Heme Metabolism PDF - Almaarefa University

# Heme Metabolism ## Almaarefa University **Nartaqi Ma'a Al-Ma'rifa** ## Objectives - To study Heme Synthesis - To understand the Heme Catabolism in brief - To study the Biochemical Basis and Clinical implications of some examples of Porphyrias - Catabolism of Heme into bilirubin ## Heme is pre...

# Heme Metabolism ## Almaarefa University **Nartaqi Ma'a Al-Ma'rifa** ## Objectives - To study Heme Synthesis - To understand the Heme Catabolism in brief - To study the Biochemical Basis and Clinical implications of some examples of Porphyrias - Catabolism of Heme into bilirubin ## Heme is present in Hemoproteins: | Type of hemoprotein | Main function | |---|---| | Hemoglobin | Oxygen transport in blood | | Myoglobin | Oxygen storage in muscles | | Cytochromes | Electron transport in respiratory chain | | Cytochrome P450 | Hydroxylation reactions (Detoxicate) | | Catalase and peroxidases | Degradation of hydrogen peroxide | | Tryptophan pyrrolase | Oxidation of tryptophan | | Nitric oxide synthase | Synthesis of nitric oxide | ## Structure of Heme - Heme is a Metaloporphyrin - Heme = porphyrin ring (Protoporphyrin IX) + Iron ### Porphyrins: - They are cyclic compounds formed by fusion of 4 pyrrole rings (tetrapyrrole) linked by methenyl (=CH-) bridges. The pyrrole rings are named as I, II, III, IV. - A characteristic property of porphyrins is the formation of complexes with metal ions which binds to the nitrogen atom of the pyrrole rings to form complexes. - **Structure of heme:** - **M = Methyl** - **V = Vinyl** - **P = Propionyl** ## Site of Heme synthesis: - Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic group on enzymes and electron transport chain. - The major locations of heme synthesis are the liver & the erythroid progenitor cells of the bone marrow. - Heme production in the liver is required for the formation of hemoproteins (e.g. Cytochrome P450 involved in detoxification) while in the erythroid cells, it is necessary for the synthesis of hemoglobin. - The process of synthesis involves 8 steps.. The steps 1, 6, 7, and 8 are taking place inside mitochondria, while steps 2, 3, 4 and 5 are in cytoplasm. ## Overview of Heme synthesis: - The image shows the chemical reactions involved in heme synthesis. ## Step 1: Formation of δ-ALA - Occurs in the mitochondria - Requires Pyridoxal phosphate (B6) - Catalyzed by δ-amino levulenic acid synthase - From citric acid cycle, Succinyl-CoA condenses with Glycine to form δ-aminolevulinate (ALA). ## Step 2: Formation of Porphobilinogen (PBG) - Occurs in the cytoplasm - Catalyzed by ALA dehydratase - Inhibited by Lead (Acquired porphyria) - Two molecules of δ-aminolevulinate (ALA) are converted to one molecule of porphobilinogen (PBG). ## Last Step: Formation of heme - Occurs in the mitochondria - Catalyzed by Ferrochelatase - Inhibited by Lead (Acquired porphyria) - The image illustrates the final step in heme synthesis, where a molecule of protoporphyrin IX reacts with ferrous iron (Fe²⁺) to form heme. ## Regulation of Heme synthesis: - Heme biosynthesis is regulated **differently** in erythroid and liver cells. - The compartmentalization of the enzymes, makes the regulation easier. ### 1- In liver: - The rate controlling enzyme for heme biosynthesis is ALA synthase. - Heme, or its Fe(III) oxidized products (Hematin and Hemin), They control this enzyme's activity through three mechanisms: - feedback inhibition, - inhibition of the transport of ALA synthase (ALAS) from its site of synthesis in the cytosol to its reaction site in the mitochondria, - repression of ALAS synthesis. ### iii. Effect of drugs on ALA synthase activity: -Drugs as barbiturates and grisofulvin (antifungal), increase ALA synthase activity as these drugs are metabolized by heme containing cytochrome p450 in liver resulting in more consumption of heme. Accordingly, heme concentration is reduced resulting in stimulation of action of ALA synthase. -Drugs metabolized by cytochrome P450 monooxygenase in the liver: - Synthesis of cytochrome P450 - ↑Consumption of heme - a component of cytochrome P450 proteins. - The concentration of heme in liver Cells. - LAS1(derepression) - The synthesis of ALAS1( -Isoniazid (INH) (anti-tuberculous) that decreases the availability of pyridoxal phosphate needed for ALA synthase key enzyme for heme synthesis. -High cellular concentration of glucose prevents induction of ALA synthase. This is the basis of glucose to relieve the acute attack of porphyrias (300-500 g/day) ### 2- In the erythroid cells: - The enzyme ALA synthase does not appear to control the heme synthesis. - Uroporphyrinogen synthase and ferrochelatse mostly regulate heme formation in these cells. Heme stimulates globin synthesis in right proportion to form Hb. ## Porphyrias - The term porphyria is derived from the Greek πορφύρα, porphyra, meaning "purple pigment". Original descriptions are attributed to Hippocrates. - Although porphyrias are not very prevalent, physicians must be aware of them. - An inherited (genetic) defect in an enzyme of heme synthesis results in accumulation of one or more of porphyrin precursors depending on location of block of the heme synthesis pathway. These precursors increase in blood & appear in urine of patients. - The porphyrias are classified as erythropoietic or hepatic, depending on the major site, where the enzyme deficiency is manifested. - Porphyrias inheritance: All types of porphyrias exhibit Autosomal dominant (AD) inheritance except congenital erythropoietic porphyrias (AR). - In general, individuals with an enzyme defect: - Prior to the synthesis of the tetrapyrroles manifest abdominal pain and neuropsychiatric manifestations (due to toxic effect of accumulated (ALA & PBG) - Whereas those with enzyme defects leading to the accumulation of tetrapyrrole intermediates show photosensitivity (that is, their skin itches and burns [pruritus] when exposed to visible light) - Porphyrias may be acquired caused by poisons as lead poisoning due to block of heme synthesis at the level of ALA dehydratase and Ferrochelatase (heme synthase) enzymes. - Diagnosis of porphyrias: To demonstrate porphyrins, UV fluorescence is the best technique.. When urine is observed under ultraviolet light; porphyrins if present, will emit strong red fluorescence. ## Types of Porphyria - The image shows the different types of porphyrias and the enzymes involved in their development. ## 1- Acute intermittent Porphria (AIP) - Acute hepatic porphyria caused by deficiency of the enzyme Hydroxymethylbilane synthase (HMBS). - Usually expressed after puberty in humans. The symptoms include **abdominal pain**, and **neuropsychiatric disturbances** with accumulation of porphyrin precursors such as δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). - The attacks are provoked by after administration of drugs (e.g. barbiturates, grisoflulvin, alcohol, oral contraceptive pills,..), infections, menstrual cycle,... - These patients are **not photosensitive**. - Treated by administration of heme preparations (hematin or Hemin). - **The image shows a diagram of the chemical reaction catalyzed by HMBS, and two vials of hematin, a drug used to treat AIP.** ## 2- Porphyria cutenea tarda (PCT) - Chronic cutaneous hepatic porphyria - The most common porphyria+++. - Caused by deficiency of the enzyme **uroporphyrinogen decarboxylase**. - Increased excretion of **uroporphyrins**. - **Cutaneous photosensitivity** is the most important clinical manifestation of these Patients. - **The image shows a diagram of the chemical reaction catalyzed by uroporphyrinogen decarboxylase, and a photo of a person with PCT, showing the characteristic skin lesions.** ## Degradation of Heme - This is the degradation pathway for heme. - The image shows the breakdown of heme in macrophages, and the subsequent conversion of biliverdin to bilirubin. ## Bilirubin Metabolism - The image illustrates the different stages of bilirubin metabolism, starting with its production in macrophages and ending with its excretion in feces. - **Key points:** - 80% of heme is degraded in the spleen. - Bilirubin is produced from the breakdown of heme in macrophages. - Bilirubin is conjugated in the liver with glucuronic acid to make it water-soluble for excretion. - Unconjugated bilirubin is toxic to the brain. ## Summary of Heme Synthesis & Degradation - The image summarizes the entire process of heme synthesis and degradation, from the initial precursor molecules through the various enzymes involved to the breakdown of heme and excretion of bilirubin. - The key enzymes involved in heme synthesis are ALA synthase, porphobilinogen deaminase, uroporphyrinogen III cosynthase, uroporphyrinogen III decarboxylase, coproporphyrinogen III oxidase, and protoporphyrinogen IX oxidase. The rate controlling enzyme is ALA synthase. - The primary enzyme involved in heme degradation is heme oxygenase, followed by biliverdin reductase. - Heme can be degraded in various cells such as macrophages, reticuloendothelial system, and erythrocytes. - The final product of heme degradation is bilirubin, which is conjugated in the liver and excreted in the bile. - Genetic defects in any of the enzymes involved in heme synthesis or degradation can lead to various porphyrias with distinct clinical manifestations.