Mitochondrial Transport of Protoporphyrinogen IX in Erythroid Cells
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Hyperbilirubinemia
Porphyrins Porphyrins (Porphins) are cyclic tetrapyrol compounds formed by the linkage )). of four pyrrole rings through methenyl bridges (( HC In the reduced porphyrins (Porphyrinogens) the linkage of four pyrrole rings (tetrapyrol) through methylene bridges (( CH2 )) The characteristic property of porphyrins is the formation of complexes with the metal ion bound to nitrogen atoms of the pyrrole rings. e.g. Heme (iron porphyrin). Proteins which contain heme ((hemoproteins)) are widely distributed e.g. Hemoglobin, Myoglobin, Cytochromes, Catalase & Tryptophan pyrrolase. Natural porphyrins have substituent side chains on the eight hydrogen atoms numbered on the pyrrole rings. These side chains are: CH 1-Methyl-group (M)… (( 3 )) 2-Acetate-group (A)… (( CH2COOH )) 3-Propionate-group (P)… (( CH2CH2COOH )) 4-Vinyl-group (V)… (( CH CH2 )) Porphyrins with asymmetric arrangement of the side chains are classified as type III porphyrins while those with symmetric arrangement of the side chains are classified as type I porphyrins. Only types I & III are present in nature & type III series is more important because it includes heme. 1 Heme Biosynthesis Heme biosynthesis occurs through the following steps: 1-The starting reaction is the condensation between succinyl-CoA ((derived from citric acid cycle in the mitochondria)) & glycine, this reaction is a rate limiting reaction in the hepatic heme synthesis, it occurs in the mitochondria & is catalyzed by ALA synthase (Aminolevulinate synthase) enzyme in the presence of pyridoxal phosphate as a cofactor. The product of this reaction is α-amino-β-ketoadipate which is rapidly decarboxylated to form δ-aminolevulinate (ALA). 2-In the cytoplasm condensation reaction between two molecules of ALA is catalyzed by ALA dehydratase enzyme to form two molecules of water & one 2 molecule of porphobilinogen (PBG) which is a precursor of pyrrole. -
Noncanonical Coproporphyrin-Dependent Bacterial Heme Biosynthesis Pathway That Does Not Use Protoporphyrin
Noncanonical coproporphyrin-dependent bacterial heme biosynthesis pathway that does not use protoporphyrin Harry A. Daileya,b,c,1, Svetlana Gerdesd, Tamara A. Daileya,b,c, Joseph S. Burcha, and John D. Phillipse aBiomedical and Health Sciences Institute and Departments of bMicrobiology and cBiochemistry and Molecular Biology, University of Georgia, Athens, GA 30602; dMathematics and Computer Science Division, Argonne National Laboratory, Argonne, IL 60439; and eDivision of Hematology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132 Edited by J. Clark Lagarias, University of California, Davis, CA, and approved January 12, 2015 (received for review August 25, 2014) It has been generally accepted that biosynthesis of protoheme of a “primitive” pathway in Desulfovibrio vulgaris (13). This path- (heme) uses a common set of core metabolic intermediates that way, named the “alternative heme biosynthesis” path (or ahb), has includes protoporphyrin. Herein, we show that the Actinobacteria now been characterized by Warren and coworkers (15) in sulfate- and Firmicutes (high-GC and low-GC Gram-positive bacteria) are reducing bacteria. In the ahb pathway, siroheme, synthesized unable to synthesize protoporphyrin. Instead, they oxidize copro- from uroporphyrinogen III, can be further metabolized by suc- porphyrinogen to coproporphyrin, insert ferrous iron to make Fe- cessive demethylation and decarboxylation to yield protoheme (14, coproporphyrin (coproheme), and then decarboxylate coproheme 15) (Fig. 1 and Fig. S1). A similar pathway exists for protoheme- to generate protoheme. This pathway is specified by three genes containing archaea (15, 16). named hemY, hemH, and hemQ. The analysis of 982 representa- Current gene annotations suggest that all enzymes for pro- tive prokaryotic genomes is consistent with this pathway being karyotic heme synthetic pathways are now identified. -
A Primitive Pathway of Porphyrin Biosynthesis and Enzymology in Desulfovibrio Vulgaris
Proc. Natl. Acad. Sci. USA Vol. 95, pp. 4853–4858, April 1998 Biochemistry A primitive pathway of porphyrin biosynthesis and enzymology in Desulfovibrio vulgaris TETSUO ISHIDA*, LING YU*, HIDEO AKUTSU†,KIYOSHI OZAWA†,SHOSUKE KAWANISHI‡,AKIRA SETO§, i TOSHIRO INUBUSHI¶, AND SEIYO SANO* Departments of *Biochemistry and §Microbiology and ¶Division of Biophysics, Molecular Neurobiology Research Center, Shiga University of Medical Science, Seta, Ohtsu, Shiga 520-21, Japan; †Department of Bioengineering, Faculty of Engineering, Yokohama National University, 156 Tokiwadai, Hodogaya-ku, Yokohama 240, Japan; and ‡Department of Public Health, Graduate School of Medicine, Kyoto University, Sakyou-ku, Kyoto 606, Japan Communicated by Rudi Schmid, University of California, San Francisco, CA, February 23, 1998 (received for review March 15, 1998) ABSTRACT Culture of Desulfovibrio vulgaris in a medium billion years ago (3). Therefore, it is important to establish the supplemented with 5-aminolevulinic acid and L-methionine- biosynthetic pathway of porphyrins in D. vulgaris, not only methyl-d3 resulted in the formation of porphyrins (sirohydro- from the biochemical point of view, but also from the view- chlorin, coproporphyrin III, and protoporphyrin IX) in which point of molecular evolution. In this paper, we describe a the methyl groups at the C-2 and C-7 positions were deuter- sequence of intermediates in the conversion of uroporphy- ated. A previously unknown hexacarboxylic acid was also rinogen III to coproporphyrinogen III and their stepwise isolated, and its structure was determined to be 12,18- enzymic conversion. didecarboxysirohydrochlorin by mass spectrometry and 1H NMR. These results indicate a primitive pathway of heme biosynthesis in D. vulgaris consisting of the following enzy- MATERIALS AND METHODS matic steps: (i) methylation of the C-2 and C-7 positions of Materials. -
Significance of Heme and Heme Degradation in the Pathogenesis Of
International Journal of Molecular Sciences Review Significance of Heme and Heme Degradation in the Pathogenesis of Acute Lung and Inflammatory Disorders Stefan W. Ryter Proterris, Inc., Boston, MA 02118, USA; [email protected] Abstract: The heme molecule serves as an essential prosthetic group for oxygen transport and storage proteins, as well for cellular metabolic enzyme activities, including those involved in mitochondrial respiration, xenobiotic metabolism, and antioxidant responses. Dysfunction in both heme synthesis and degradation pathways can promote human disease. Heme is a pro-oxidant via iron catalysis that can induce cytotoxicity and injury to the vascular endothelium. Additionally, heme can modulate inflammatory and immune system functions. Thus, the synthesis, utilization and turnover of heme are by necessity tightly regulated. The microsomal heme oxygenase (HO) system degrades heme to carbon monoxide (CO), iron, and biliverdin-IXα, that latter which is converted to bilirubin-IXα by biliverdin reductase. Heme degradation by heme oxygenase-1 (HO-1) is linked to cytoprotection via heme removal, as well as by activity-dependent end-product generation (i.e., bile pigments and CO), and other potential mechanisms. Therapeutic strategies targeting the heme/HO-1 pathway, including therapeutic modulation of heme levels, elevation (or inhibition) of HO-1 protein and activity, and application of CO donor compounds or gas show potential in inflammatory conditions including sepsis and pulmonary diseases. Keywords: acute lung injury; carbon monoxide; heme; heme oxygenase; inflammation; lung dis- ease; sepsis Citation: Ryter, S.W. Significance of Heme and Heme Degradation in the Pathogenesis of Acute Lung and Inflammatory Disorders. Int. J. Mol. 1. Introduction Sci. -
The Function of PROTOPORPHYRINOGEN IX OXIDASE in Chlorophyll Biosynthesis Requires Oxidised Plastoquinone in Chlamydomonas Reinh
The function of PROTOPORPHYRINOGEN IX OXIDASE in chlorophyll biosynthesis requires oxidised plastoquinone in Chlamydomonas reinhardtii Pawel Brzezowski, Brigitte Ksas, Michel Havaux, Bernhard Grimm, Marie Chazaux, Gilles Peltier, Xenie Johnson, Jean Alric To cite this version: Pawel Brzezowski, Brigitte Ksas, Michel Havaux, Bernhard Grimm, Marie Chazaux, et al.. The function of PROTOPORPHYRINOGEN IX OXIDASE in chlorophyll biosynthesis requires oxidised plastoquinone in Chlamydomonas reinhardtii. Communications Biology, Nature Publishing Group, 2019, 2, pp.159. 10.1038/s42003-019-0395-5. cea-02149191 HAL Id: cea-02149191 https://hal-cea.archives-ouvertes.fr/cea-02149191 Submitted on 6 Jun 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License ARTICLE https://doi.org/10.1038/s42003-019-0395-5 OPEN The function of PROTOPORPHYRINOGEN IX OXIDASE in chlorophyll biosynthesis requires oxidised plastoquinone in Chlamydomonas reinhardtii 1234567890():,; Pawel Brzezowski 1,2, Brigitte Ksas3, Michel Havaux3, Bernhard Grimm2, Marie Chazaux1, Gilles Peltier1, Xenie Johnson 1 & Jean Alric 1 In the last common enzymatic step of tetrapyrrole biosynthesis, prior to the branching point leading to the biosynthesis of heme and chlorophyll, protoporphyrinogen IX (Protogen) is oxidised to protoporphyrin IX (Proto) by protoporphyrinogen IX oxidase (PPX). -
PPO-Inhibiting Herbicides and Structurally Relevant Schiff Bases: Evaluation of Inhibitory Activities Against Human Protoporphyrinogen Oxidase
processes Article PPO-Inhibiting Herbicides and Structurally Relevant Schiff Bases: Evaluation of Inhibitory Activities against Human Protoporphyrinogen Oxidase Milan Jakubek 1,2,3 , Michal Masaˇrík 1,2,4,5, Tomáš Bˇríza 1,2,3, Robert Kaplánek 1,2,3 , KateˇrinaVeselá 1,2,3, Nikita Abramenko 1 and Pavel Martásek 1,* 1 Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 121 08 Prague, Czech Republic; [email protected] (M.J.); [email protected] (M.M.); [email protected] (T.B.); [email protected] (R.K.); [email protected] (K.V.); [email protected] (N.A.) 2 BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic 3 Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, 166 28 Prague, Czech Republic 4 Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic 5 Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic * Correspondence: [email protected] Abstract: The study of human protoporphyrinogen oxidase (hPPO) inhibition can contribute signif- icantly to a better understanding of some pathogeneses (e.g., porphyria, herbicide exposure) and the development of anticancer agents. Therefore, we prepared new potential inhibitors with Schiff Citation: Jakubek, M.; Masaˇrík,M.; base structural motifs (2-hydroxybenzaldehyde-based Schiff bases 9–13 and chromanone derivatives Bˇríza,T.; Kaplánek, R.; Veselá, K.; 17–19) as structurally relevant to PPO herbicides. The inhibitory activities (represented by the half Abramenko, N.; Martásek, P. -
Conversion of Amino Acids to Specialized Products
Conversion of Amino Acids to Specialized Products First Lecture Second lecture Fourth Lecture Third Lecture Structure of porphyrins Porphyrins are cyclic compounds that readily bind metal ions (metalloporphyrins)—usually Fe2+ or Fe3+. Porphyrins vary in the nature of the side chains that are attached to each of the four pyrrole rings. - - Uroporphyrin contains acetate (–CH2–COO )and propionate (–CH2–CH2–COO ) side chains; Coproporphyrin contains methyl (–CH3) and propionate groups; Protoporphyrin IX (and heme) contains vinyl (–CH=CH2), methyl, and propionate groups Structure of Porphyrins Distribution of side chains: The side chains of porphyrins can be ordered around the tetrapyrrole nucleus in four different ways, designated by Roman numerals I to IV. Only Type III porphyrins, which contain an asymmetric substitution on ring D are physiologically important in humans. Physiologically important In humans Heme methyl vinyl 1) Four Pyrrole rings linked together with methenyle bridges; 2) Three types of side chains are attached to the rings; arrangement of these side chains determines the activity; 3) Asymmetric molecule 3) Porphyrins bind metal ions to form metalloporphyrins. propionyl Heme is a prosthetic group for hemoglobin, myoglobin, the cytochromes, catalase and trptophan pyrrolase Biosynthesis of Heme The major sites of heme biosynthesis are the liver, which synthesizes a number of heme proteins (particularly cytochrome P450), and the erythrocyte-producing cells of the bone marrow, which are active in hemoglobin synthesis. Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic group on enzymes and electron transport chain. The initial reaction and the last three steps in the formation of porphyrins occur in mitochondria, whereas the intermediate steps of the biosynthetic pathway occur in the cytosol. -
Abdulrahem Batool Bdour
34 Batool bdour Abdulrahem ... Diala Abu-Hassan Hello there, in this lecture we’ll talk about Heme, the irony unit in the heart of a number of proteins, stay tuned! It’s going to get colorful towards the end. Amino acids are used to synthesize a variety of other molecules with specialized functions. And today we’ll talk about ◆ Porphyrins’ structure: It’s a cyclic structure composed of four pyrrole rings, connected This is a pyrrole ring together. In each ring there’s a nitrogen towards the center of with 2 side chains porphyrin structure and there are two side chains coming out from each ring. Heme: Is a porphyrin with a ferrous atom (Fe2+) in the middle. It’s the most prevalent metalloporphyrin in humans. Heme is found in hemoglobin, myoglobin, the cytochromes, catalase, nitric oxide synthase, and peroxidase. Hemeproteins are rapidly synthesized and degraded. 6–7g of hemoglobin are synthesized each day to replace heme lost through the normal turnover of erythrocytes Porphyrins differ from each other in the side chains that come out of the pyrrole ring and the order or distribution of these side chains. Side chains Example: On the sides of this box, we have the structures of two porphyrins: uroporphyrin I & uroporphyrin III. There are two types of side chains that are repeated on each pyrrole ring, designated A and P which stand for acetate and propionate. How to differentiate between these two porphyrins? we look at the order of these side chains. On A, B & C pyrroles of both porphyrins, A and P Uroporphyrin I (1) are in the order A-P/A-P/A-P. -
Protoporphyrinogen Oxidase Inhibitor: an Ideal Target for Herbicide Discovery
CHEMISTRY IN CHINA CHIMIA 2011, 65, No. 12 961 doi:10.2533/chimia.2011.961 Chimia 65 (2011) 961–969 © Schweizerische Chemische Gesellschaft Protoporphyrinogen Oxidase Inhibitor: An Ideal Target for Herbicide Discovery Ge-Fei Hao, Yang Zuo, Sheng-Gang Yang, and Guang-Fu Yang* Abstract: As the last common enzyme in the biosynthetic pathway leading to heme and chlorophyll, protoporphyrinogen oxidase (PPO; EC 1.3.3.4) is an ideal target for herbicide development. Currently, about 30 PPO inhibitors have been developed as agricultural herbicides. PPO inhibitors have displayed environmentally benign, but advantageous characteristics, including low toxicity, low effective concentration, broad herbicidal spectrum (active against both monocotyledon and dicotyledon weeds), quick onset of action, and long lasting effect. Over the last several years, great achievements have been made in revealing the structural biology of PPO. Five PPO crystal structures, four isolated in enzyme-inhibitor complexes and one in the native form, have been determined, including those from Nicotiana tabacum, Myxococcus Xanthus, Bacillus subtilis, and human. Although PPO inhibitors have been developed for over forty years, we continue to uncover exciting future prospects for novel PPO-inhibiting herbicides. In this review, we have summarized the structures of PPOs from plants, human, and bacteria; the interactions between PPOs and inhibitors; the quantitative structure–activity relationships of PPO inhibitors; and the molecular design of new PPO inhibitors. Keywords: Herbicide · Inhibitor · Molecular design · Protoporphyrinogen oxidase · QSAR associate Professor in 1998 and Professor protoporphyrin IX (Scheme 1). PPO has in 2001. Since 2002, he was selected as been found in mammals, plants, fungi, and the Dean of College of Chemistry, Central bacteria. -
Analysis of Heme Biosynthetic Pathways in a Recombinant Escherichia Coli S Stephanie Pranawidjaja1,2, Su-In Choi1, Bibiana W
J. Microbiol. Biotechnol. (2015), 25(6), 880–886 http://dx.doi.org/10.4014/jmb.1411.11050 Research Article Review jmb Analysis of Heme Biosynthetic Pathways in a Recombinant Escherichia coli S Stephanie Pranawidjaja1,2, Su-In Choi1, Bibiana W. Lay2, and Pil Kim1* 1Department of Biotechnology, the Catholic University of Korea, Bucheon 420-742, Republic of Korea 2Faculty of Biotechnology, Atma Jaya Catholic University of Indonesia, Jakarta Selatan 12930, Indonesia Received: November 18, 2014 Revised: December 18, 2014 Bacterial heme was produced from a genetic-engineered Escherichia coli via the porphyrin Accepted: December 22, 2014 pathway and it was useful as an iron resource for animal feed. The amount of the E. coli- synthesized heme, however, was only few milligrams in a culture broth and it was not enough for industrial applications. To analyze heme biosynthetic pathways, an engineered E. coli First published online artificially overexpressing ALA synthase (hemA from Rhodobacter sphaeroides) and pantothenate December 24, 2014 kinase (coaA gene from self geneome) was constructed as a bacterial heme-producing strain, *Corresponding author and both the transcription levels of pathway genes and the intermediates concentrations were Phone: +82-2-2164-4922; determined from batch and continuous cultures. Transcription levels of the pathway genes Fax: +82-2-2164-4865; were not significantly changed among the tested conditions. Intracellular intermediate E-mail: [email protected] concentrations indicated that aminolevulinic acid (ALA) and coenzyme A (CoA) were enhanced by the hemA-coaA co-expression. Intracellular coproporphyrinogen I and protoporphyrin IX accumulation suggested that the bottleneck steps in the heme biosynthetic S upplementary data for this paper are available on-line only at pathway could be the spontaneous conversion of HMB to coproporphyrinogen I and the http://jmb.or.kr. -
Kent Academic Repository Full Text Document (Pdf)
Kent Academic Repository Full text document (pdf) Citation for published version Dailey, Harry A. and Dailey, Tamara A. and Gerdes, Svetlana and Jahn, Dieter and Jahn, Martina and O'Brian, Mark R. and Warren, Martin J. (2017) Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product. Review of: Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product by UNSPECIFIED. Microbiology and Molecular DOI https://doi.org/10.1128/MMBR.00048-16 Link to record in KAR http://kar.kent.ac.uk/60615/ Document Version Publisher pdf Copyright & reuse Content in the Kent Academic Repository is made available for research purposes. Unless otherwise stated all content is protected by copyright and in the absence of an open licence (eg Creative Commons), permissions for further reuse of content should be sought from the publisher, author or other copyright holder. Versions of research The version in the Kent Academic Repository may differ from the final published version. Users are advised to check http://kar.kent.ac.uk for the status of the paper. Users should always cite the published version of record. Enquiries For any further enquiries regarding the licence status of this document, please contact: [email protected] If you believe this document infringes copyright then please contact the KAR admin team with the take-down information provided at http://kar.kent.ac.uk/contact.html REVIEW crossm Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product Downloaded from Harry A. Dailey,a Tamara A. Dailey,a Svetlana Gerdes,b Dieter Jahn,c Martina Jahn,d Mark R. -
Porphyrins; Urine
LAB #: Sample Report CLIENT #: 12345 PATIENT: Sample Patient DOCTOR: Sample Doctor ID: Doctor's Data, Inc. SEX: Female 3755 Illinois Ave. AGE: 26 St. Charles, IL 60174 U.S.A. !!"#$%&#'()*+,#'(- PORPHYRINS RESULT REFERENCE PERCENTILE nmol/g creatinine INTERVAL 95th 99th Uroporphyrins 69 < 20 Heptacarboxylporphyrins 2.6 < 4 Hexacarboyxlporphyrins 0.94 < 3.5 Pentacarboxylporphyrins 1.4 < 3 Coproporphyrin I 31 < 24 Coproporphyrin III 100 < 70 Coproporphyrin I/Coproporphyrin III 0.3 < 0.8 Total Porphyrins 210 < 110 Precoproporphyrin I* 1.4 < 2 Precoproporphyrin II* 1.7 < 1.2 Precoproporphyrin III* 0 < 1.2 Total Precoproporphyrins* 3.1 < 4 Precoproporphyrins*/Uroporphyrins 0.045 < 0.1 INFORMATION Urinary porphyrins are oxidized intermediate metabolites of heme Porphyrins Pattern Recognition Guide: biosynthesis and can serve as biomarkers of disorders in heme production. Abnormal porphyrin profiles have been associated with genetic disorders, poor nutritional status, oxidative stress, Mercury ↑ Penta, ↑ Copro III, ↑ Precopros, ↑ Precorpros : Uros and high level exposure to toxic chemicals or toxic metals. The ↑ ↑ ratio of Precoproporphyrins-to-Uroporphyrins is reported to Arsenic Uros, Copro I : Copro III increase the sensitivity for detecting abnormalities in individuals Lead ↑ Copro III with low heme biosynthesis. Alcohol, sedatives, analgesics, antibiotics estrogens and oral contraceptives can affect the levels Hexachlorobenzene, Dioxin ↑ Uros of urinary porphyrins. Anemia, pregnancy, and liver disease can Methylchloride, also affect porphyrin