bind...
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Analytical ultracentrifugation has been used to analyze the oligomeric structure of the isolated regulatory domain of phenylalanine hydroxylase. The protein exhibits a monomer-dimer equilibrium with a dissociation constant of ~46 μM; this value is unaffected by the removal of the 24 N-terminal residues or by phosphorylation of Ser16. In contrast, phenylalanine binding (Kd = 8 μM) stabilizes the...
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The mechanism of phenylalanine regulation of rat liver phenylalanine hydroxylase was studied. We show that phenylalanine "activates" phenylalanine hydroxylase, converting it from an inactive to active form, by binding at a true allosteric regulatory site. One phenylalanine molecule binds per enzyme subunit; it remains at this site during catalytic turnover and, while there, cannot be hydroxylat...
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Mammalian phenylalanine hydroxylase (PAH) has a potential allosteric regulatory binding site for l-phenylalanine (l-Phe), in addition to its catalytic site. This arrangement is supported by a crystal structure of a homodimeric truncated form of the regulatory domain of human PAH (hPAH-RD 1-118/19-118) [Patel D et al. (2016) Sci Rep doi: 10.1038/srep23748]. In this study, a fusion protein of the...
متن کاملMouse phenylalanine hydroxylase. Homology and divergence from human phenylalanine hydroxylase.
The laboratory mouse represents an important model for the study of phenylalanine metabolism and the pathochemistry of phenylketonuria, yet mouse phenylalanine hydroxylase (PAH) has not been extensively studied. We report the cloning and sequencing of a mouse PAH cDNA, the expression of enzymic activity from the mouse PAH cDNA clone and the identification of mouse PAH and human PAH by two-dimen...
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ژورنال
عنوان ژورنال: Journal of Biological Chemistry
سال: 2018
ISSN: 0021-9258
DOI: 10.1074/jbc.ra118.004909