DOCSLIB.ORG

Biochemical Investigations in the Rare Disease Alkaptonuria: Studies on the Metabolome and the Nature of Ochronotic Pigment

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Biochemical Investigations in the Rare Disease Alkaptonuria: Studies on the Metabolome and the Nature of Ochronotic Pigment Biochemical Investigations in the Rare Disease Alkaptonuria: Studies on the Metabolome and the Nature of Ochronotic Pigment Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor of Philosophy by Brendan Paul Norman September 2019 ACKNOWLEDGEMENTS It is hard to describe the journey this PhD has taken me on without reverting to well-worn clichés. There has been plenty of challenges along the way, but ultimately I can look back on the past four years with a great sense of pride, both in the work presented here and the skills I have developed. Equally important though are the relationships I have established. I have lots of people to thank for playing a part in this thesis. First, I would like to thank my supervisors, Jim Gallagher, Lakshminarayan Ranganath and Norman Roberts for giving me this fantastic opportunity. Your dedication to research into alkaptonuria (AKU) is inspiring and our discussions together have always been thoughtful and often offered fresh perspective on my work. It has been a pleasure to work under your supervision and your ongoing support and encouragement continues to drive me on. It has truly been a pleasure to be part of the AKU research group. Andrew Davison deserves a special mention - much of the highs and lows of our PhD projects have been experienced together. Learning LC-QTOF-MS was exciting (and continues to be) but equally daunting at the start of our projects (admittedly more so for me as a Psychology graduate turned mass spectrometrist!). I am very proud of what we have achieved together, largely starting from scratch on the instrument, and we are continuing to learn all the time. Thank you to the AKU research group more widely, including the AKU Society: to Peter Wilson, Hazel Sutherland, Anna Milan, Juliette Hughes, Jane Dillon, Leah Taylor, George Bou-Gharios, Jonathan Jarvis, Andy Hughes, Milad Khedr and Eman Alawadhi. Thanks to Agilent Technologies for contributing to the funding for this PhD. Special thanks go to Gordon Ross - I have learned so much working under your guidance and expertise throughout this project. Through you and everyone else at Agilent I have always been made to feel very welcome as part of the wider Agilent community. This thesis would not have been possible without the specialist training provided by Gordon and others within the company. I look forward to continuing our collaboration going forward. Thanks also to Hania Khouri and Richard Blankley at Agilent for your kind assistance with technical aspects of the project. I am grateful for the funding from Agilent to attend the 2018 Metabolomics Society conference in Seattle. I must not forget to mention the NMR folks. Thanks to Wing Ying Chow and Marie Phelan for lending their expertise in NMR. I feel the NMR data has added considerable value to the project and I have enjoyed learning about this technique besides MS. I have made friendships that I will never forget during my time in Liverpool. Eddie, Sahem, Pete, Leah, Fran, Mikele and Juliette to name but a few. Not forgetting the Bullring Irish coffee club ft. Dr Craig. We have had some great times together. Thanks to Jaini for putting a roof over my head. Finally, I would like to thank my family and especially mum and dad for your unconditional love and support in everything I do. I hope I can keep on making you proud. i ABSTRACT Alkaptonuria (AKU) is a rare inherited disorder of tyrosine metabolism caused by lack of the enzyme homogentisate 1,2-dioxygenase (HGD). The primary biochemical consequence of HGD deficiency is increased circulating concentration of homogentisic acid (HGA); this is the central cause of the devastating multi-systemic damage observed in AKU. One of the most striking pathophysiological features of AKU is accumulation of ochronotic pigment derived from HGA in tissues throughout the body. HGA has an affinity for cartilaginous tissue. Presence of ochronotic pigment in cartilage of load- bearing joints causes severe early-onset osteoarthropathy; the greatest cause of morbidity in AKU. This thesis addresses two major unanswered questions in AKU. First is the wider metabolic consequences both of HGD deficiency and those observed following treatment with the promising HGA-lowering agent nitisinone. A metabolomics approach was employed to address these questions, with the aim of discovering biomarkers with potential clinical value in monitoring disease in AKU and in assessing the wider metabolic consequences of nitisinone treatment. Second, this thesis explores the nature of ochronotic pigment derived from HGA. The chemical structure of ochronotic pigment is not known, nor are the mechanisms by which HGA interacts with and binds into the cartilage extracellular matrix. Various analytical chemistry techniques were employed to study the chemical properties of ochronotic pigment and pigmented cartilage in patients and mice with AKU. The data from chemical analyses presented in this thesis provide new insights into the nature of ochronotic pigment. The chemical structure of ochronotic pigment remains unknown, but the pigment had long been widely cited as a polymer in the literature. First, these data fundamentally challenge the idea that ochronotic pigment is a polymeric species. Through study of ochronotic tissue samples, the data also indicate for the first time a specific alteration to the cartilage matrix that enables binding of HGA-derived species. An LC-QTOF-MS metabolic phenotyping strategy was developed, enabling identification of hundreds of metabolites simultaneously, based on chemical properties of accurate mass and chromatographic retention time. Application of this technique to AKU showed that the biochemical alterations following a) targeted deletion of the HGD gene in mice to cause AKU, and b) nitisinone treatment, reflect a complex, interconnected network of metabolite changes. The data not only stimulate myriad further lines of research into AKU pathophysiology but also reveal previously uncharacterised association between metabolites at a network level. These studies provide a prime example of how rare diseases such as inborn errors of metabolism can offer unique windows into metabolism and human physiology more generally. ii ABBREVIATIONS 18F-NaF PET 18F-NaF positron emission tomography 3-MT 3-methoxytyramine 5-HIAA 5-hydroxyindoleacetic acid AKU Alkaptonuria AM Accurate mass AMRT Accurate mass - retention time APCI Atmospheric-pressure chemical ionisation BDI-II Beck’s Depression Inventory-II BQA Benzoquinone acetic acid CEF Compound exchange file CID Collision-induced dissociation CNS Central nervous system CP Cross polarisation CSF Cerebrospinal fluid DHMA 3,4-Dihydroxymandelaldehyde DNP Dynamic nuclear polarisation ENU N-ethyl-N-nitrosourea ESI Electrospray ionisation FC Fold change FDA U.S. Food and Drug Administration FSLG Frequency-switched Lee-Goldburg (NMR pulse seq.) FTICR Fourier-transform ion cyclon resonance GAG Glycosaminoglycan GC Gas chromatography HETCOR HETeronuclear CORrelation spectroscopy HGA Homogentisic acid HGD Homogentisate 1,2-dioxygenase HPLA 3-(4-hydroxyphenyl)lactic acid HPPD 4-hydroxyphenylpyruvic acid dioxygenase HSQC Heteronuclear Single Quantum Coherence spectroscopy HT-I Hereditary tyrosinaemia type-I HVA Homovanillic acid INEPT Insensitive Nuclei Enhanced by Polarisation Transfer LC Liquid chromatography LC-QTOF-MS Liquid chromatography quadrupole time-of flight mass spectrometry MA Metadrenaline MALDI Matrix-assisted laser desorption/ionisation MAS Magic angle spinning MHPG 3-methoxy-4-hydroxyphenylglycol MPP Mass Profiler Professional MS Mass spectrometry iii NAC National Alkaptonuria Centre NIH National Institutes of Health NMA Normetadrenaline NMDA N-methyl-D-aspartate NMR Nuclear magnetic resonance NTFA 2-Nitro-4-trifluoromethylbenzoic acid OA Osteoarthritis PBS Phosphate buffered saline PCA Principal components analysis PG Proteoglycan PLS Partial least squares ppm Parts per million QA Quality assurance QC Quality control RA Rheumatoid arthritis RF Radiofrequency RT Retention time ssNMR Solid-state nuclear magnetic resonance TIC Total ion chromatogram TOCSY TOtal Correlation SpectroscopY TOF Time-of-flight iv TABLE OF CONTENTS 1.0 GENERAL INTRODUCTION ........................................................................ 1 1.1.1 AKU is an historic disease .................................................................. 2 1.1.2 The genetic basis of AKU ................................................................... 3 1.1.3 AKU is a disease of tyrosine metabolism ............................................ 4 1.1.4 Clinical presentation of AKU ............................................................... 6 1.1.5 Distribution of ochronosis is not uniform ........................................... 10 1.1.6 Effect of ochronosis .......................................................................... 12 1.1.7 Treatment of AKU ................................................................................ 14 1.1.8 Model systems of AKU .................................................................... 17 1.2 Metabolomics ......................................................................................... 20 1.2.1 The metabolome and metabolomics ................................................. 20 1.2.2 Non-targeted metabolomics: opportunities and challenges ............... 21 1.2.3 LC-QTOF-MS: application to metabolomics ...................................... 27 1.2.4 Metabolomics in the clinical laboratory and its potential
Load more

Recommended publications
  • Melanocytes and Their Diseases
    Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Melanocytes and Their Diseases Yuji Yamaguchi1 and Vincent J. Hearing2 1Medical, AbbVie GK, Mita, Tokyo 108-6302, Japan 2Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 Correspondence: [email protected] Human melanocytes are distributed not only in the epidermis and in hair follicles but also in mucosa, cochlea (ear), iris (eye), and mesencephalon (brain) among other tissues. Melano- cytes, which are derived from the neural crest, are unique in that they produce eu-/pheo- melanin pigments in unique membrane-bound organelles termed melanosomes, which can be divided into four stages depending on their degree of maturation. Pigmentation production is determined by three distinct elements: enzymes involved in melanin synthesis, proteins required for melanosome structure, and proteins required for their trafficking and distribution. Many genes are involved in regulating pigmentation at various levels, and mutations in many of them cause pigmentary disorders, which can be classified into three types: hyperpigmen- tation (including melasma), hypopigmentation (including oculocutaneous albinism [OCA]), and mixed hyper-/hypopigmentation (including dyschromatosis symmetrica hereditaria). We briefly review vitiligo as a representative of an acquired hypopigmentation disorder. igments that determine human skin colors somes can be divided into four stages depend- Pinclude melanin, hemoglobin (red), hemo- ing on their degree of maturation. Early mela- siderin (brown), carotene (yellow), and bilin nosomes, especially stage I melanosomes, are (yellow). Among those, melanins play key roles similar to lysosomes whereas late melanosomes in determining human skin (and hair) pigmen- contain a structured matrix and highly dense tation.
    [Show full text]
  • Cloning, Biochemical Characterization and Inhibition of Alanine Racemase from Streptococcus Iniae
    bioRxiv preprint doi: https://doi.org/10.1101/611251; this version posted April 16, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Cloning, Biochemical Characterization and Inhibition of Alanine racemase from Streptococcus iniae Murtala Muhammad, Yangyang Li, Siyu Gong, Yanmin Shi, Jiansong Ju, Baohua Zhao*, Dong Liu* College of Life Science, Hebei Normal University, Shijiazhuang 050024, China; *Correspondence: Baohua Zhao and Dong Liu; E-mail: [email protected], [email protected]; College of Life Science, Hebei Normal University, Shijiazhuang 050024, China. Running Title: Inhibitors of alanine racemase Summary statement: Antimicrobial target 1 bioRxiv preprint doi: https://doi.org/10.1101/611251; this version posted April 16, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT Streptococcus iniae is a pathogenic and zoonotic bacteria that impacted high mortality to many fish species, as well as capable of causing serious disease to humans. Alanine racemase (Alr, EC 5.1.1.1) is a pyridoxal-5′-phosphate (PLP)-containing homodimeric enzyme that catalyzes the racemization of L-alanine and D-alanine. In this study, we purified alanine racemase from the pathogenic strain of S. iniae, determined its biochemical characteristics and inhibitors. The alr gene has an open reading frame (ORF) of 1107 bp, encoding a protein of 369 amino acids, which has a molecular mass of 40 kDa. The optimal enzyme activity occurred at 35°C and a pH of 9.5.
    [Show full text]
  • University of Cincinnati
    UNIVERSITY OF CINCINNATI Date: August 29, 2006 I, Smita Chawla hereby submit this work as a part of the requirements of the degree of: Doctor of Philosophy (Ph. D.) in: Pharmaceutical Sciences It is entitled: Effect of deoxyArbutin and it’s second-generation derivatives on melanocyte viability and function. on Human Nail Permeabili ty . This work and its defense approved by: R. Randall Wickett, Ph.D., Chair Raymond E. Boissy, Ph.D. William Cacini, Ph.D. Prashiela Manga, Ph.D. Marty O. Visscher, Ph.D. EFFECT OF DEOXYARBUTIN AND ITS SECOND-GENERATION DERIVATIVES ON MELANOCYTE VIABILITY AND FUNCTION A dissertation submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in the Division of Pharmaceutical Sciences of the College of Pharmacy 2006 by Smita Chawla B.S. in Pharmaceutical Sciences Mumbai University, Mumbai, India, 2001 Committee Chair: Randall Wickett, Ph.D. ABSTRACT Therapeutic treatment of skin pigmentary disorders such as melasma, solar lentigines, and post inflammatory hyperpigmentation has been challenging and seldom completely successful. The majority of these therapies target tyrosinase, a key enzyme required for pigment synthesis. The lack of success is due to the less than desired efficacy and safety of tyrosinase inhibitors marketed as skin lightening agents (i.e. hydroquinone, kojic acid and arbutin). We propose that the tyrosinase inhibitor deoxyArbutin (dA) and second-generation derivatives of dA, deoxyFuran, thio-dA, and fluoro-dA, have the potential to be effective inhibitors of skin melanization. In this study, we have analyzed the modulating effects of dA and its derivatives on melanocyte function and viability.
    [Show full text]
  • Gem-Diamine 1-N-Iminosugars As Versatile Glycomimetics: Synthesis, Biological Activity and Therapeutic Potential
    The Journal of Antibiotics (2009) 62, 407–423 & 2009 Japan Antibiotics Research Association All rights reserved 0021-8820/09 $32.00 www.nature.com/ja REVIEW ARTICLE Gem-diamine 1-N-iminosugars as versatile glycomimetics: synthesis, biological activity and therapeutic potential Yoshio Nishimura Iminosugars, which carry a basic nitrogen in the carbohydrate ring, have attracted increasing interest as new glycomimetics. Gem-diamine 1-N-iminosugars, a new class of iminosugars, have a nitrogen atom in place of the anomeric carbon. Various kinds of 1-N-iminosugars have been synthesized from glyconolactones as a chiral source in a totally stereospecific manner and/or by the convergent strategy from siastatin B, a secondary metabolite of Streptomyces. The protonated form of 1-N-iminosugar mimics the charge at the anomeric position in the transition state of enzymatic glycosidic hydrolysis, resulting in a strong and specific inhibition of glycosidases and glycosyltransferases. They have been recently recognized as a new source of therapeutic drug candidates in a wide range of diseases associated with the carbohydrate metabolism of glycoconjugates, such as tumor metastasis, influenza virus infection, lysosomal storage disorder and so forth. The Journal of Antibiotics (2009) 62, 407–423; doi:10.1038/ja.2009.53; published online 3 July 2009 Keywords: glycosidase inhibitor; heparanase inhibitor; influenza virus infection; lysosomal storage disease; 1-N-iminosugar; siastatin B; tumor metastasis INTRODUCTION form of gem-diamine 1-N-iminosugar 6 may mimic the putative Iminosugars, which are carbohydrate analogs that most frequently glycopyranosyl cation 7 that was formed during enzymatic glycosidic carry the nitrogen atom at the position of the endocyclic oxygen, form hydrolysis (Figure 2).
    [Show full text]
  • Heparin - Wikipedia, the Free Encyclopedia
    Heparin - Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Heparin From Wikipedia, the free encyclopedia Heparin (from Ancient Greek ηπαρ (hepar), liver), also Heparin known as unfractionated heparin, a highly-sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule.[1] It can also be used to form an inner anticoagulant surface on various experimental and medical devices such as test tubes and renal dialysis machines. Although used principally in medicine for anticoagulation, the true physiological role in the body remains unclear, because blood anti-coagulation is achieved mostly by heparan sulfate proteoglycans derived from endothelial cells.[2] Heparin is usually stored within the secretory granules of mast cells and released only into the vasculature at sites of tissue injury. It has been proposed that, rather than anticoagulation, the main purpose of heparin is defense at such sites against invading bacteria and other foreign materials.[3] In addition, it is conserved across a number of widely different species, including some invertebrates that do not have a similar blood coagulation system. Systematic (IUPAC) name see Heparin structure Clinical data AHFS/Drugs.com monograph 1 Heparin structure Pregnancy cat. C 1.1 Abbreviations Legal status ? 1.2 Three-dimensional structure Routes i.v., s.c. 2 Medical use Pharmacokinetic data 2.1 Mechanism of Action 2.2 Administration Bioavailability nil 2.3 Production Metabolism hepatic 2.4
    [Show full text]
  • Investigating the Antimicrobial Potential of Thalassomonas
    Investigating the antimicrobial potential of Thalassomonas actiniarum By Fazlin Pheiffer A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy (PhD) Department of Biotechnology, University of the Western Cape Supervisor: Prof Marla Trindade Co-supervisor: Dr Leonardo van Zyl 2020 http://etd.uwc.ac.za/ Declaration Declaration I, Fazlin Pheiffer, hereby declare that ‘Investigating the antimicrobial potential of Thalassomonas actiniarum’ is my own work, that it has not been submitted for any degree or examination in any other university, and that all the sources I have used or quoted have been indicated and acknowledged by complete references. Date: 16 March 2021 Signed: i http://etd.uwc.ac.za/ Abstract Abstract The World Health Organisation predicts that by the year 2050, 10 million people could die annually as a result of infections caused by multidrug resistant bacteria. Individuals with compromised immune systems, caused by underlying disease such as HIV, MTB and COVID-19, are at a greater risk. Antibacterial resistance is a global concern that demands the discovery of novel drugs. Natural products, used since ancient times to treat diseases, are the most successful source of new drug candidates with bioactivities including antibiotic, antifungal, anticancer, antiviral, immunosuppressive, anti-inflammatory and biofilm inhibition. Marine bioprospecting has contributed significantly to the discovery of novel bioactive NPs with unique structures and biological activities, superior to that of compounds from terrestrial origin. Marine invertebrate symbionts are particularly promising sources of marine NPs as the competition between microorganisms associated with invertebrates for space and nutrients is the driving force behind the production of antibiotics, which also constitute pharmaceutically relevant natural products.
    [Show full text]
  • The Cinnamic Acid Pathway and Hispidin Biosynthesis In
    THE CINNAMIC ACID PATHWAY AND HISPIDIN BIOSYNTHESIS IN CULTURES OF POLYPORUS HISPIDUS FRIES by PETER WILLIAM PERRIN B.Sc, University of British Columbia, 1968 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in the Department of Botany We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA September, 1972 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying'of this thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of The University of British Columbia Vancouver 8, Canada Date i ABSTRACT The biosynthesis of hispidin, 6-(3,4-dihydroxystyryl)- 4-hydroxy-2-pyrone, was examined in cultures of Polyporus hispidus Fr. Cultural studies were undertaken to determine the most suitable medium for investigating the biosynthesis of this pigment. These studies showed that light was nec• essary for hispidin formation and that the development of basidiocarps with viable spores could be achieved on agar media. On the liquid medium employed for biochemical studies, the maximum rate of hispidin production was observed to lag the maximum rate of growth by about five days. Trimethylhispidin, 4-methylhispidin and yangonin were synthesized for comparative purposes and for dilution in tracer experiments.
    [Show full text]
  • The Clinical Significance of the Organic Acids Test
    The Clinical Significance of the Organic Acids Test The Organic Acids Test (OAT) provides an accurate metabolic snapshot of what is going on in the body. Besides offering the most complete and accurate evaluation of intestinal yeast and bacteria, it also provides information on important neurotransmitters, nutritional markers, glutathione status, oxalate metabolism, and much more. The test includes 76 urinary metabolite markers that can be very useful for discovering underlying causes of chronic illness. Patients and physicians report that treating yeast and bacterial abnormalities reduces fatigue, increases alertness and energy, improves sleep, normalizes bowel function, and reduces hyperactivity and abdominal pain. The OAT Assists in Evaluating: ■ Krebs Cycle Abnormalities ■ Neurotransmitter Levels ■ Nutritional Deficiencies ■ Antioxidant Deficiencies ■ Yeast and Clostridia Overgrowth ■ Fatty Acid Metabolism ■ Oxalate Levels ■ And More! The OAT Pairs Well with the Following Tests: ■ GPL-TOX: Toxic Non-Metal Chemical Profile ■ IgG Food Allergy + Candida ■ MycoTOX Profile ■ Phospholipase A2 Activity Test Learn how to better integrate the OAT into your practice, along with our other top tests by attending one of our GPL Academy Practitioner Workshops! Visit www.GPLWorkshops.com for workshop dates and locations. The following pages list the 76 metabolite markers of the Organic Acids Test. Included is the name of the metabolic marker, its clinical significance, and usual initial treatment. INTESTINAL MICROBIAL OVERGROWTH Yeast and Fungal Markers Elevated citramalic acid is produced mainly by Saccharomyces species or Propionibacteria Citramalic Acid overgrowth. High-potency, multi-strain probiotics may help rebalance GI flora. A metabolite produced by Aspergillus and possibly other fungal species in the GI tract. 5-Hydroxy-methyl- Prescription or natural antifungals, along with high-potency, multi-strain probiotics, furoic Acid may reduce overgrowth levels.
    [Show full text]
  • Effects of Enzymatic and Thermal Processing on Flavones, the Effects of Flavones on Inflammatory Mediators in Vitro, and the Absorption of Flavones in Vivo
    Effects of enzymatic and thermal processing on flavones, the effects of flavones on inflammatory mediators in vitro, and the absorption of flavones in vivo DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Gregory Louis Hostetler Graduate Program in Food Science and Technology The Ohio State University 2011 Dissertation Committee: Steven Schwartz, Advisor Andrea Doseff Erich Grotewold Sheryl Barringer Copyrighted by Gregory Louis Hostetler 2011 Abstract Flavones are abundant in parsley and celery and possess unique anti-inflammatory properties in vitro and in animal models. However, their bioavailability and bioactivity depend in part on the conjugation of sugars and other functional groups to the flavone core. Two studies were conducted to determine the effects of processing on stability and profiles of flavones in celery and parsley, and a third explored the effects of deglycosylation on the anti-inflammatory activity of flavones in vitro and their absorption in vivo. In the first processing study, celery leaves were combined with β-glucosidase-rich food ingredients (almond, flax seed, or chickpea flour) to determine test for enzymatic hydrolysis of flavone apiosylglucosides. Although all of the enzyme-rich ingredients could convert apigenin glucoside to aglycone, none had an effect on apigenin apiosylglucoside. Thermal stability of flavones from celery was also tested by isolating them and heating at 100 °C for up to 5 hours in pH 3, 5, or 7 buffer. Apigenin glucoside was most stable of the flavones tested, with minimal degradation regardless of pH or heating time.
    [Show full text]
  • Amino Acid Disorders
    471 Review Article on Inborn Errors of Metabolism Page 1 of 10 Amino acid disorders Ermal Aliu1, Shibani Kanungo2, Georgianne L. Arnold1 1Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 2Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI, USA Contributions: (I) Conception and design: S Kanungo, GL Arnold; (II) Administrative support: S Kanungo; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: E Aliu, GL Arnold; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Georgianne L. Arnold, MD. UPMC Children’s Hospital of Pittsburgh, 4401 Penn Avenue, Suite 1200, Pittsburgh, PA 15224, USA. Email: [email protected]. Abstract: Amino acids serve as key building blocks and as an energy source for cell repair, survival, regeneration and growth. Each amino acid has an amino group, a carboxylic acid, and a unique carbon structure. Human utilize 21 different amino acids; most of these can be synthesized endogenously, but 9 are “essential” in that they must be ingested in the diet. In addition to their role as building blocks of protein, amino acids are key energy source (ketogenic, glucogenic or both), are building blocks of Kreb’s (aka TCA) cycle intermediates and other metabolites, and recycled as needed. A metabolic defect in the metabolism of tyrosine (homogentisic acid oxidase deficiency) historically defined Archibald Garrod as key architect in linking biochemistry, genetics and medicine and creation of the term ‘Inborn Error of Metabolism’ (IEM). The key concept of a single gene defect leading to a single enzyme dysfunction, leading to “intoxication” with a precursor in the metabolic pathway was vital to linking genetics and metabolic disorders and developing screening and treatment approaches as described in other chapters in this issue.
    [Show full text]
  • Recent Developments in Identification of Genuine Odor- and Taste-Active Compounds in Foods
    Recent Developments in Identification of Genuine Odor- and Taste-Active Compounds in Foods Edited by Remedios Castro-Mejías and Enrique Durán-Guerrero Printed Edition of the Special Issue Published in Foods www.mdpi.com/journal/foods Recent Developments in Identification of Genuine Odor- and Taste-Active Compounds in Foods Recent Developments in Identification of Genuine Odor- and Taste-Active Compounds in Foods Editors Remedios Castro-Mej´ıas Enrique Dur´an-Guerrero MDPI Basel Beijing Wuhan Barcelona Belgrade Manchester Tokyo Cluj Tianjin • • • • • • • • • Editors Remedios Castro-Mej´ıas Enrique Duran-Guerrero´ Analytical Chemistry Analytical Chemistry Universidad de Cadiz´ Department Puerto Real University of Cadiz Spain Puerto Real Spain Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Foods (ISSN 2304-8158) (available at: www.mdpi.com/journal/foods/special issues/Recent Developments Identification Genuine Odor- Taste-Active Compounds Foods). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Volume Number, Page Range. ISBN 978-3-0365-1668-4 (Hbk) ISBN 978-3-0365-1667-7 (PDF) © 2021 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2007/0143878 A1 Bhat Et Al
    US 20070143878A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0143878 A1 Bhat et al. (43) Pub. Date: Jun. 21, 2007 (54) NUCLEC ACID MOLECULES AND OTHER of application No. 09/198.779, filed on Nov. 24, 1998, MOLECULES ASSOCATED WITH THE now abandoned. TOCOPHEROL PATHWAY Said application No. 09/233,218 is a continuation-in part of application No. 09/227,586, filed on Jan. 8, (76) Inventors: Barkur G. Bhat, St. Louis, MO (US); 1999, now abandoned. Sekhar S. Boddupalli, Manchester, MO Said application No. 09/233,218 is a continuation-in (US); Ganesh M. Kishore, Creve part of application No. 09/229,413, filed on Jan. 12, Coeur, MO (US); Jingdong Liu, 1999, now abandoned. Ballwin, MO (US); Shaukat H. Rangwala, Ballwin, MO (US); (60) Provisional application No. 60/067,000, filed on Nov. Mylavarapu Venkatramesh, Ballwin, 24, 1997. Provisional application No. 60/066,873, MO (US) filed on Nov. 25, 1997. Provisional application No. 60/069.472, filed on Dec. 9, 1997. Provisional appli Correspondence Address: cation No. 60/074,201, filed on Feb. 10, 1998. Pro ARNOLD & PORTER, LLP visional application No. 60/074.282, filed on Feb. 10, 555 TWELFTH STREET, N.W. 1998. Provisional application No. 60/074,280, filed ATTN IP DOCKETING on Feb. 10, 1998. Provisional application No. 60/074, WASHINGTON, DC 20004 (US) 281, filed on Feb. 10, 1998. Provisional application No. 60/074,566, filed on Feb. 12, 1998. Provisional (21) Appl. No.: 11/329,160 application No. 60/074,567, filed on Feb. 12, 1998.
    [Show full text]