DOCSLIB.ORG

First Structure of Full-Length Mammalian Phenylalanine Hydroxylase Reveals the Architecture of an Autoinhibited Tetramer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
First Structure of Full-Length Mammalian Phenylalanine Hydroxylase Reveals the Architecture of an Autoinhibited Tetramer First structure of full-length mammalian phenylalanine hydroxylase reveals the architecture of an autoinhibited tetramer Emilia C. Arturoa,b, Kushol Guptac, Annie Hérouxd, Linda Stitha, Penelope J. Crosse,f,g, Emily J. Parkere,f,g, Patrick J. Lollb, and Eileen K. Jaffea,1 aMolecular Therapeutics, Fox Chase Cancer Center, Temple University Health Systems, Philadelphia, PA 19111; bBiochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102; cBiochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; dEnergy Sciences Directorate/Photon Science Division, Brookhaven National Laboratory, Upton, NY 11973; eBiomolecular Interaction Centre, University of Canterbury, Christchurch 8041, New Zealand; fDepartment of Chemistry, University of Canterbury, Christchurch 8041, New Zealand; and gMaurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1142, New Zealand Edited by Judith P. Klinman, University of California, Berkeley, CA, and approved January 21, 2016 (received for review August 27, 2015) Improved understanding of the relationship among structure, dy- There are >500 disease-associated missense variants of human namics, and function for the enzyme phenylalanine hydroxylase PAH; the amino acid substitutions are distributed throughout (PAH) can lead to needed new therapies for phenylketonuria, the the 452-residue protein and among all its domains (Fig. 1A) most common inborn error of amino acid metabolism. PAH is a (7–9). Of those disease-associated variants that have been stud- multidomain homo-multimeric protein whose conformation and ied in vitro (e.g., ref. 10), some confound the allosteric response, multimerization properties respond to allosteric activation by the and some are interpreted as structurally unstable. We also sug- substrate phenylalanine (Phe); the allosteric regulation is neces- gest that the activities of some disease-associated variants may be sary to maintain Phe below neurotoxic levels. A recently introduced dysregulated by an altered equilibrium among conformers having model for allosteric regulation of PAH involves major domain different intrinsic levels of activity, arguing by analogy to the motions and architecturally distinct PAH tetramers [Jaffe EK, Stith L, enzyme porphobilinogen synthase (PBGS) and its porphyria- Lawrence SH, Andrake M, Dunbrack RL, Jr (2013) Arch Biochem Bio- associated variants (11). Consistent with this notion, we have phys 530(2):73–82]. Herein, we present, to our knowledge, the first recently established that PAH can assemble into architecturally X-ray crystal structure for a full-length mammalian (rat) PAH in an autoinhibited conformation. Chromatographic isolation of a mono- distinct tetrameric conformers (12), and propose that these disperse tetrameric PAH, in the absence of Phe, facilitated determi- conformers differ in activity due to differences in active-site ac- nation of the 2.9 Å crystal structure. The structure of full-length PAH cess. This idea has important implications for drug discovery, as supersedes a composite homology model that had been used exten- it implies that small molecules could potentially modulate the sively to rationalize phenylketonuria genotype–phenotype relation- conformational equilibrium of PAH, as has already been dem- ships. Small-angle X-ray scattering (SAXS) confirms that this tetramer, onstrated for PBGS (e.g., ref. 13). Deciphering the relationship which dominates in the absence of Phe, is different from a Phe- among PAH structure, dynamics, and function is a necessary first stabilized allosterically activated PAH tetramer. The lack of structural step in testing this hypothesis. detail for activated PAH remains a barrier to complete understanding of phenylketonuria genotype–phenotype relationships. Nevertheless, Significance the use of SAXS and X-ray crystallography together to inspect PAH structure provides, to our knowledge, the first complete view of the Phenylketonuria and milder hyperphenylalaninemias consti- enzyme in a tetrameric form that was not possible with prior partial tute the most common inborn error of amino acid metabo- crystal structures, and facilitates interpretation of a wealth of bio- lism, usually caused by defective phenylalanine hydroxylase chemical and structural data that was hitherto impossible to evaluate. (PAH). Although a highly restricted diet prevents intellectual impairment during development, additional therapies are re- phenylalanine hydroxylase | phenylketonuria | X-ray crystallography | quired to combat cognitive dysfunction, executive dysfunc- small-angle X-ray scattering | allosteric regulation tion, and psychiatric disorders that arise due to dietary lapses throughout life. New therapies can arise from thorough un- ammalian phenylalanine hydroxylase (PAH) (EC 1.14.16.1) derstanding of the conformational space available to full- Mis a multidomain homo-multimeric protein whose dys- length PAH, which has defied crystal structure determination function causes the most common inborn error in amino acid for decades. We present the first X-ray crystal structure of metabolism, phenylketonuria (PKU), and milder forms of hy- full-length PAH, whose solution relevance is supported by perphenylalaninemia (OMIM 261600) (1). PAH catalyzes the small-angle X-ray scattering. The current structure is an auto- hydroxylation of phenylalanine (Phe) to tyrosine, using nonheme inhibited tetramer; the scattering data support the existence iron and the cosubstrates tetrahydrobiopterin and molecular oxygen of an architecturally distinct tetramer that is stabilized by the (2, 3). A detailed kinetic mechanism has recently been derived from allosteric activator phenylalanine. elegant single-turnover studies (4). PAH activity must be carefully regulated, because although Phe is an essential amino acid, high Author contributions: K.G. and E.K.J. designed research; E.C.A., K.G., A.H., L.S., P.J.C., E.J.P., and P.J.L. performed research; E.C.A., K.G., A.H., P.J.C., E.J.P., P.J.L., and E.K.J. analyzed data; Phe levels are neurotoxic. Thus, Phe allosterically activates PAH by and E.C.A., K.G., P.J.L., and E.K.J. wrote the paper. binding to a regulatory domain. Phosphorylation at Ser16 potenti- The authors declare no conflict of interest. ates the effects of Phe, with phosphorylated PAH achieving full This article is a PNAS Direct Submission. activation at lower Phe concentrations than the unphosphorylated Data deposition: The atomic coordinates and structure factors have been deposited in the protein (5, 6). Allosteric activation by Phe is accompanied by a Protein Data Bank, www.pdb.org (PDB ID code 5DEN). major conformational change, as evidenced by changes in protein 1To whom correspondence should be addressed. Email: [email protected]. fluorescence and proteolytic susceptibility, and by stabilization of a This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tetrameric conformer (3). 1073/pnas.1516967113/-/DCSupplemental. 2394–2399 | PNAS | March 1, 2016 | vol. 113 | no. 9 www.pnas.org/cgi/doi/10.1073/pnas.1516967113 Downloaded by guest on September 23, 2021 domain enzyme, possibly because the presence of multiple dis- A tinct conformers frustrated efforts to crystallize the full-length protein. Recognition of the existence of alternate tetrameric assemblies and the ability to isolate a single species has now allowed us to generate monodisperse samples of full-length rat PAH suitable for biophysical analysis using X-ray crystallography and small-angle X-ray scattering (SAXS). We report here, to our knowledge, the first crystal structure for full-length PAH, at a resolution of 2.9 Å, which supersedes a composite homology Long edge model that has been used since 1999 to help rationalize PKU-related B genotype/phenotype relationships (14). D C Results PAH Crystal Structure. This study focuses on rat PAH, which is 96% similar (92% identical) to the human enzyme. The 15 most common disease-associated amino acids are fully conserved be- tween rat and human, making the rodent protein an excellent model system for study of PKU. Rat PAH, heterologously expressed in Escherichia coli and purified via phenyl-Sepharose affinity chromatography (15), can be further fractionated on an B A ion-exchange column to partially resolve two tetrameric species (faster migrating and slower migrating) and one dimeric species, Short edge Short as determined by native PAGE (Fig. S1). In fractionated PAH samples, the distribution of these species is stable over long time 90° courses, suggesting that these fractions are good starting points for crystallization trials. The faster-migrating tetramer is the pre- A dominant component in these preparations (12), and using the D fraction most enriched in this species, we were able to produce BIOCHEMISTRY well-diffracting crystals that yielded a 2.9 Å structure (Fig. 1B and Table S2), to our knowledge, the first structure for any full-length mammalian PAH. The full-length structure and the previously used composite homology model are compared in Fig. 1C [with the caveat that the composite model combined a two-domain rat PAH structure (regulatory plus catalytic) with a two-domain hu- man PAH structure (catalytic plus multimerization) (6, 14, 16), whereas the three-domain crystal structure is rat PAH]. BCThe crystal asymmetric unit contains one tetramer, which C adopts an autoinhibited form in which the autoregulatory region partially occludes the enzyme active
Load more

Recommended publications
  • Molecule of the Month: Phenylalanine Hydroxylase
    Molecule of the Month: Phenylalanine Hydroxylase An unusual cofactor is used in the synthesis of aromatic amino acids The Protein Alphabet The proteins that make up the skin, muscle, hair, bones and other organs in your body are primarily composed of a set of 20 building blocks, called amino acids. Amino acids are the alphabet in the protein language: when combined in a specific order, they make up meaningful structures (proteins) with varied and specific functions. Amino acids have distinct shapes, sizes, charges and other characteristics. Many amino acids are synthesized in your body from breakdown products of sugars and fats, or are converted from other amino acids by the action of specific enzymes. However, a few of them, called essential amino acids, cannot be synthesized or converted in your body and have to be obtained from the food you eat. Phenylalanine is one such essential amino acid. It is closely related to another amino acid, tyrosine, which just has an additional hydroxyl (OH) group. Liver cells contain an enzyme called phenylalanine hydroxylase, which can add this group and convert phenylalanine to tyrosine. Thus as long as this enzyme is functional and there is a reasonable supply of phenylalanine, tyrosine can be synthesized in your body and does not have to be included in the food that you eat. Phenylalanine Hydroxylase Four molecules of phenylalanine hydroxylase interact to form a tetramer, which is the functional unit for this enzyme. Each molecule in the tetramer is organized into three domains: a regulatory domain, a catalytic domain where the enzyme activity resides and a tetramerization domain that assembles four chains into the tetramer.
    [Show full text]
  • Drug-Induced Movement Disorders
    Medical Management of Early PD Samer D. Tabbal, M.D. May 2016 Associate Professor of Neurology Director of The Parkinson Disease & Other Movement Disorders Program Mobile: +961 70 65 89 85 email: [email protected] Conflict of Interest Statement No drug company pays me any money Outline So, you diagnosed Parkinson disease .Natural history of the disease .When to start drug therapy? .Which drug to use first for symptomatic treatment? ● Levodopa vs dopamine agonist vs MAOI Natural History of Parkinson Disease Before levodopa: Death within 10 years After levodopa: . “Honeymoon” period (~ 5-7 years) . Motor (ON/OFF) fluctuations & dyskinesias: ● Drug therapy effective initially ● Surgical intervention by 10-15 years - Deep brain stimulation (DBS) therapy Motor Response Dyskinesia 5-7 yrs >10 yrs Dyskinesia ON state ON state OFF state OFF state time time Several days Several hours 1-2 hour Natural History of Parkinson Disease Prominent gait impairment and autonomic symptoms by 20-25 years (Merola 2011) Behavioral changes before or with motor symptoms: . Sleep disorders . Depression . Anxiety . Hallucinations, paranoid delusions Dementia at anytime during the illness . When prominent or early: diffuse Lewy body disease Symptoms of Parkinson Disease Motor Symptoms Sensory Symptoms Mental Symptoms: . Cognitive and psychiatric Autonomic Symptoms Presenting Symptoms of Parkinson Disease Mood disorders: depression and lack of motivation Sleep disorders: “acting out dreams” and nightmares Early motor symptoms: Typically Unilateral . Rest tremor: chin, arms or legs or “inner tremor” . Bradykinesia: focal and generalized slowness . Rigidity: “muscle stiffness or ache” Also: (usually no early postural instability) . Facial masking with hypophonia: “does not smile anymore” or “looks unhappy all the time” .
    [Show full text]
  • The Distribution of Tyrosine Hydroxylase-Lmmunoreactive Fibers in Primate Neocortex Is Widespread but Regionally Specific
    The Journal of Neuroscience, January 1987, 7(l): 279-290 The Distribution of Tyrosine Hydroxylase-lmmunoreactive Fibers in Primate Neocortex Is Widespread but Regionally Specific David A. Lewis,lea Michael J. Campbell,’ Stephen L. Foote, I.2 Menek Goldstein,3 and John H. Morrison’ ‘Scripps Clinic and Research Foundation, La Jolla, California 92037, 2Department of Psychiatry, University of California, San Diego, California 92037, and 3N.Y.U. Medical Center, New York, New York 10016 An antiserum directed against tyrosine hydroxylase (TH), an alleled by an elaboration and specialization of the noradrenergic enzyme involved in dopamine and norepinephrine synthe- and serotoninergic projections to neocortex. Compared to rat, sis, was used to visualize axons immunohistochemically in both of these systems in primates exhibit substantial regional monkey n’eocortex. Labeled fibers were distributed through- heterogeneity in the density and laminar distribution of cortical out the entire neocottex, but they had striking patterns of fibers (Brown et al., 1979; Morrison et al., 1982a, b; Takeuchi regional and laminar specialization. For example, primary and Sano, 1983). Midbrain dopaminergic neurons also project motor cortex contained the greatest density of TH-labeled to neocortex, but little is known about the distribution of do- fibers, whereas primary sensory regions were sparsely in- paminergic fibers in primate neocortex. Initial studies on the nervated. Marked heterogeneity of fiber density was also rat revealed that dopaminergic fibers were restricted to limited present among the association regions of the frontal, pari- portions of the prefrontal, cingulate, and perirhinal cortical re- etal, and temporal lobes. In addition, the laminar pattern of gions (Thierry et al., 1973; Berger et al., 1974, 1976; Fuxe et innervation in a given region was correlated with its fiber al., 1974; Hokfelt et al., 1974b; Lindvall et al., 1974).
    [Show full text]
  • Tyrosine Hydroxylase Deficiency in Three Greek Patients with a Common
    1086 R. PONS ET AL. Boston, MA; Jay Gorell, MD (deceased), Shana Krstev- Tyrosine Hydroxylase Deficiency ska, MD: Henry Ford Health System, Detroit, MI; Ryan Uitti, MD, Margaret Turk, RN: Mayo Clinic in Three Greek Patients with a Jacksonville, Jacksonville, FL; James Bower, MD, Common Ancestral Mutation Susan Torgrimson, RN Mayo Clinic Rochester, Roch- ester, MN; Marwan Sabbagh, MD, Zoran Obradov, Roser Pons, MD,1* Mercedes Serrano, MD PhD,2,3 CRC: Sun Health Research Institute, Sun City, AZ. Aida Ormazabal, PhD,2,3 Claudio Toma, PhD,4 Angels Garcia-Cazorla, MD PhD,2,3 Estela Area, PhD,5 Marta Ribase´s, PhD,6 Emmanuel Kanavakis, MD,1 Kaliopi Drakaki, MD,1 Aristotelis Giannakopoulos, MD,1 REFERENCES Irene Orfanou, MD,1 Sotiris Youroukos, MD,1 4 2,3 1. Parkinson Study Group. DATATOP: a multicenter controlled Bru Cormand, PhD, and Rafael Artuch, MD, PhD clinical trial in early Parkinson’s disease. Arch Neurol 1989;46:1052–1060. 1First Department of Pediatrics, Agia Sofia Hospital, 2. NINDS NET-PD Investigators. A randomized clinical trial of University of Athens, Athens, Greece; 2Department of Neuro- coenzyme Q10 and GPI-1485 in early Parkinson disease. Neurol- pediatrics, Sant Joan de De´u Hospital, Center for Biomedical ogy 2007;68:20–28. Research on Rare Diseases (CIBERER), Barcelona, Spain; 3. Tilley BC, Palesch YY, Kieburtz K, et al. Optimizing the 3Department of Clinical Biochemistry, Sant Joan de De´u ongoing search for new treatments for Parkinson disease: using Hospital, Center for Biomedical Research on Rare Diseases futility designs. Neurology 2006;66:628–633. 4 4.
    [Show full text]
  • Download Article (PDF)
    CHEMISTRY OF ENZYME INHffiiTORS OF MICROBIAL ORIGIN HAMAO UMEZAWA Institute of Microbial Chemistry and Department of Antibiotics, National Institute of Health, Tokyo, Japan ABSTRACT Study of antibiotics has furnished interesting materials to chemistry of natural products. I initiated the screening study of enzyme inhibitors produced by microorganisms and isolated Ieupeptin and antipain inhibiting trypsin and papain, chymostatin inhibiting chymotrypsin, pepstatin inhibiting pepsin, panosialin inhibiting sialidases, oudenone inhibiting tyrosine hydroxylase, dopastin inhibiting dopamine ß-hydroxylase, aquayamycin and chrothiomycin inhibiting tyrosine hydroxylase and dopamine ß-hydroxylase. Structures and syntheses ofmost ofthese compounds have been studied. I also found dopamine ß-hydroxylase-inhibiting activity of fusaric acid and oosponol, and xanthine­ oxidase inhibiting activity of 5-formyluracil which were produced by micro­ organisms. Chemical study of enzyme inhibitors has given useful information on the structurejactivity relation. The effect of pepstatin on stomach ulcer, and the hypotensive effect of oudenone and fusaric acid have been observed clinically. Enzyme inhibitors produced by microorganisms are the most valuable new area extended from antibiotics and will furnish new materials interesting in chemistry. biosynthesis, pharmacology, and utility. Research on antibiotics has contributed to the chemistry of natural products, furnishing materials of interesting structures, chemical syntheses, biosyntheses and of interesting
    [Show full text]
  • Three Classes of Tetrahydrobiopterin-Dependent Enzymes
    DOI 10.1515/pterid-2013-0003 Pteridines 2013; 24(1): 7–11 Review Ernst R. Werner* Three classes of tetrahydrobiopterin-dependent enzymes Abstract: Current knowledge distinguishes three classes in Antalya, Turkey. For a more detailed review on bio- of tetrahydrobiopterin-dependent enzymes as based on chemistry and pathophysiology of tetrahydrobio pterin, protein sequence similarity. These three protein sequence the reader is referred to Ref. [ 1 ]. Here, a short historical clusters hydroxylate three types of substrate atoms and overview of the discovery of tetrahydrobiopterin-depend- use three different forms of iron for catalysis. The first ent enzymes is presented, followed by a summary of the class to be discovered was the aromatic amino acid biochemical properties of these enzymes. The reactions hydroxylases, which, in mammals, include phenylalanine catalyzed by the three classes of tetrahydrobiopterin- hydroxylase, tyrosine hydroxylase, and two isoforms of dependent enzymes are detailed in Figure 1 . tryptophan hydroxylases. The protein sequences of these tetrahydrobiopterin-dependent aromatic amino acid hydroxylases are significantly similar, and all mammalian Discovery of tetrahydrobiopterin- aromatic amino acid hydroxylases require a non-heme- dependent enzymes bound iron atom in the active site of the enzyme for cataly- sis. The second classes of tetrahydrobiopterin-dependent enzymes to be characterized were the nitric oxide syn- Aromatic amino acid hydroxylases thases, which in mammals occur as three isoforms. Nitric oxide synthase protein sequences form a separate cluster Phenylalanine hydroxylase was the first enzyme charac- of homologous sequences with no similarity to aromatic terized to be dependent on a tetrahydropterin [ 2 ]. It then amino acid hydroxylase protein sequences. In contrast to took five more years to identify the nature of the endo- aromatic amino acid hydroxylases, nitric oxide synthases genous cofactor as tetrahydrobiopterin [ 3 ].
    [Show full text]
  • Induced Catecholamine Depletion in Patients with Seasonal Affective Disorder in Summer Remission Raymond W
    Effects of Alpha-Methyl-Para-Tyrosine- Induced Catecholamine Depletion in Patients with Seasonal Affective Disorder in Summer Remission Raymond W. Lam, M.D., Edwin M. Tam, M.D.C.M., Arvinder Grewal, B.A., and Lakshmi N. Yatham, M.B.B.S. Noradrenergic and dopaminergic mechanisms have been the control diphenhydramine session. The AMPT session proposed for the pathophysiology of seasonal affective resulted in higher depression ratings with all nine patients disorder (SAD). We investigated the effects of having significant clinical relapse, compared with two catecholamine depletion using ␣-methyl-para-tyrosine patients during the diphenhydramine session. All patients (AMPT), an inhibitor of tyrosine hydroxylase, in patients returned to baseline scores after drug discontinuation. with SAD in natural summer remission. Nine drug-free Catecholamine depletion results in significant clinical patients with SAD by DSM-IV criteria, in summer relapse in patients with SAD in the untreated, summer- remission for at least eight weeks, completed a double-blind, remitted state. AMPT-induced depressive relapse may be a crossover study. Behavioral ratings and serum HVA and trait marker for SAD, and/or brain catecholamines may MHPG levels were obtained for 3-day sessions during play a direct role in the pathogenesis of SAD. which patients took AMPT or an active control drug, [Neuropsychopharmacology 25:S97–S101, 2001] diphenhydramine.The active AMPT session significantly © 2001 American College of Neuropsychopharmacology. reduced serum levels of HVA and MHPG compared with Published by Elsevier Science Inc. KEY WORDS: Seasonal affective disorder; Alpha-methyl- pattern, with full remission of symptoms (or a switch para-tyrosine; Catecholamines; Dopamine; Noradrenaline; into hypomania/mania) during spring/summer.
    [Show full text]
  • Mechanism of Actions of Antidepressants: Beyond the Receptors
    Derlemeler/Reviews Mechanism of Actions of Antidepressants: Beyond the Receptors Mechanism of Actions of Antidepressants: Beyond the Receptors Ayflegül Y›ld›z, M.D.1, Ali Saffet Gönül, M.D.2, Lut Tamam, M.D.3 ABSTRACT: MECHANISM OF ACTIONS OF ANTIDEPRESSANTS: BEYOND THE RECEPTORS Since the discovery of first antidepressants-monoamine oxidase inhibitors- a half century passed. There are now almost two- dozen antidepressant agents that work by nine distinct pharmacological mechanisms at the receptor level. However, opposite to the divergence in their pharmacological mechanisms at the receptor level, antidepressant drugs probably stimulate similar pathways in subcellular level. These subcellular events or so called beyond receptor effects are named neuroplasticity, and the mechanism may be called as adaptation. These after-receptor processes, through their effects on synaptic transmission, and gene expression are indeed capable of altering many molecular events in the brain. In this article, the mechanisms of actions of antidepressants at- and beyond- the receptors are discussed by documenting some of the evidence indicating such long-term alterations. Accordingly, the well-known effects of antidepressants on the receptor level are initiating events of antidepressant drug action, which enhance and prolong the actions of norepinephrine and/or serotonin and/or dopamine. Only if an adequate dose of an antidepressant is taken chronically, the increase in the synaptic norepinephrine and/or serotonin and/or dopamine stresses or perturbs the nervous
    [Show full text]
  • A Brief Overview of Tyrosine Hydroxylase and Α-Synuclein in The
    CNS & Neurological Disorders - Drug Targets, 2012, 11, 000-000 1 A Brief Overview of Tyrosine Hydroxylase and -Synuclein in the Parkinsonian Brain Wajihullah Khan*,1, M Priyadarshini2, Haytham A. Zakai1, Mohammad A. Kamal3 and Qamre Alam3 1Faculty of Applied Medical Sciences, King Abdulaziz University, P.O. Box 80205, Jeddah 21589, Kingdom of Saudi Arabia 2Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, 202002, UP, India 3King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Kingdom of Saudi Arabia Abstract: Parkinson’s disease (PD) is associated with neurodegeneration of the nigrostriatal tract and is accompanied with loss of tyrosine hydroxylase (TH) and dopamine (DA). Development of neuroprotective strategies targeting PD is often undermined by lack of proper understanding of processes contributing to the pathology. In this mini review we have tried to briefly outline the involvement of TH and -synuclein in PD. Aberrant expression of -synuclein is toxic to dopaminergic neurons. It interacts with ubiquitin-proteasomal processing system, implicated in oxidative injury and mitochondrial dysfunction which ultimately induce neurodegenration and cell death. The contributions of DJ-1 in TH regulation have also been discussed. Brain specific TH expression with the combined use of the pegylated immunoliposome (PILs) gene transfer technology and brain specific promoters as a new approach to treat PD has also been included. Keywords: Tyrosine hydroxylase, dopamine, nigrostriatal pathway, alpha-synuclein, neurodegeneration, Parkinson’s disease. INTRODUCTION calcium/calmodulin-dependent system [6]. TH is the first rate limiting step in the biosynthesis of the catecholamines, Each year, about 4 million to 6 million people suffer DA, norepinephrine and epinephrine (Fig.
    [Show full text]
  • Activation of Tyrosine Kinase Receptor Signaling Pathway by Rasagiline
    www.elsevier.com/locate/ynbdi Neurobiology of Disease 25 (2007) 35–44 Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism ⁎ Yotam Sagi, Silvia Mandel, Tamar Amit, and Moussa B.H. Youdim Eve Topf and USA National Parkinson Foundation, Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Technion-Rappaport Faculty of Medicine, P.O.B. 9697, 31096 Haifa, Israel Received 20 March 2006; revised 4 July 2006; accepted 25 July 2006 Available online 20 October 2006 The anti-Parkinson monoamine oxidase (MAO)-B inhibitor rasagiline Introduction (Azilect) was shown to possess neuroprotective activities, involving the induction of brain-derived- and glial cell line-derived neurotrophic In Parkinson’s disease (PD) approximately 50–70% of the factors (BDNF, GDNF). Employing conventional neurochemical dopamine (DA)-containing neurons are already lost at the time of techniques, transcriptomics and proteomic screening tools combined diagnosis (Morrish et al., 1998). Thus, the challenge has been to with a biology-based clustering method, we show that rasagiline, given induce neuroprotection or neurorescue by therapeutics that would chronically post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyri- respectively prevent or stop the progressive neurodegeneration. In dine), exerts neurorescue/neurotrophic activity in mice midbrain dopamine neurons. Rasagiline induced the activation of cell signaling this respect, a recent study has been initiated to identify potential mediators associated with neurotrophic factors responsive-tyrosine neuroprotective agents for testing in clinical trials (Ravina et al., kinase receptor (Trk) pathway including ShcC, SOS, AF6, Rin1 and 2003).
    [Show full text]
  • Biochemical and Pharmacologic Effects of Α-Methyltyrosine in Man
    Biochemical and pharmacologic effects of α-methyltyrosine in man Karl Engelman, … , Eric Jéquier, Albert Sjoerdsma J Clin Invest. 1968;47(3):577-594. https://doi.org/10.1172/JCI105754. Research Article Alpha methyltyrosine (α-MPT) was administered to 52 patients from 4 days to 10 months; 22 patients were cases of pheochromocytoma and 20 had essential hypertension. Inhibition of catecholamine synthesis in the range of 50-80% was achieved with divided daily drug dosage of from 1.0 to 4.0 g. Striking clinical benefit was noted in patients with pheochromocytoma in whom the drug was used in preparation for surgery and during chronic medical management. The drug appeared to have limited usefulness when used in essential hypertension, unless added to existing therapy with conventional agents. No beneficial effects were noted in thyrotoxicosis, glaucoma, and Raynaud's phenomenon. Untoward effects in order of decreasing incidence were: sedation (with insomnia on withdrawal), anxiety, tremor, diarrhea, and galactorrhea. Drug crystalluria, which has been observed in animals and is currently restrictive of clinical trials, was not observed in these studies. Evidence is presented that the minor conversion of α-MPT to methyldopa probably does not contribute significantly to the central and peripheral effects of the drug. Find the latest version: https://jci.me/105754/pdf Biochemical and Pharmacologic Effects of a -Methyltyrosine in Man KARL ENGELMAN, DAvm HORWITZ, ERIc JEQUER, and ALBERT SJoERDsMA From the Experimental Therapeutics Branch, National Heart Institute, Bethesda, Maryland A B S T R A C T Alpha methyltyrosine (a-MPT) previous paper (4) have indicated that the drug was administered to 52 patients from 4 days to is adequately absorbed from the gastrointestinal 10 months; 22 patients were cases of pheo- tract and that the degree of inhibition achieved in chromocytoma and 20 had essential hypertension.
    [Show full text]
  • Influence of Chronic Administration Of
    Influence of Chronic Administration of Antidepressant Drugs on mRNA for Galanin, Galanin Receptors, and Tyrosine Hydroxylase in Catecholaminergic and Serotonergic Cell-body Regions in Rat Brain Molly L. Rovin, Emory University Katherine A Williams, Emory University Reid S. Alisch, Emory University James C Ritchie, Emory University David Weinshenker, Emory University Charles H K West, Emory University Jay M Weiss, Emory University Journal Title: Neuropeptides Volume: Volume 46, Number 2 Publisher: Elsevier | 2012-04, Pages 81-91 Type of Work: Article | Post-print: After Peer Review Publisher DOI: 10.1016/j.npep.2012.01.001 Permanent URL: http://pid.emory.edu/ark:/25593/fjxnz Final published version: http://dx.doi.org/10.1016/j.npep.2012.01.001 Copyright information: © 2012 Elsevier Ltd. All rights reserved. This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Accessed September 25, 2021 10:13 PM EDT NIH Public Access Author Manuscript Neuropeptides. Author manuscript; available in PMC 2013 September 02. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Neuropeptides. 2012 April ; 46(2): 81–91. doi:10.1016/j.npep.2012.01.001. Influence of Chronic Administration of Antidepressant Drugs on mRNA for Galanin, Galanin Receptors, and Tyrosine Hydroxylase in Catecholaminergic and Serotonergic Cell-body Regions in Rat Brain Molly L. Rovin, B.S.2, Katherine A. Boss-Williams, Ph.D.2, Reid S. Alisch, Ph.D.1, James C. Ritchie, Ph.D.3, David Weinshenker, Ph.D.1, Charles H.K.
    [Show full text]