DOCSLIB.ORG

Hydroxylation of the Eukaryotic Ribosomal Decoding Center Affects Translational Accuracy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Hydroxylation of the Eukaryotic Ribosomal Decoding Center Affects Translational Accuracy Hydroxylation of the eukaryotic ribosomal decoding center affects translational accuracy Christoph Loenarza,1, Rok Sekirnika,2, Armin Thalhammera,2, Wei Gea, Ekaterina Spivakovskya, Mukram M. Mackeena,b,3, Michael A. McDonougha, Matthew E. Cockmanc, Benedikt M. Kesslerb, Peter J. Ratcliffec, Alexander Wolfa,4, and Christopher J. Schofielda,1 aChemistry Research Laboratory and Oxford Centre for Integrative Systems Biology, University of Oxford, Oxford OX1 3TA, United Kingdom; bTarget Discovery Institute, University of Oxford, Oxford OX3 7FZ, United Kingdom; and cCentre for Cellular and Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom Edited by William G. Kaelin, Jr., Harvard Medical School, Boston, MA, and approved January 24, 2014 (received for review July 31, 2013) The mechanisms by which gene expression is regulated by oxygen Enzyme-catalyzed hydroxylation of intracellularly localized are of considerable interest from basic science and therapeutic proteins was once thought to be rare, but accumulating recent perspectives. Using mass spectrometric analyses of Saccharomyces evidence suggests it is widespread (11). Motivated by these cerevisiae ribosomes, we found that the amino acid residue in findings, we investigated whether the translation of mRNA to closest proximity to the decoding center, Pro-64 of the 40S subunit protein is affected by oxygen-dependent modifications. A rapidly ribosomal protein Rps23p (RPS23 Pro-62 in humans) undergoes growing eukaryotic cell devotes most of its resources to the tran- posttranslational hydroxylation. We identify RPS23 hydroxylases scription, splicing, and transport of ribosomal proteins and rRNA as a highly conserved eukaryotic subfamily of Fe(II) and 2-oxoglu- (12). We therefore reasoned that ribosomal modification is a tarate dependent oxygenases; their catalytic domain is closely re- candidate mechanism for the regulation of protein expression. lated to transcription factor prolyl trans-4-hydroxylases that act as Here we provide evidence that posttranslational prolyl hy- oxygen sensors in the hypoxic response in animals. The RPS23 droxylation of ribosomal protein S23 (RPS23) is an evolutionarily hydroxylases in S. cerevisiae (Tpa1p), Schizosaccharomyces pombe conserved modification that regulates translation termination. and green algae catalyze an unprecedented dihydroxylation mod- Mutations to RPS23 and its bacterial homolog (S12) have long ification. This observation contrasts with higher eukaryotes, been associated with translational accuracy, following from sem- where RPS23 is monohydroxylated; the human Tpa1p homolog inal work characterizing Escherichia coli growth phenotypes in the trans TPA1 OGFOD1 catalyzes prolyl -3-hydroxylation. deletion presence of the antibiotic streptomycin (13, 14). The finding that ∼ modulates termination efficiency up to 10-fold, including of S12 mutations that increased or decreased the accuracy of stop pathophysiologically relevant sequences; we reveal Rps23p hy- codon recognition in E. coli had similar effects in yeast suggested droxylation as its molecular basis. In contrast to most previously characterized accuracy modulators, including antibiotics and the prion state of the S. cerevisiae translation termination factor Significance eRF3, Rps23p hydroxylation can either increase or decrease trans- BIOCHEMISTRY lational accuracy in a stop codon context-dependent manner. We The processing of DNA sequences into proteins is fine-tuned to identify conditions where Rps23p hydroxylation status determines meet the conflicting demands of accuracy and speed. DNA viability as a consequence of nonsense codon suppression. The mutations can introduce premature stop codons, leading to results reveal a direct link between oxygenase catalysis and the inactive proteins. We report that oxygen-dependent post- regulation of gene expression at the translational level. They will translational modification of the ribosomal decoding center also aid in the development of small molecules altering transla- affects stop codon readthrough in an mRNA sequence-dependent tional accuracy for the treatment of genetic diseases linked to manner. Our work demonstrates that oxygenases catalyzing nonsense mutations. RPS23 hydroxylation are conserved in eukaryotes, including yeasts, flies, and humans. In basal eukaryotes, RPS23 under- translation | hypoxia | ribosomal hydroxylation | 2-oxoglutarate goes two hydroxylations, whereas in animals we only observe oxygenase | nonsense readthrough one hydroxylation. Yeast ribosomes lacking hydroxylation man- ifest altered stop codon readthrough up to ∼10-fold. The results reveal oxygen-dependent modifications that regulate trans- he rises in atmospheric oxygen levels provided life with a new lational accuracy and suggest unprecedented approaches to energy source, but necessitated the evolution of regulatory T modulating ribosomal accuracy for medicinal application. mechanisms (1). Defining how cells regulate protein biosynthesis by the direct addition of oxygen to cellular molecules is of cur- Author contributions: C.L. and C.J.S. designed research; C.L., R.S., A.T., W.G., E.S., M.M.M., rent basic and medicinal interest. Recent work suggests the and A.W. performed research; C.L., R.S., A.T., and A.W. contributed new reagents/analytic presence of multiple regulatory levels and interfaces between O2 tools; C.L., R.S., A.T., W.G., E.S., M.M.M., M.A.M., M.E.C., B.M.K., P.J.R., A.W., and C.J.S. and gene expression, many of which are catalyzed by Fe(II)- and analyzed data; and C.L. and C.J.S. wrote the paper. 2-oxoglutarate (2OG)-dependent oxygenases, some of which are The authors declare no conflict of interest. therapeutic targets (2). The hypoxic response in animals, but This article is a PNAS Direct Submission. not lower organisms, is substantially mediated by prolyl trans-4- Freely available online through the PNAS open access option. hydroxylation of the hypoxia-inducible transcription factor (HIF) 1To whom correspondence may be addressed. E-mail: [email protected]. (3–6). In addition to the gene-specific regulation of transcrip- uk or [email protected]. tion via HIF, oxygen-dependent modifications at other interfaces 2R.S. and A.T. contributed equally to this work. have been discovered: hydroxylation of splicing-related proteins 3Present address: School of Chemical Sciences, Faculty of Science and Technology and (7), histone lysyl demethylation (8), and 5-methylcytosine hydrox- Institute of Systems Biology, Universiti Kebangsaan Malaysia, Bangi 43600, Malaysia. 4 ylation (9). In addition to signaling, posttranslational hydroxyl- Present address: Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München–German Research Center for Environmental Health, 85764 Neuherberg, ations can also have structural roles: prolyl trans-4-hydroxylation Germany. stabilizes the collagen triple helix, whereas trans-3-hydroxylation This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. appears to be destabilizing in collagen (10). 1073/pnas.1311750111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1311750111 PNAS | March 18, 2014 | vol. 111 | no. 11 | 4019–4024 Downloaded by guest on September 29, 2021 RPS23 serves as a conserved “accuracy center” (15), a proposal observed (Fig. 1B). Together with immunoreactivity against an later supported by crystallographic analyses (16, 17). RPS23 antibody, these observations identify the modified protein We report that in basal eukaryotes, RPS23 contains an un- as Rps23p (unmodified calculated 15,906 Da), and imply Rps23p precedented dihydroxyprolyl modification, whereas human RPS23 undergoes posttranslational mono- and dihydroxylation mod- only undergoes a single prolyl trans-3-hydroxylation. RPS23 prolyl- ifications (+16 and +32 Da). 3-hydroxylation affects stop codon readthrough in a sequence- specific manner, consistent with the location of the hydroxylation Anoxia Affects Translational Accuracy via Tpa1p. Because RPS23 site within the ribosomal decoding center. Small-molecule in- mutations are associated with the modulation of translational hibition of the RPS23 hydroxylases increases production of full- accuracy (14, 15), we investigated whether the identified oxidative length proteins from sequences containing clinically relevant modifications to Rps23p act similarly, using a dual-luciferase assay nonsense mutations, suggesting that ribosome hydroxylation is measuring readthrough of the yeast bypass of stop codon 4 (BSC4) of therapeutic interest. (19) stop codon sequence (Table S1). Renilla and Firefly luciferase (Rluc and Fluc) cDNAs are separated by an in-frame stop codon Results or a sense codon control; their relative ratio allows quantification Eukaryotic Ribosomes Undergo Posttranslational Hydroxylation. In of stop codon readthrough as a measure of translational accuracy Saccharomyces cerevisiae, hypoxic stress [3% (vol/vol) atmo- (Fig. S2A). Whereas hypoxic (0.1% O2) S. cerevisiae gave similar spheric O2] decreases polysome levels and increases free 40S results to normoxia, translational accuracy significantly increased ribosomal subunits (Fig. S1 A and B). This effect is exacerbated in an anoxic environment (Fig. 1C). Although we were unable to in severe hypoxia (0.1% O2; Fig. S1C). The only known oxidative analyze the Rps23p hydroxylation level during reoxygenation due modification to the yeast translational machinery is the essential to the low levels of cell mass obtained under anoxic conditions,
Load more

Recommended publications
  • Enzymatic Encoding Methods for Efficient Synthesis Of
    (19) TZZ__T (11) EP 1 957 644 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12N 15/10 (2006.01) C12Q 1/68 (2006.01) 01.12.2010 Bulletin 2010/48 C40B 40/06 (2006.01) C40B 50/06 (2006.01) (21) Application number: 06818144.5 (86) International application number: PCT/DK2006/000685 (22) Date of filing: 01.12.2006 (87) International publication number: WO 2007/062664 (07.06.2007 Gazette 2007/23) (54) ENZYMATIC ENCODING METHODS FOR EFFICIENT SYNTHESIS OF LARGE LIBRARIES ENZYMVERMITTELNDE KODIERUNGSMETHODEN FÜR EINE EFFIZIENTE SYNTHESE VON GROSSEN BIBLIOTHEKEN PROCEDES DE CODAGE ENZYMATIQUE DESTINES A LA SYNTHESE EFFICACE DE BIBLIOTHEQUES IMPORTANTES (84) Designated Contracting States: • GOLDBECH, Anne AT BE BG CH CY CZ DE DK EE ES FI FR GB GR DK-2200 Copenhagen N (DK) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • DE LEON, Daen SK TR DK-2300 Copenhagen S (DK) Designated Extension States: • KALDOR, Ditte Kievsmose AL BA HR MK RS DK-2880 Bagsvaerd (DK) • SLØK, Frank Abilgaard (30) Priority: 01.12.2005 DK 200501704 DK-3450 Allerød (DK) 02.12.2005 US 741490 P • HUSEMOEN, Birgitte Nystrup DK-2500 Valby (DK) (43) Date of publication of application: • DOLBERG, Johannes 20.08.2008 Bulletin 2008/34 DK-1674 Copenhagen V (DK) • JENSEN, Kim Birkebæk (73) Proprietor: Nuevolution A/S DK-2610 Rødovre (DK) 2100 Copenhagen 0 (DK) • PETERSEN, Lene DK-2100 Copenhagen Ø (DK) (72) Inventors: • NØRREGAARD-MADSEN, Mads • FRANCH, Thomas DK-3460 Birkerød (DK) DK-3070 Snekkersten (DK) • GODSKESEN,
    [Show full text]
  • Significance of Urinary Hydroxyproline in Man
    SIGNIFICANCE OF URINARY HYDROXYPROLINE IN MAN Darwin J. Prockop, Albert Sjoerdsma J Clin Invest. 1961;40(5):843-849. https://doi.org/10.1172/JCI104318. Find the latest version: https://jci.me/104318/pdf SIGNIFICANCE OF URINARY HYDROXYPROLINE IN MAN By DARWIN J. PROCKOP AND ALBERT SJOERDSMA (From the Section of Experimental Therapeutics, National Heart Institute, Bethesda, Md.) (Submitted for publication September 27, 1960; accepted January 12, 1961) Since nearly all of the hydroxyproline of the of Marfan's syndrome (2) reflect a rapid rate of body is found in collagen, it has been suggested collagen degradation. (1, 2) that the urinary excretion of this imino An incidental discovery in the study was that acid may be an important index of collagen me- the increase in urinary hydroxyproline after in- tabolism. The origin of urinary hydroxyproline, gestion of gelatin represents an increased excre- however, is not definitely established. The iso- tion of hydroxyproline peptides. This appears to topic studies of Stetten (3) in rats indirectly sug- be the first demonstration that significant amounts gested that most of the free and peptide hydroxy- of peptides can be excreted following ingestion of proline in the body arises from the breakdown of a protein. collagen, since she found that hydroxyproline-N'5 was not significantly incorporated into collagen. MATERIALS AND METHODS Ziff, Kibrick, Dresner and Gribetz (1), on the The 8 subjects utilized in the study were hospitalized other hand, observed an increased excretion of for periods of 3 to 12 weeks; 3 were patients with Mar- hydroxyproline when it was added to the diet of fan's syndrome, 2 of whom were previously shown to have elevated excretions of hydroxyproline (2).
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2007/0254315 A1 Cox Et Al
    US 20070254315A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0254315 A1 Cox et al. (43) Pub. Date: Nov. 1, 2007 (54) SCREENING FOR NEUROTOXIC AMINO (60) Provisional application No. 60/494.686, filed on Aug. ACID ASSOCATED WITH NEUROLOGICAL 12, 2003. DSORDERS Publication Classification (75) Inventors: Paul A. Cox, Provo, UT (US); Sandra A. Banack, Fullerton, CA (US); Susan (51) Int. Cl. J. Murch, Cambridge (CA) GOIN 33/566 (2006.01) GOIN 33/567 (2006.01) Correspondence Address: (52) U.S. Cl. ............................................................ 435/721 PILLSBURY WINTHROP SHAW PITTMAN LLP (57) ABSTRACT ATTENTION: DOCKETING DEPARTMENT Methods for screening for neurological disorders are dis P.O BOX 105OO closed. Specifically, methods are disclosed for screening for McLean, VA 22102 (US) neurological disorders in a Subject by analyzing a tissue sample obtained from the subject for the presence of (73) Assignee: THE INSTITUTE FOR ETHNO elevated levels of neurotoxic amino acids or neurotoxic MEDICINE, Provo, UT derivatives thereof associated with neurological disorders. In particular, methods are disclosed for diagnosing a neu (21) Appl. No.: 11/760,668 rological disorder in a subject, or predicting the likelihood of developing a neurological disorder in a Subject, by deter (22) Filed: Jun. 8, 2007 mining the levels of B-N-methylamino-L-alanine (BMAA) Related U.S. Application Data in a tissue sample obtained from the subject. Methods for screening for environmental factors associated with neuro (63) Continuation of application No. 10/731,411, filed on logical disorders are disclosed. Methods for inhibiting, treat Dec. 8, 2003, now Pat. No. 7,256,002.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Splicing-Correcting Therapeutic Approaches for Retinal Dystrophies: Where Endogenous Gene Regulation and Specificity Matter
    New Developments Splicing-Correcting Therapeutic Approaches for Retinal Dystrophies: Where Endogenous Gene Regulation and Specificity Matter Niccolo` Bacchi,1 Simona Casarosa,1,2 and Michela A. Denti1,3 1Centre for Integrative Biology (CIBIO) - University of Trento, Trento, Italy 2Neuroscience Institute - National Research Council (CNR), Pisa, Italy 3Neuroscience Institute - National Research Council (CNR), Padova, Italy Correspondence: Simona Casarosa, Splicing is an important and highly regulated step in gene expression. The ability to modulate Centre for Integrative Biology it can offer a therapeutic option for many genetic disorders. Antisense-mediated splicing- (CIBIO) - University of Trento, Via correction approaches have recently been successfully exploited for some genetic diseases, Sommarive 9, 38123 Trento, Italy; and are currently demonstrating safety and efficacy in different clinical trials. Their [email protected]. application for the treatment of retinal dystrophies could potentially solve a vast panel of Michela A. Denti, Centre for Inte- grative Biology (CIBIO) - University cases, as illustrated by the abundance of mutations that could be targeted and the versatility of ofTrento,ViaSommarive9,38123 the technique. In this review, we will give an insight of the different therapeutic strategies, Trento, Italy; focusing on the current status of their application for retinal dystrophies. [email protected]. Keywords: splicing correction, antisense oligonucleotides, retinal dystrophy, gene therapy SC and MAD contributed equally to the work presented here and should therefore be regarded as equivalent authors. Submitted: April 8, 2014 Accepted: April 11, 2014 Citation: Bacchi N, Casarosa S, Denti MA. Splicing-correcting therapeutic approaches for retinal dystrophies: where endogenous gene regulation and specificity matter. Invest Oph- thalmol Vis Sci.
    [Show full text]
  • Ciliopathies Gene Panel
    Ciliopathies Gene Panel Contact details Introduction Regional Genetics Service The ciliopathies are a heterogeneous group of conditions with considerable phenotypic overlap. Levels 4-6, Barclay House These inherited diseases are caused by defects in cilia; hair-like projections present on most 37 Queen Square cells, with roles in key human developmental processes via their motility and signalling functions. Ciliopathies are often lethal and multiple organ systems are affected. Ciliopathies are London, WC1N 3BH united in being genetically heterogeneous conditions and the different subtypes can share T +44 (0) 20 7762 6888 many clinical features, predominantly cystic kidney disease, but also retinal, respiratory, F +44 (0) 20 7813 8578 skeletal, hepatic and neurological defects in addition to metabolic defects, laterality defects and polydactyly. Their clinical variability can make ciliopathies hard to recognise, reflecting the ubiquity of cilia. Gene panels currently offer the best solution to tackling analysis of genetically Samples required heterogeneous conditions such as the ciliopathies. Ciliopathies affect approximately 1:2,000 5ml venous blood in plastic EDTA births. bottles (>1ml from neonates) Ciliopathies are generally inherited in an autosomal recessive manner, with some autosomal Prenatal testing must be arranged dominant and X-linked exceptions. in advance, through a Clinical Genetics department if possible. Referrals Amniotic fluid or CV samples Patients presenting with a ciliopathy; due to the phenotypic variability this could be a diverse set should be sent to Cytogenetics for of features. For guidance contact the laboratory or Dr Hannah Mitchison dissecting and culturing, with ([email protected]) / Prof Phil Beales ([email protected]) instructions to forward the sample to the Regional Molecular Genetics Referrals will be accepted from clinical geneticists and consultants in nephrology, metabolic, laboratory for analysis respiratory and retinal diseases.
    [Show full text]
  • Amino Acids by GRAHAM C
    1 Amino Acids BY GRAHAM C. BARRETT 1 Introduction The literature of 1996 is covered in this Chapter, which aims to report and appraise newly-published knowledge of the chemistry of amino acids. Biological aspects are given prominence only where the chemical interest is enhanced by explaining the life science context. Literature citations forming the basis for this Chapter have been obtained from Chemical Abstracts (Volume 124, Issue no. 11 to Volume 126, Issue no. 9 inclusive), and from papers consulted in major Journals that have consistently been used by authors of relevant material. The expanding volume of the relevant literature continues to demand ingenuity in somehow getting a litre of wholesome nourishment into the half-litre pot that this Chapter represents, and restrictions have been placed on citations of the patent literature and material of a more routine nature. Authors who repeat- publish and over-fragment their material are responsible to a significant extent for the ever-increasing number of references for this Chapter, and this Reviewer’s conscience rests easily when grouping such papers together without detailed comment on each of them. As usual, the carboxylic acid grouping is understood to be implied by the term ‘amino acid’ for the purposes of this Chapter, though interest in boron and phosphorus oxy-acid analogues and also in sulfonic acid analogues, is continuing to grow. Methods applicable .for the synthesis of a-aminoalkaneboronic acids (Refs. 65, 146, 147), a-aminoalkanesulfonic acids (Refs. 154, 845), and a- aminoalkanephosphonic acids and other phosphorus oxyacids (Refs. 32, 62, 80, 82, 85, 87, 88, 152, 326, 374, 437, 843) are usually derived from extensions of standard methods in the amino acid field, and representative examples of syntheses of amino oxyacid analogues are described, side-by-side with corresponding methods for amino carboxylic acids, in appropriate locations in this Chapter.
    [Show full text]
  • Interpretive Guide for Amino Acids
    Interpretive Guide for Amino Acids Intervention Options LOW HIGH Essential Amino Acids Arginine (Arg) Arg Mn Histidine (His) Folate, His Isoleucine (Ile) * B6, Check for insulin insensitivity Leucine (Leu) * B6, Check for insulin insensitivity Lysine (Lys) Carnitine Vitamin C, Niacin, B6, Iron, a-KG Methionine(Met) * B6, á-KG, Mg, SAM Phenylalanine (Phe) * Iron,VitaminC,Niacin,LowPhediet Threonine(Thr) * B6, Zn Tryptophan(Trp) Trpor5-HTP Niacin, B6 Valine (Val) * B6, Check for insulin insensitivity Essential Amino Acid Derivatives Neuroendocrine Metabolism y-Aminobutyric Acid (GABA) a-KG, B6 Glycine (Gly) Gly Folate, B6,B2,B5 Serine (Ser) B6, Mn, Folate * Taurine (Tau) Tau, B6 Vit. E, Vit. C, B-Carotene, CoQ10, Lipoate Tyrosine(Tyr) Iron,Tyr,VitaminC,Niacin Cu, Iron, Vitamin C, B6 Ammonia/Energy Metabolism a-Aminoadipic Acid B6, a-KG Asparagine (Asn) Mg Aspartic Acid (Asp) a-KG, B6 Mg, Zn Citrulline (Cit) Mg, Aspartic acid Glutamic Acid (Glu) B6, a-KG Niacin, B6 Glutamine (Gln) a-KG, B6 Ornithine (Orn) Arg Mg, a-KG, B6 Sulfur Metabolism Cystine (Cys) NAC B2 Cystathionine B6 Homocystine (HCys) B6, Folate, B12, Betaine Additional Metabolites a-Amino-N-Butyric Acid a-KG, B6 B6, a-KG Alanine (Ala) * B6 Anserine Zn n-Alanine Lactobacillus and Bifidobacteria, B6 n-Aminoisobutyric Acid B6 Carnosine Zn Ethanolamine Mg Hydroxylysine (HLys) Vitamin C, Iron, a-KG Hydroxyproline (HPro) Vitamin C, Iron, a-KG 1-Methylhistidine Vitamin E, B12, Folate 3-Methylhistidine BCAAs, Vit. E, Vit. C, n-Carotene, CoQ10, Lipoate Phosphoethanolamine (PE) SAM, B12, Folate, Betaine Phosphoserine Mg Proline (Pro) a-KG Vitamin C, Niacin Sarcosine B2 * Use balanced or custom mixtures of essential amino acids Nordic Laboratiroes∙ Nygade 6, 3.sal ∙ 1164 Copenhagen K ∙ DenmarkTel: +45 33 75 1000 ∙ e-mail: [email protected] In association with ©Metametrix, Inc.
    [Show full text]
  • OFD1 and Flotillins Are Integral Components of a Ciliary Signaling Protein Complex Organized by Polycystins in Renal Epithelia and Odontoblasts
    OFD1 and Flotillins Are Integral Components of a Ciliary Signaling Protein Complex Organized by Polycystins in Renal Epithelia and Odontoblasts Stephanie Jerman1, Heather H. Ward2, Rebecca Lee1, Carla A. M. Lopes3, Andrew M. Fry3, Mary MacDougall4, Angela Wandinger-Ness1* 1 Department of Pathology MSC08-4640 and Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America, 2 Department of Internal Medicine, Division of Nephrology MSC10-5550, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America, 3 Department of Biochemistry, University of Leicester, Leicester, United Kingdom, 4 Institute of Oral Health Research & Department of Oral and Maxillofacial Surgery, School of Dentistry, University of Alabama, Birmingham, Alabama, United States of America Abstract Mutation of the X-linked oral-facial-digital syndrome type 1 (OFD1) gene is embryonic lethal in males and results in craniofacial malformations and adult onset polycystic kidney disease in females. While the OFD1 protein localizes to centriolar satellites, centrosomes and basal bodies, its cellular function and how it relates to cystic kidney disease is largely unknown. Here, we demonstrate that OFD1 is assembled into a protein complex that is localized to the primary cilium and contains the epidermal growth factor receptor (EGFR) and domain organizing flotillin proteins. This protein complex, which has similarity to a basolateral adhesion domain formed during cell polarization, also contains the polycystin proteins that when mutant cause autosomal dominant polycystic kidney disease (ADPKD). Importantly, in human ADPKD cells where mutant polycystin-1 fails to localize to cilia, there is a concomitant loss of localization of polycystin-2, OFD1, EGFR and flotillin-1 to cilia.
    [Show full text]
  • Amino Acids by G.C.BARRETT
    1 Amino Acids By G.C.BARRETT 1 Introduction The chemistry and biochemistry of the amino acids as represented in the 1992 literature, is covered in this Chapter. The usual policy for this Specialist Periodical Report has been continued, with almost exclusive attention in this Chapter, to the literature covering the natural occurrence, chemistry, and analysis methodology for the amino acids. Routine literature covering the natural distribution of well-known amino acids is excluded. The discussion offered is brief for most of the papers cited, so that adequate commentary can be offered for papers describing significant advances in synthetic methodology and mechanistically-interesting chemistry. Patent literature is almost wholly excluded but this is easily reached through Section 34 of Chemical Abstracts. It is worth noting that the relative number of patents carried in Section 34 of Chemical Abstracts is increasing (e.g. Section 34 of Chem-Abs., 1992, Vol. 116, Issue No. 11 contains 45 patent abstracts, 77 abstracts of papers and reviews), reflecting the perception that amino acids and peptides are capable of returning rich commercial rewards due to their important physiological roles and consequent pharmaceutical status. However, there is no slowing of the flow of journal papers and secondary literature, as far as the amino acids are concerned. The coverage in this Chapter is arranged into sections as used in all previous Volumes of this Specialist Periodical Report, and major Journals and Chemical Abstracts (to Volume 118, issue 11) have
    [Show full text]
  • Ratio of Phosphate to Amino Acids
    National Institute for Health and Care Excellence Final Neonatal parenteral nutrition [D10] Ratio of phosphate to amino acids NICE guideline NG154 Evidence reviews February 2020 Final These evidence reviews were developed by the National Guideline Alliance which is part of the Royal College of Obstetricians and Gynaecologists FINAL Error! No text of specified style in document. Disclaimer The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian. Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties. NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive.
    [Show full text]
  • Conditioning Medicine
    Conditioning Medicine www.conditionmed.org REVIEW ARTICLE | OPEN ACCESS A new pharmacological preconditioning-based target: from drosophila to kidney transplantation Michel Tauc1*, Nicolas Melis1*, Miled Bourourou2, Sébastien Giraud3, Thierry Hauet3, and Nicolas Blondeau2 One of the biggest challenges in medicine is to dampen the pathophysiological stress induced by an episode of ischemia. Such stress, due to various pathological or clinical situations, follows a restriction in blood and oxygen supply to tissue, causing a shortage of oxygen and nutrients that are required for cellular metabolism. Ischemia can cause irreversible damage to target tissue leading to a poor physiological recovery outcome for the patient. Contrariwise, preconditioning by brief periods of ischemia has been shown in multiple organs to confer tolerance against subsequent normally lethal ischemia. By definition, preconditioning of organs must be applied preemptively. This limits the applicability of preconditioning in clinical situations, which arise unpredictably, such as myocardial infarction and stroke. There are, however, clinical situations that arise as a result of ischemia-reperfusion injury, which can be anticipated, and are therefore adequate candidates for preconditioning. Organ and more particularly kidney transplantation, the optimal treatment for suitable patients with end stage renal disease (ESRD), is a predictable surgery that permits the use of preconditioning protocols to prepare the organ for subsequent ischemic/reperfusion stress. It therefore seems crucial to develop appropriate preconditioning protocols against ischemia that will occur under transplantation conditions, which up to now mainly referred to mechanical ischemic preconditioning that triggers innate responses. It is not known if preconditioning has to be applied to the donor, the recipient, or both.
    [Show full text]