Phenylalanine hydroxylase (PAH, EC 18.104.22.168) is a key enzyme in human amino acid metabolism and is active in the human liver. PAH catalyses the oxidation of Phe to Tyr at an active site formed by the reductive co-factor (6R)-tetrahydrobiopterin (BH4) and by a non-heme iron in ferrous state. Monooxygenase function is achieved by the incorporation of one oxygen atom from molecular oxygen into the amino acid substrate, while the second atom is bound by the co-factor that forms 4a-hydroxypterin. The underlying catalytic mechanism involving changes in iron oxidation and coordination state is shared by all aromatic acid hydroxylases and has been discussed in detail elsewhere .
Dysfunction of PAH leads to the well-studied genetic disease phenylketonuria (PKU), which can be readily detected via phenylketones stemming from the transamination of phenylalanine to phenylpyruvate . Consequently, Phe levels are elevated in PKU patients, leading to neurological disorders . Therefore, a strict diet low in Phe is imposed on PKU patients. The molecular link between elevated Phe levels and neural disorders is not fully clear yet but is believed to involve the amino acid carrier l-type amino acid transporter 1 (LAT1) . Increased Phe concentrations could unbalance the transport of other aromatic amino acids Tyr and Trp, which have a central function as precursors of neurotransmitters. A manifold of mutations has been described in PAH, leading to different forms of PKU. Most mutations lead to PAH misfolding, reduced enzyme stability and impaired molecular motions within a protein [5–7].
Mammalian PAH forms a homotetramer of 50 kDa per subunit. No complete structure of an intact eukaryotic PAH is available to date. Still, large parts can be assembled from different partially overlapping X-ray structures. Each subunit is formed by an N-terminal regulatory domain (residues 1–116) , a catalytic domain (residues 117–410) , and a short C-terminal coiled coil oligomerization domain (residues 411–452) . The highly flexible residues 1–18, including a phosphorylation site at Ser-16, have not been crystallized yet. Nevertheless, molecular modeling studies identified accessible conformations for this region of PAH . An overview of the complex structural assembly of human tetrameric PAH based on a structural model from Jaffe et al.  is shown in Figure 1. The evolutionary aspects of PAH structure and function have recently been reviewed by Flydal and Martinez .
Regulation of PAH activity
The central role of PAH in the committed step of phenylalanine catabolism requires strict regulatory processes. Thus, several molecular mechanisms that regulate enzyme activity at different levels of complexity have evolved.
Activation of PAH by incubation with Phe as well as its inhibition by BH4 has been known for a long time . Phe acts not only as a substrate but also as an activator with positive cooperativity . The binding site of Phe is still controversial. The isolated regulatory domain was shown to bind Phe , although there is evidence that Phe also binds directly to the catalytic domain and exhibits regulatory functions [17, 18].
Binding of BH4 does not lead to major changes in the active site of PAH . Still, its binding mode is altered in the presence of an amino acid substrate . BH4 has a stabilizing effect on the three-dimensional structure of PAH, which can be exploited for the design of small molecule pharmacological chaperones .
Allosteric regulation of PAH
Besides these presumably active site-directed regulatory effects, several more complex allosteric pathways are described in the literature and have recently been reviewed by Fitzpatrick . Allosteric regulation is a complex phenomenon, where remote sites in an enzyme couple with the active sites. Conformational transitions that occur in a protein emphasize the importance of protein dynamics and involve energy basins in the free-energy landscape of the whole system . Biological macromolecules such as phenylalanine hydroxylase are flexible in solution, thus undergoing steady conformational transitions .
A direct link to the allosteric regulation of PAH was shown for PKU-associated PAH mutants. Although maintaining an intact quaternary structure, some mutated enzymes do not exhibit a positive cooperative phenylalanine binding . Thus, the dynamic features in PAH are crucial to rationalize its complex regulation. It is proposed that PAH exists in different states in solution, including a tense (T) and a relaxed (R) state. The tense state exhibits a low binding activity for Phe, whereas the relaxed state represents the high-activity state in the thermodynamic equilibrium. The mechanisms and structures for both states are not clear yet, although it has been shown that the equilibrium of states is also crucial in vivo . Conformational changes between the populated states include the exposure of an additional hydrophobic surface, including Trp-120, and an increase in size upon activation with Phe [27, 28]. Absence of this preactivation with Phe causes a lag phase in Tyr formation due to the high-energy barrier between the two states. Phe binding to the allosteric site was described to be even stronger than active site binding . Phe release from the allosteric site includes major conformational rearrangements and is therefore a slow process . Additionally, an interplay between residues of the catalytic and the regulatory domain has been described .
Binding of BH4 induces a population shift in the opposite direction as incubation with Phe. The tense state becomes energetically more favorable, shifting the conformational equilibrium of PAH towards a lower substrate affinity. The dynamic process underlying this shift has been investigated using in silico molecular dynamics simulations, which highlight the diverse dynamic processes in PAH . A rigidification of PAH in the tense state induced by BH4 binding is in agreement with the co-factor’s chaperone activity, stabilizing the protein’s three-dimensional fold [25, 33].
Besides the classical main regulatory mechanisms via Phe and BH4, phosphorylation of Ser-16 was described to activate PAH synergistic to Phe binding [11, 34, 35]. Several kinases were shown to allow phosphorylation at this site, with cAMP-dependent protein kinase A (PKA) as the most likely physiological player . X-ray structures of phosphorylated PAH do not show the phosphorylation site, nor do they show any drastic changes between phosphorylated and unphosphorylated PAH . Thus, molecular modeling provided the only structural insight into the phosphorylation-dependent PAH regulation in solution. Dynamic conformational changes within PAH that render the active site more easily accessible, in agreement with the activating effect of phosphorylation, have been described . The effects of phosphorylation are, in general, smaller compared to Phe-induced transitions [26, 37]. Recently, major changes in hydrogen/deuterium (H/D) exchange kinetics in particular regions of PAH were demonstrated by mass spectrometry . These regions undergo major changes in flexibility and accessibility upon Phe binding, which remained hidden by static X-ray structures.
Further regulatory mechanisms of PAH activity with physiological relevance are the binding of phospholipids (e.g., lysolecithin) , modification of Cys-237 [40, 41], possibly oxidative stress [42, 43], as well as several mutations in the protein .
A dynamic view of PAH regulation
Recently, a novel paradigm of PAH regulation was proposed. The “morpheein model” holds the changes in oligomeric assembly responsible for altered enzyme activity . Different assemblies of monomers in thermodynamic equilibrium cause differences in the three-dimensional structure of PAH and thus enzymatic turnover. Thus, a high-activity tetramer and a low-activity tetramer of PAH are proposed . The novel morpheein model of PAH is consistent with previously published data on PAH . Additionally, regulation of the quaternary structure level could open interesting new opportunities for drug design .
The morpheein model explains the drastic changes in local dynamics upon Phe incubation, as observed by H/D exchange mass spectrometry in a hinge region between the regulatory and the catalytic domain including Trp-120 . This region is also susceptible to limited proteolysis, highlighting its flexibility in the Phe-bound state . With the adaption of the quaternary structure, PAH is mobilized and is, overall, more accessible and flexible. A flexible region near the active site, the Tyr138-loop, is drastically mobilized by Phe incubation and, to a minor extent, by the phosphorylation of Ser-16 [38, 47]. This is in agreement with the activation of the catalytic center, which is otherwise assumed to be inaccessible because of the physical blockage by the autoregulatory N-terminal . Consistently, an N-terminally truncated form of PAH lacking the access restriction to the active site was shown to resemble the activity of the Phe-incubated form . Furthermore, mutations far from the catalytic site of PAH have been shown to influence enzymatic activity. Within the morpheein model, they could shift the conformational equilibrium and thereby affect substrate turnover .
The transition between the different morpheeins is believed to include a decomposition of the tetrameric assembly (in fact, a dimer of dimers), which forms intermediate dimers . Thus, major conformational changes are necessary to switch PAH between the states of low and high activity. Methodologies capable of monitoring the underlying dynamic processes within a protein are necessary for a detailed characterization. Molecular dynamics (MD) simulations of biological systems are an interesting alternative to experimental techniques [51, 52], whose originators – Martin Karplus, Michael Levitt, and Arieh Warshel  – have been honored recently with a Nobel Prize. In silico simulations allow the tracing of molecular motions in biological systems at atomistic levels at the microsecond time scale . With a dedicated computer infrastructure, simulation trajectories extending over milliseconds have been described . Events accessible to large-scale MD simulations include ligand binding , exploration of allosteric communication pathways , characterization of local flexibility patterns , as well as complete folding simulations of smaller proteins [59, 60].
Several MD studies of PAH have already been reported in the literature. These studies focus on co-factor binding and specificity [32, 61–63], phenylalanine binding to the regulatory domain , distinct mutations , as well as on the effect of the phosphorylation of Ser-16 . We have recently presented computational studies aiming to characterize the structural effect of oxidative stress via side-chain oxidation  and ligand binding to a distal site in a monomeric bacterial PAH . All studies agree that PAH activity critically depends on conformational flexibility and report major changes in enzyme structure and dynamics by the involved effectors. The striking conformational plasticity of PAH is evident from MD-generated structural ensembles, highlighting several mobile domains even within the catalytic domain (see Figure 2A).
Small modifications of the structure of PAH can cause major changes in the system’s dynamics. Reanalysis of the trajectories of native and oxidized PAH from an earlier study  indicated unexpected effects. Introduction of an additional disulfide bond to the system does not lead to a rigidification of the system as expected from the elimination of the degrees of freedom but rather to a mobilization and thus to a gain in conformational entropy (see Figure 2B). We quantified the change in conformational entropy by performing a normal mode analysis on the whole trajectories of native and oxidized PAH using the cpptraj program of AmberTools . We included 1000 equal-spaced snapshots of two 100-ns trajectories in our reanalysis after an equilibration phase including 1 ns of unrestrained simulation (see Ref.  for details). We calculated the conformational entropy from a quasiharmonic analysis  of the mass-weighted covariance matrix of all 16 replica exchange molecular dynamics simulations of both native and oxidized PAH. Besides the expected increase in conformational entropy with increasing temperature, we found the oxidized state of PAH to be more flexible than the native state in all 16 simulation pairs at the same temperature. This trend underlines the described dynamic contraction of the binding site upon side-chain oxidation . Therefore, the dynamic effects in PAH are not easy to predict from static structures. MD simulations are an attractive technique to explore flexibility-related phenomena in PAH in silico.
Based on recent structural models of PAH in native tetrameric assembly, MD studies should be an attractive tool to investigate the changes in enzyme dynamics related to tetramerization and activation state. We believe that the inclusion of these aspects into current computational models would provide a novel insight into the molecular mechanisms of PAH regulation. Enzyme regulation involving changes in assembly state has already been established for several enzymatic systems including influenza neuraminidase. Molecular dynamics simulations were found to be helpful in the characterization of the changes in the system’s dynamics after the formation of additional macromolecular interfaces by tetramerization .
Understanding of static structures is insufficient to capture the complex regulatory mechanisms in PAH. Thus, dynamic methods are necessary to allow further insight into the conformational transitions associated with PAH activity and modulation. Conformational dynamics are of crucial importance for a comprehensive picture of biomolecular functions in physiological conditions. Hence, techniques such as MD simulations that allow the tracing of molecular motions at the atomistic level are increasingly important. Once regulatory pathways are sufficiently explored, targeting the respective dynamic hotspots with novel drug candidates could directly lead to the discovery of novel therapeutics for PKU. MD studies can also provide information about the potential modulators of PAH activity that may relate to moderate hyperphenylalaninemia, which often develops in chronic diseases without a PAH-specific genetic background . Thus, protein dynamics could be a key to the structure-based drug design of challenging targets.
Julian E. Fuchs thanks the Austrian Academy of Sciences for a DOC fellowship at the Institute of General, Inorganic and Theoretical Chemistry at the University of Innsbruck. The authors thank Aurora Martinez for fruitful discussions and Roland Huber for support in trajectory reanalysis.
Centerwall WR, Centerwall SA. Phenylketonuria (Folling’s disease). The story of its discovery. J Hist Med 1961;16:292–6.Google Scholar
Bik-Multanowski M, Peitrzyk JJ. LAT1 gene variants – potential factors influencing the clinical course of phenylketonuria. J Inherit Metab Dis 2006;29:684–6.Google Scholar
Pey AL, Stricher F, Serrano L, Martinez A. Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases. Am J Hum Genet 2007;81:1006–24.PubMedCrossrefGoogle Scholar
Gersting SW, Kemter KF, Staudigl M, Messing DD, Danecka MK, Lagler FB, et al. Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability. Am J Hum Genet 2008;83:5–17.Google Scholar
Daubner SC, Hillas PJ, Fitzpatrick PF. Expression and characterization of the catalytic domain of human phenylalanine hydroxylase. Arch Biochem Biophys 1997;348:295–302.Google Scholar
Kobe B, Jennings IG, House CM, Michell BJ, Goodwill KE, Santasiero BD, et al. Structural basis of autoregulation of phenylalanine hydroxylase. Nat Struct Biol 1999;6:442–8.CrossrefPubMedGoogle Scholar
Fusetti F, Erlandsen H, Flatmark T, Stevens RC. Structure of tetrameric human phenylalanine hydroxylase and its implications for phenylketonuria. J Biol Chem 1998;273:16962–7.Google Scholar
Miranda FF, Teigen K, Thorolfsson M, Svebak RM, Knappskog PM, Flatmark T, et al. Phosphorylation and mutations of Ser(16) in human phenylalanine hydroxylase. Kinetic and structural effects. J Biol Chem 2002;277:40937–43.Google Scholar
Jaffe EK, Stith L, Lawrence SH, Andrake M, Dunbrack RL, Jr. A new model for allosteric regulation of phenylalanine hydroxylase: implications for disease and therapeutics. Arch Biochem Biophys 2013;530:73–82.Google Scholar
Nielsen KH. Rat liver phenylalanine hydroxylase. A method for the measurement of activity, with particular reference to the distinctive features of the enzyme and the pteridine cofactor. Eur J Biochem 1969;7:360–9.PubMedCrossrefGoogle Scholar
Shiman R, Gray DW. Substrate activation of phenylalanine hydroxylase. A kinetic characterization. J Biol Chem 1980;255:4793–800.Google Scholar
Gjetting T, Petersen M, Guldberg P, Guttler F. Missense mutations in the N-terminal domain of human phenylalanine hydroxylase interfere with binding of regulatory phenylalanine. Am J Hum Genet 2001;68:1353–60.CrossrefPubMedGoogle Scholar
Martinez A, Haavik J, Flatmark T. Cooperative homotropic interaction of L-noradrenaline with the catalytic site of phenylalanine 4-monooxygenase. Eur J Biochem 1990;193:211–9.Google Scholar
Thorolfsson M, Ibarra-Molero B, Fojan P, Petersen SB, Sanchez-Ruiz JM, Martinez A. L-phenylalanine binding and domain organization in human phenylalanine hydroxylase: a differential scanning calorimetry study. Biochemistry 2002;41:7573–85.CrossrefPubMedGoogle Scholar
Andersen OA, Flatmark T, Hough E. High resolution crystal structure of the catalytic domain of human phenylalanine hydroxylase in its catalytically active Fe(II) form and binary complex with tetrahydrobiopterin. J Mol Biol 2001;314:279–91.Google Scholar
Andersen OA, Stokka AJ, Flatmark T, Hough E. 2.0A resolution structure of the ternary complexes of human phenylalanine hydroxylase catalytic domain with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine or L-norleucine: substrate specificity and molecular motions related to substrate binding. J Mol Biol 2000;333:747–57.Google Scholar
Santos-Sierra S, Kirchmair J, Perna AM, Reiss D, Kemter K, Roschinger W, et al. Novel pharmacological chaperones that correct phenylketonuria in mice. Hum Mol Genet 2012;21:1877–87.CrossrefGoogle Scholar
Fitzpatrick PF. Allosteric regulation of phenylalanine hydroxylase. Arch Biochem Biophys 2012;519:194–201.Google Scholar
Tsai CJ, Nussinov R. A unified view of “how allostery works”. PLoS Comput Biol 2014;20:e1003394.Google Scholar
Frauenfelder H, Sligar SG, Wolynes PG. The energy landscapes and motions of proteins. Science 1991;254(5038):1598–603.Google Scholar
Erlandsen H, Pey AL, Gamez A, Perez B, Desviat LR, Aquado C, et al. Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Proc Natl Acad Sci USA 2004;101:16903–8.Google Scholar
Shiman R, Mortimore GE, Schworer CM, Gray DW. Regulation of phenylalanine hydroxylase activity by phenylalanine in vivo, in vitro, and in perfused rat liver. J Biol Chem 1982;257:11213–6.Google Scholar
Shiman R, Gray DW, Pater A. A simple purification of phenylalanine hydroxylase by substrate-induced hydrophobic chromatography. J Biol Chem 1979;254:11300–6.Google Scholar
Koizumi S, Tanaka F, Kaneda N, Kano K, Nagatsu T. Nanosecond pulse fluorometry of conformational change in phenylalanine hydroxylase associated with activation. Biochemistry 1988;27:640–6.PubMedCrossrefGoogle Scholar
Shiman R, Jones SH, Gray DW. Mechanism of phenylalanine regulation of phenylalanine hydroxylase. J Biol Chem 1990;265:11633–42.Google Scholar
Shiman R, Xia T, Hill MA, Gray DW. Regulation of rat liver phenylalanine hydroxylase: II. Substrate binding and role of activation in the control of enzymatic activity. J Biol Chem 1994;269:24647–56.Google Scholar
Flydal MI, Mohn TC, Pey AL, Stiltberg-Liberles J, Teigen K, Martinez A. Superstoichiometric binding of L-Phe to phenylalanine hydroxylase from Caenorhabditis elegans: evolutionary implications. Amino Acids 2010;39:1463–75.CrossrefPubMedGoogle Scholar
Pey AL, Thorolfsson M, Teigen K, Ugarte M, Martinez A. Thermodynamic characterization of the binding of tetrahydrobiopterins to phenylalanine hydroxylase. J Am Chem Soc 2004;126:13670–8.Google Scholar
Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U. Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab 2011;104 Suppl:S2–9.Google Scholar
Kaufman S. The phenylalanine hydroxylating system. Adv Enzymol Relat Areas Mol Biol 1993;67:77–264.Google Scholar
Abita JP, Milstien S, Chang N, Kaufman S. In vitro activation of rat liver phenylalanine hydroxylase by phosphorylation. J Biol Chem 1976;251:5310–4.Google Scholar
Doskeland AP, Martinez A, Knappskog PM, Flatmark T. Phosphorylation of recombinant human phenylalanine hydroxylase: effect on catalytic activity, substrate activation and protection against non-specific cleavage of the fusion protein by restriction protease. Biochem J 1996;313:409–14.Google Scholar
Li J, Fitzpatrick PF. Regulation of phenylalanine hydroxylase: conformational changes upon phosphorylation detected by H/D exchange and mass spectrometry. Arch Biochem Biophys 2013;535:115–9.Google Scholar
Fisher DB, Kaufman S. The stimulation of rat liver phenylalanine hydroxylase by phospholipids. J Biol Chem 1972;247:2250–2.Google Scholar
Parniak MA, Kaufman S. Rat liver phenylalanine hydroxylase. Activation by sulfhydryl modification. J Biol Chem 1981;256:6876–82.Google Scholar
Gibbs BS, Benkovic SJ. Affinity labeling of the active site and the reactive sulfhydryl associated with activation of rat liver phenylalanine hydroxylase. Biochemistry 1991;30:6795–802.CrossrefPubMedGoogle Scholar
Ploder M, Neurauter G, Spittler A, Schroecksnadel K, Roth E, Fuchs D. Serum phenylalanine in patients post trauma and with sepsis correlate to neopterin concentrations. Amino Acids 2008;35:303–7.CrossrefPubMedGoogle Scholar
Zangerle R, Kurz K, Neurauter G, Kitchen M, Sarcletti M, Fuchs D. Increased blood phenylalanine to tyrosine ratio in HIV-1 infection and correction following effective antiretroviral therapy. Brain Behav Immun 2010;24:403–8.CrossrefGoogle Scholar
Thorolfsson M, Teigen K, Martinez A. Activation of phenylalanine hydroxylase: effect of substitutions at Arg68 and Cys237. Biochemistry 2003;42:3419–28.Google Scholar
Selwood T, Jaffe EK. Dynamic dissociating homo-oligomers and the control of protein function. Arch Biochem Biophys 2012;519:131–43.Google Scholar
Li J, Dangott LJ, Fitzpatrick PF. Regulation of phenylalanine hydroxylase: conformational changes upon phenylalanine binding detected by hydrogen/deuterium exchange and mass spectrometry. Biochemistry 2010;49:3327–35.PubMedCrossrefGoogle Scholar
Stokka AJ, Carvalho RN, Barroso JF, Flatmark T. Probing the role of crystallographically defined/predicted hinge-bending regions in the substrate-induced global conformational transition and catalytic activation of human phenylalanine hydroxylase by single-site mutagenesis. J Biol Chem 2004;279:26571–80.Google Scholar
Jennings IG, Teh T, Kobe B. Essential role of the N-terminal autoregulatory sequence in the regulation of phenylalanine hydroxylase. FEBS Lett 2001;488:196–200.Google Scholar
Jaffe EK, Stith L. ALAD porphyria is a conformational disease. Am J Hum Genet 2007;80:329–37.Google Scholar
Hodak H. The Nobel Prize in chemistry 2013 for the development of multiscale models of complex chemical systems: a tribute to Martin Karplus, Michael Levitt and Arieh Warshel. J Mol Biol 2014;426:1–3.Google Scholar
Goetz AW, Williamson MJ, Xu D, Poole D, LeGrand S, Walker RC. Routine microsecond molecular dynamics simulations with AMBER on GPUs: 1. Generalized Born. J Chem Theory Comput 2012;8:1542–55.CrossrefGoogle Scholar
Shaw DE, Maragakis P, Lindorff-Larsen K, Piana S, Dror RO, Eastwood MP, et al. Atomic-level characterization of the structural dynamics of proteins. Science 2010;330:341–6.Google Scholar
Buch I, Giorgino T, De Fabritiis G. Complete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulations. Proc Natl Acad Sci USA 2011;108:10184–9.Google Scholar
Dror RO, Green HF, Valant C, Borhani DW, Valcourt JR, Pan AC, et al. Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature 2013;503:295–9.Google Scholar
Fuchs JE, von Grafenstein S, Huber RG, Wallnoefer HG, Liedl KR. Specificity of a protein-protein interface: local dynamics direct substrate recognition of effector caspases. Proteins 2014;82: 546–55.CrossrefGoogle Scholar
Piana S, Lindorff-Larsen K, Shaw DE. Atomic-level description of ubiquitin folding. Proc Natl Acad Sci USA 2013;110:5915–20.Google Scholar
Piana S, Lindorff-Larsen K, Shaw DE. Atomistic description of the folding of a dimeric protein. J Phys Chem B 2013;117:12935–42.Google Scholar
Pey AL, Martinez A, Charubala R, Maitland DJ, Teigen K, Calvo A, et al. Specific interaction of the diastereomers 7(R)- and 7(S)-tetrahydrobiopterin with phenylalanine hydroxylase: implications for understanding primapterinuria and vitiligo. FASEB J 2006;20:2130–2.CrossrefGoogle Scholar
Chadha N, Tiwari AK, Kumas V, Milton MD, Mishra AK. In silico thermodynamics stability change analysis involved in BH4 responsive mutations in phenylalanine hydroxylase: QM/MM and MD simulations analysis. J Biomol Struct Dyn 2014;epub ahead of print. DOI: 10.1080/07391102.2014.897258.CrossrefGoogle Scholar
Carluccio C, Fraternali F, Salvatore F, Fornili A, Zagari A. Structural features of the regulatory ACT domain of phenylalanine hydroxylase. PLoS One 2013;8:e79482.Google Scholar
Miranda FF, Thorolfsson M, Teigen K, Sanchez-Ruiz JM, Martinez A. Structural and stability effects of phosphorylation: localized structural changes in phenylalanine hydroxylase. Protein Sci 2004;13:1219–26.PubMedCrossrefGoogle Scholar
Fuchs JE, Huber RG, von Grafenstein S, Wallnoefer HG, Spitzer GM, Fuchs D, et al. Dynamics regulation of phenylalanine hydroxylase by simulated redox manipulation. PLoS ONE 2012;7:e53005.Google Scholar
Teeter MM, Case DA. Harmonic and quasiharmonic descriptions of crambin. J Phys Chem 1990;94:8091–7.Google Scholar
Von Grafenstein S, Wallnoefer HG, Kirchmair J, Fuchs JE, Huber RG, Schmidtke M, et al. Interface dynamics explain assembly dependency of influenza neuraminidase catalytic activity. J Biomol Struct Dyn 2013;epub ahead of print. DOI: 10.1080/07391102.2013.855142.CrossrefGoogle Scholar
Neurauter G, Schroecksnadel K, Scholl-Buergi S, Sperner-Unterweger B, Schubert C, Ledochowski M, et al. Chronic immune stimulation correlates with reduced phenylalanine turn-over. Curr Drug Metabol 2008;9:622–7.CrossrefGoogle Scholar
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Published Online: 2014-07-23
Published in Print: 2014-07-01