Published on May 23, 2014
PowerPoint Presentation: HAEME SYNTHESIS AND CATABOLISM BY DR MUHAMMAD MUSTANSAR PowerPoint Presentation: Majority of amino acids used for de novo protein synthesis (80%) derives from the degradation of existing proteins Only 30 g (6%) used for synthesis of specialized products Amino Acid Pools are in Steady State PowerPoint Presentation: Only 70 g (14%) of total amino acid utilization is used for energy or stored as glycogen/fatty acids in the well-fed state (nitrogen balance) PowerPoint Presentation: Heme is the most important porphyrin containing compound. Heme is a derivative of the porphyrin. Porphyrins are cyclic compounds formed by fusion of 4 pyrrole rings linked by methenyl (=CH-) bridges. HEME SYNTHESIS PowerPoint Presentation: Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic group on enzymes and electron transport chain. By weight, the major locations of heme synthesis are the liver and the erythroid progenitor cells of the bone marrow. PowerPoint Presentation: Hemoglobin PowerPoint Presentation: HEME-CONTAINING PROTEINS Hemoglobin Myoglobin Cytochromes Catalase Some peroxidases PowerPoint Presentation: Metal ions can bind with nitrogen atoms of pyrrole rings to form complexes. Since an atom of iron is present, heme is a ferroprotoporphyrin. The pyrrole rings are named as l, ll, lll, lV and the bridges as alpha, beta, gamma and delta. PowerPoint Presentation: Porphyrin: Cyclic molecule formed by linkage of four pyrrole rings through methenyl bridges PORPHYRINS Heme structure Heme is a metaloporphyrine (cyclic tetrapyrrole): Heme structure Heme is a metaloporphyrine (cyclic tetrapyrrole) Heme contains: conjugated system of double bonds → red colour 4 nitrogen (N) atoms 1 iron cation (Fe 2+ ) → bound in the middle of tetrapyrrole skelet by coordination covalent bonds methine bridge pyrrole ring PowerPoint Presentation: Hb is a spherical molecule consisting of 4 peptide subunits ( globins ) = quartenary structure Hb of adults (Hb A) is a tetramer consisting of 2 - and 2 β -globins → each globin contains 1 heme group with a central Fe 2+ ion (ferrous ion) Structure of hemoglobin PowerPoint Presentation: NH NH HN HN A B C D A A P A P P P A Uroporphyrinogen III PowerPoint Presentation: NH NH HN HN HOOC-H 2 C- HOOC-H 2 C- -CH 2 -CH 2 -COOH -CH 2 -COOH CH 2 CH 2 COOH CH 2 CH 2 COOH COOH CH 2 CH 2 COOH CH 2 Uroporphyrinogen III PowerPoint Presentation: NH N HN N H 3 C- H 3 C- -CH=CH 2 -CH 3 CH 2 CH 2 COOH CH 2 CH 2 COOH CH 3 Protoporphyrin IX CH=CH 2 PowerPoint Presentation: HEME Fe 2+ chelated by Protoporphyrin IX Assisted by Ferrochelatase CH3- PowerPoint Presentation: COOH CH 2 CH 2 COSCoA CH 2 NH 2 COOH SUCCINYL CoA GLYCINE IN MITOCHONDRIA AMINOLEVULINIC ACID SYNTHASE RATE-CONTROLLING STEP IN HEPATIC HEME SYNTHESIS COOH CH 2 CH 2 C=O CH 2 NH 2 ALA PowerPoint Presentation: REACTIONS FOR PROTOPORPHYRIN IX PowerPoint Presentation: Biosynthesis of Heme Heme can be synthesised by almost all the tissues in the body. Heme is primarily synthesised in the liver and the erythrocyte-producing cells of bone marrow (erythroid cells). Heme is synthesised in the normoblasts, but not in the matured ones. PowerPoint Presentation: The pathway is partly cytoplasmic and partly mitochondrial. Step 1: ALA synthesis The synthesis starts with the condensation of succinyl CoA and glycine in the presence of pyridoxal phosphate to form delta amino levulinic acid (ALA). PowerPoint Presentation: The enzyme ALA synthase is located in the mitochondria and is the rate-limiting enzyme of the pathway. PowerPoint Presentation: Iron atom is co-ordinately linked with 5 nitrogen atoms (4 nitrogen of pyrrole rings of protoporphyrin and 1 st nitrogen atom of a histidine residue of globin). PowerPoint Presentation: SUMMARY OF HEME SYNTHESIS PowerPoint Presentation: STRUCTURE OF HEME Ferrous iron (Fe2+) Protoporphyrin IX: contains 4 pyrrole rings linked together by methenyl bridges PowerPoint Presentation: Heme is the prosthetic group of hemoglobin, myoglobin, & cytochromes. Heme is an asymmetric molecule. E.g., note the positions of methyl side chains around the ring system. PowerPoint Presentation: Heme 8 8 Succinyl CoA Glycine** ** Amino acid (building blocks of protein) synthesized in your body HEME SYNTHESIS PowerPoint Presentation: The liver is the main non-RBC source of heme synthesis Heme produced in the liver is used mainly for the synthesis of the cytochrome P 450 class of enzymes that are involved in detoxification Regulated at level of ALA synthase: Formation of 5-ALA is the rate-limiting step in heme synthesis in the liver HEME SYNTHESIS: Liver HEME SYNTHESIS: Red blood cells: HEME SYNTHESIS: Red blood cells 85% of total heme synthesis occurs in red blood cells (RBC) Ceases when RBC’s mature Heme stimulates protein synthesis in reticulocytes Synthesis is regulated at the level of the enzymes ferrochelatase* and porphobilinogen deaminase** PowerPoint Presentation: Simplified scheme of the formation of erythrocytes PowerPoint Presentation: The heme ring system is synthesized from glycine & succinyl-CoA . Using isotopic tracers, it was initially found that N & C atoms of heme are derived from glycine and acetate. It was later determined that the labeled acetate enters Krebs Cycle as acetyl-CoA, and the labeled carbon becomes incorporated into succinyl-CoA, the more immediate precursor of heme. PowerPoint Presentation: Heme synthesis begins with condensation of glycine & succinyl-CoA, with decarboxylation, to form d-aminolevulinic acid ( ALA ). PowerPoint Presentation: Pyridoxal phosphate (PLP) serves as coenzyme for d-Aminolevulinate Synthase (ALA Synthase), an enzyme evolutionarily related to transaminases. PowerPoint Presentation: Condensation with succinyl-CoA takes place while the amino group of glycine is in Schiff base linkage to the PLP aldehyde. CoA & the glycine carboxyl are lost following the condensation. PowerPoint Presentation: Uroporphyrinogen I Coproporphyrinogen I Overview of Heme Synthesis Succinyl CoA + Glycine -aminolevulinic acid -aminolevulinic acid Porphobilinogen Uroporphyrinogen III Coproporphyrinogen III Coproporphyrinogen III Protoporphyrinogen IX Protoporphyrin IX Heme ALA synthase cytoplasm mitochondrial matrix PowerPoint Presentation: Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic group on enzymes and electron transport chain. By weight, the major locations of heme synthesis are the liver and the erythroid progenitor cells of the bone marrow. PowerPoint Presentation: ALA Synthase is the committed step of the heme synthesis pathway, & is usually rate-limiting for the overall pathway. Regulation occurs through control of gene transcription. Heme functions as a feedback inhibitor, repressing transcription of the ALA Synthase gene in most cells. PowerPoint Presentation: A variant of ALA Synthase expressed only in developing erythrocytes is regulated instead by availability of iron in the form of iron-sulfur clusters.