Hemoglobin Synthesis and Porphyrias Lecture Notes PDF

## Hemoglobin Synthesis and Porphyrias **Dr. Aliya Jafri** **Assistant Professor** **Biochemistry** **SMC, JSMU.** ### Learning Objectives - Explain the pathway of hemoglobin synthesis - List the abnormalities of Hemoglobin synthesis - Classify Porphyria - Discuss Porphyria ### Not a 'vampire...

## Hemoglobin Synthesis and Porphyrias **Dr. Aliya Jafri** **Assistant Professor** **Biochemistry** **SMC, JSMU.** ### Learning Objectives - Explain the pathway of hemoglobin synthesis - List the abnormalities of Hemoglobin synthesis - Classify Porphyria - Discuss Porphyria ### Not a 'vampire's' disease - red brown teeth, hair growth, mutilation and disfigurement The image shows pictures of peoples' teeth, faces and hands - indicating that porphyria causes: - Red-brown teeth - Excess hair growth - Mutilation - Facial disfigurement ### Vampire Disease/ Porphyria The image shows pictures of peoples' teeth, faces and hands - indicating that porphyria causes: - Red-brown teeth - Facial disfigurement ### Case : George III **History** - Attacks of severe abdominal pain, over excited activity, paralysis and delirium. - Began in 1765 (age 27) - Became frequent by 1788 **Presenting symptoms** - 1811, violently insane - Blind ### King George III - Mad King George - Had acute bouts of abdominal pain and mental confusion - May have been porphyria sufferer - Complicated by all the drugs his doctors gave him - Vampires and Werewolves? - Some have put forth that Porphyrias misinterpreted in Middle Ages. - Consider photosensitivity. - Red blood (even teeth). - Hypertrichosis (excess hair growth on body) ### Porphyrins - **Cyclic compounds that bind metals usually iron** - Most common porphyrin in humans is heme - One ferrous (Fe+2) group in tetrapyrole ring - Prosthetic group for: - Hemoglobin - Myoglobin - Cytochrome (CYP450 & Electron Transport chain) - Catalase enzyme - Tryptophan pyrrolase - NOS (Nitric oxide synthase) ### Structure of Porphyrins - Cyclic, with 4 pyrrole rings attached by methenyl bridges - Side chains may vary - Uroporphyrin has Acetate and Propionate chains - Coproporphyrin has Methyl and Propionate chains - Order of chains define subgroups of porphyrins: Only Type III porphyrins are normally important for humans ### Properties of porphyrins - Porphyrins are cyclic compounds formed by the linkage of four pyrrole rings. - Methenyl bridges (-HC=) connect the pyrrole rings. - Two groups - acetyl group (A) and propionyl group (P) - are found attached to each pyrrole ring on the porphyrin molecule. - The nature and distribution of the side chains determine the physical characteristics of porphyrins (for e.g. solubility). - Based on the arrangement of the A and P groups, the molecule is classified into four groups designated type I to type IV. - Type III porphyrins contain an asymmetric substitution on ring D and are physiologically important to humans. ### Porphyrins The image shows four different porphyrins, split into two pairs: | Name | Position | | :----------------- | :------- | | Uroporphyrin I | Top left | | Uroporphyrin III | Top right | | Coproporphyrin I | Bottom left | | Coproporphyrin III | Bottom right | Each is a cross shape diagram with the following abbreviations marking each corner of the cross: - A: Acetate - P: Propionate - M: Methyl - V: Vinyl ### Porphyrins - Porphyrins can act as a tetra dentate chelating molecule for metals. - The four nitrogen atoms function as "teeth" to hold the metal ions in place. - Chelatase' enzyme facilitates the insertion of metal ion into the porphyrin ring. - E.g. Ferrochelataseis responsible for the insertion of Fe2+ into porphyrin to form heme. - After insertion, the metals are held on by electrostatic interaction of the nitrogen's electrons ### Case Study - A 6 year old child was brought in OPD with complaints of having learning difficulties in school. On inquiring further his parents revealed his habit of eating paint chips. - What could be the most likely diagnosis? ### HEME - Heme is a derivative of a family of compounds called Porphyrins. - Porphyrins are cyclic compounds formed by fusion of 4 pyrrole rings linked by methenyl (=C - ) bridges. - Many important proteins contain heme as a prosthetic group. - Hemeproteins are a group of specialized proteins that contain heme as a tightly bound prosthetic group. #### Heme proteins - Hemoglobin (oxygen transport) - Myoglobin (oxygen transport) - Cytochromes (electron transport) - Catalase (H₂O₂ utilization) ### Heme structure - Heme is a complex of porphyrin IX and ferrous iron (Fe2+) The image shows a complex diagram of a pyrrole ring and the structure of heme containing: - Ferrous Iron (Fe2+) - Four pyrrole rings - A variety of chemical bonds and groups ### Structure of Heme - Iron containing Porphyrin. - Is a complex of Protoporphyrin IX and ferrous iron Fe++ - The iron is held in the center of the heme molecule by bonds to the four nitrogen of the Pyrrole rings joined by four methenyl bridges. - Porphyrin is formed from 4 rings - The side chains 1,35, & 8 are Methyl. - The side chains 2 & 4 are Vinyl. - The side chains 6 & 7 are Propionic Acid. ### Heme synthesis - site | Location | Sub-location | | :-------- | :------------- | | Tissues | - Liver | | | - Bone marrow | | Cell | - Mitochondria | | | - Cytoplasm | ### Heme synthesis within Liver - 10% of heme synthesis in the body. - Mostly incorporated into Cytochrome P450 family of enzymes. - Cytochrome P450 are responsible for metabolism of xenobiotic such as drugs, alcohol. - Liver heme synthesis is up-regulated in response to drug/alcohol metabolism ### Reactions of Heme synthesis | Steps | Description | | :-------------------------------- | :------------------------------------------------------------------ | | Aminolevulenic acid (ALA) synthesis | - | | Formation of Porphobillinogen | - | | Formation of Hydroxymethylbilane | - | | Formation of Uroporphyrinogen | - | | Synthesis of Coproporphyrinogen | - | | Synthesis of Protoporphyrinogen | - | | Generation of Protoporphyrin | - | ### Heme biosynthesis The image shows a flow chart diagram of the processes of heme biosynthesis with the following key steps: - Formation of Aminolevulinic acid - Formation of Porphobilinogen - Formation of Hydroxymethylbilane - Formation of Uroporphyrinogen III - Formation of Coproporphyrinogen III - Formation of Protoporphyrinogen - Formation of Protoporphyrin IX - Formation of Heme Each stage of the process is labeled with the following enzyme names: - ALA synthase - ALA dehydratase - Hydroxymethylbilane synthase - Uroporphyrinogen III synthase - Uroporphyrinogen decarboxylase - Protoporphyrinogen oxidase - Coproporphyrinogen Oxidase - Ferrochelatase The overall reaction requires both mitochondria and cytoplasm components. - **Major sites of synthesis in the body:** - Bone marrow erythroid cells: about 85% of heme produced in the body. Synthesis rate is relatively constant at all times. - Liver (~10%): where cytochrome P450 is synthesized. Synthesis is up-regulated in response to drug/alcohol metabolism - **Cellular location:** - Mitochondria: the initial reaction and the last three steps - Cytosol: the intermediate 4 steps - **Note:** mature RBCs don't have a mitochondria and cannot make heme ### Heme biosynthesis: formation of ALA - ALA = 6-aminolevulinic acid - The committed and rate-limiting step of porphyrin biosynthesis. - Occurs in the mitochondria. - Glycine and Succinyl CoA condense to form ALA. - All the C and N atoms of the porphyrin molecule are provided by Glycine ( a nonessential amino acid ) and Succinyl Coenzyme A ( an intermediate of the TCA cycle ). - Reaction is catalyzed by ALA synthase - Pyridoxal phosphate is a required coenzyme for this reaction. ### Aminolevulinic acid (ALA) synthase - ALA synthase is a mitochondrial enzyme. Two isoforms: - ALA-S1 is located mostly in liver cells and to a smaller extent in other cells in the body. - Heme production for the liver cytochrome P450 mono-oxygenase system. - Gene is located on chromosome-3. - Loss of function mutation in ALA‑S1 gene causes impaired metabolism of xenobiotics - ALA-S2 is produced in erythroid tissue. - Heme production for RBC hemoglobin. - Gene is located on the X-chromosome. - Loss of function mutations in ALA-S2 results in anemia. ### Inhibition of ALA Synthase by Hemin (End Product) - When porphyrin production exceeds the availability of globin, heme accumulates and is converted to hemin by the oxidation of Fe2+ to Fe3+ - Hemin decreases the activity of hepatic ALA synthase. by decreasing the synthesis of the enzyme. ### Synthesis of Porphobilinogen (PBG) - δ-aminolevulinate (2 molecules) → Porphobilinogen - 2H₂O - ALA leaves the mitochondria → cytoplasm - 2x ALA condense together to form porphobilinogen - Reaction is catalyzed by porphobilinogen synthase (ALA dehydratase) ### Inhibition of Porphobilinogen Synthase by Pb - Pb results in elevated blood ALA as impaired heme synthesis leads to de-repression of transcription of the ALA Synthase gene. - High Ала is thought to cause some of the neurological effects of lead poisoning, although Pb also may directly affect the nervous system. - ALA is toxic to the brain, perhaps due to: - Similar ALA & neurotransmitter GABA (γ- aminobutyric acid) structures. - ALA autoxidation generates reactive oxygen species (oxygen radicals). ### Formation of tetrapyrrole intermediates - Condensation of four porphobilinogens produces the linear tetrapyrrole molecule, hydroxymethylbilane (HMB). - Catalyzed by the enzyme HMB synthase. - Cyclization and isomerization of HMB to uroporphyrinogen III (tetrapyrrole ring). - Catalyzed by Uroporphyrinogen III synthase. - Decarboxylation of the acetate groups of uroporphyrinogen III to generate coproporphyrinogen III. - Catalyzed by Uroporphyrinogen decarboxylase. - These reactions all occur in the cytosol. ### Formation of protoporphyrin IX - Coproporphyrinogen III enters the mitochondria. - Two propionate side chains are decarboxylated to vinyl groups generating protoporphyrinogen IX. - Oxidation of protoporphyrinogen IX to protoporphyrin IX. - The introduction of iron (as Fe2+) into protoporphyrin IX to form heme (see next slide...) ### Formation of Heme - Last step in the formation is heme is the incorporation of iron (as Fe2+) into the porphyrin ring. - The introduction of iron into protoporphyrin IX occurs spontaneously by electrostatic interactions. - The rate of iron incorporation is enhanced by the enzyme ferrochelatase. - Ferrochelatase is inhibited by lead. - The other enzyme in porphyrin biosynthesis that is inhibited by lead is ALA dehydratase (discussed earlier). ### Lead poisoning - Enzymes in heme biosynthetic pathway that are inhibited by lead: - ALA dehydratase - Ferrochelatase - Other heavy metals may also inhibit these enzymes. - Symptoms resemble porphyrias. - Ала and/or protoporphyrin accumulate in urine. ### Lead poisoning The image shows a diagram of the heme biosynthesis process where the following enzymes are highlighted as being inhibited by lead: - ALA synthase inhibited by lead - Ferrochelatase inhibited by lead - Protoporphyrinogen oxidase inhibited by lead ### Lead poisoning - Lead buildup in the body causes serious health problems **Symptoms:** - Headaches - Irritability - Reduced sensations - Aggressive behavior - Difficulty sleeping - Abdominal pain - Poor appetite - Constipation - Anemia **Additional complications for children:** - Lead is more harmful to children as it can affect developing nerves and brains. - Loss of developmental skills - Behavior, attention problems - Hearing loss - Kidney damage - Reduced IQ - Slowed body growth ### Overview of Heme Synthesis The image shows a diagram of the heme synthesis pathway with the following stages: - Formation of δ-aminolevulinic acid - Formation of Porphobilinogen - Formation of Uroporphyrinogen III - Formation of Coproporphyrinogen III - Formation of Protoporphyrinogen IX - Formation of Protoporphyrin IX - Formation of Heme The diagram highlights the importance of the mitochondria and cytoplasm in the biosynthesis of heme. ### Step-1 (mitochondria) - From citric acid cycle: Succinyl-CoA - Non essential amino acid: Glycine - Condensation reaction catalyzed by ALA synthase - Delta Amino Levulinic Acid (ALA). ### Step-2 (cytosol) - (2molecules) 6-aminolevulinate (ALA) - ALA dehydratase (zinc-containing enzyme and is sensitive to inhibition by lead) - porphobilinogen (PBG) (First precursor of pyrrole) ### Step-3 (cytosol) - (4molecules) porphobilinogen (PBG) - Condenses (4NH3) - Hydroxymethylbilane (HMB) (linear tetrapyrrole) - uroporphyrinogen I synthase - PBG deaminase - HMB synthase ### Step-4 (cytosol) - Hydroxymethylbilane (HMB) - uroporphyrinogen I (HMB cyclizes spontaneously) - uroporphyrinogen III synthase - uroporphyrinogen III (Forms under normal conditions) ### Step-5 (mitochondria) - Uroporphyrinogen I - 5H - Light - Uroporphyrin I - Coproporphyrinogen I - 6H - Light - Coproporphyrin I - Uroporphyrinogen III - 6H - Light - Uroporphyrin III - Coproporphyrinogen III - 6H - Light - Coproporphyrin III ### Step-6 (mitochondria) - Coproporphyrinogen III - Coproporphyrinogen oxidase - Protoporphyrinogen IX ### Step-7 (mitochondria) - Protoporphyrinogen IX - Protoporphyrinogen oxidase - Protoporphyrin IX ### Step-8 (mitochondria) - Heme synthase - Protoporphyrin IX - Ferrochetalase - Heme - Fe ### Porphyria The image shows a chart summarising the different types of porphyria and the enzymes involved in the biosynthesis of heme. The following types of porphyria are listed: - X-linked protoporphyria (XLP) - X-linked sideroblastic Anemia (XSLA) - ALA-dehydratase Deficiency porphyria (ADP) - Acute intermittent porphyria (AIP) - Congenital erythropoietic porphyria (CEP) - Porphyria cutanea tarda (PCT) - Hepatoerythropoietic porphyria (HEP) - Hereditary coproporphyria (HCP) - Variegate porphyria (VP) - Erythropoietic protoporphyria (EPP) The chart also highlights the following steps in heme biosynthesis: - Succinyl CoA + Glycine - 6-Aminolevulinic acid - Porphobilinogen - Hydroxymethylbilane - Uroporphyrinogen III - Coproporphyrinogen III - Protoporphyrinogen IX - Protoporphyrin IX - Protoporphyrin IX - Haem ### Porphyria - ALA synthase is also allosterically inhibited by hematin - When there is excss of free heme without globin chains to bind with, the Fe2+ is oxidized to Fe3+ forming hematin. Hematin will inhibit ALA synthase to prevent excessive unwanted production of heme. - Hematin will also inhibit the translocation of ALA synthase from the cytoplasm into the mitochondria where its substrate, succinyl CoA is formed. Thus heme synthesis is inhibited till there are sufficient globin chains to bind with. ### Porphyria - Lack of Vit B6 will decrease the synthesis of ALA. - Drugs like INH (isonicotinic acid hydrazide) that decreas the availability of pyridoxal phosphate may also affect heme synthesis. ### Porphyria - Heme synthesis may be inhibited by heavy metals. - The steps catalyzed by ALA dehydratase and ferrochelatase are inhibited by lead. ### Erythropoietin - The kidneys also secrete a hormone erythropoietin. - The function to stimulate the production of red blood cells. - The kidney produces 85~95% of the body's erythropoietin so when the kidney is damaged (kidney disease or failure), not enough erythropoietin is produced to maintain normal red blood cell levels. This leads to anemia. ### Disorders of Heme synthesis - Porphyrias are group of inborn errors of metabolism associated with the biosynthesis of heme. - (Greek 'porphyria' means purple). - These are characterized by increased production and excretion of porphyrins and/or their precursors (ALA + PBG). - Many of the Porphyrias are inherited as Autosomal dominant traits. ### Porphyria The image shows the close up of a person's face which is affected by porphyria. ### Porphyia The image shows the close up of a person's hands which are affected by porphyria. ### Porphyria - A 50-year-old presented with ful on the backs of his hands. - He had artial co that had begun about 3 years earlier after a head injury and had been taking phe since The onset of the seizure disorder. - He take an cans of beer. The patient's was reddish orange. - Cultures obtained from skin lesions failed to grow organisms. - A 24 hour urine collection showed elevated uroporphyrın (1,000mg:normal, <27mg) ### Porphyrias - Porphyrias are genetic diseases in which activity of one of the enzymes involved in heme synthesis is decreased (e.g., PBG Synthase, Porphobillinogen, Deaminase, etc...). - **Symptoms vary depending on** - The enzyme - The severity of the deficiency - Whether heme synthesis is affected primarily in liver or in developing erythrocytes. ### Porphyria The image shows a diagram of the types of porphyria: - Hereditary - ADD - ARD - Congenital Erythropoietic Porphyria - Acquired - Lead poisoning - ALAD porphyria The diagram also highlights the categories of porphyria: - Hepatic - Erythroietic ### Classification of Porphyrias - Based on the affected step in the heme biosynthesis pathway: - Enzyme defect prior to the synthesis of the tetrapyrroles: Affected individuals, in general, manifest abdominal and neuro-psychiatric signs. - Enzyme defects leading to the accumulation of tetrapyrrole intermediates: Affected individuals show photosensitivity. Exposure of skin to visible light causes skin itches and burns. Light exposure → Tetrapyrrole photo oxidation → reactive oxygen species formation → oxidative damage to skin cells - Based on body cells/tissues where heme biosynthesis is affected: - Erythropoietic porphyrias: heme biosynthesis in the erythropoietic cells of the bone marrow is affected. - Hepatic porphyrias: heme biosynthesis in the liver is affected. - Tissue-based porphyrias (acute or chronic) ### Acute hepatic porphyrias The image shows a flow chart diagram of the processes of heme biosynthesis with the following key steps: - Formation of Aminolevulinic acid - Formation of Porphobilinogen - Formation of Hydroxymethylbilane - Formation of Uroporphyrinogen III - Formation of Coproporphyrinogen III - Formation of Protoporphyrinogen - Formation of Protoporphyrin IX - Formation of Heme Each stage of the process is labeled with the following enzyme names: - ALA synthase - ALA dehydratase - Hydroxymethylbilane synthase - Uroporphyrinogen III synthase - Uroporphyrinogen decarboxylase - Protoporphyrinogen oxidase - Coproporphyrinogen Oxidase - Ferrochelatase The overall reaction requires both mitochondria and cytoplasm components. - ALA dehydratase (ALAD) deficiency & ALA accumulation in the urine. - Tetrapyrrole intermediates DO NOT accumulate. - No photosensitivity. - Hydroxymethylbilane synthase deficiency. - ALA and PBG both accumulation in the urine. - Urine darkens on exposure to air. - Tetrapyrrole intermediates DO NOT accumulate. - No photosensitivity. - First tetrapyrrole structure to be formed. - HMB is a linear tetrapyrrole. ### Acute hepatic porphyrias The image shows a flow chart diagram of the processes of heme biosynthesis with the following key steps: - Formation of Aminolevulinic acid - Formation of Porphobilinogen - Formation of Hydroxymethylbilane - Formation of Uroporphyrinogen III - Formation of Coproporphyrinogen III - Formation of Protoporphyrinogen - Formation of Protoporphyrin IX - Formation of Heme Each stage of the process is labeled with the following enzyme names: - ALA synthase - ALA dehydratase - Hydroxymethylbilane synthase - Uroporphyrinogen III synthase - Uroporphyrinogen decarboxylase - Protoporphyrinogen oxidase - Coproporphyrinogen Oxidase - Ferrochelatase The overall reaction requires both mitochondria and cytoplasm components. - ALAD deficiency. - HMBS deficiency. - Severe abdominal pain. - Neuropsychiatric disturbances ranging from anxiety to delirium. - Symptoms precipitated by administration of drugs such as barbiturates and ethanol, which induce the synthesis of cytochrome P450. - This further decreases the amount of available heme, which, in turn, promotes the increased synthesis of ALA-S1 ### Erythropoietic Porphyrias The image shows a flow chart diagram of the processes of heme biosynthesis with the following key steps: - Formation of Aminolevulinic acid - Formation of Porphobilinogen - Formation of Hydroxymethylbilane - Formation of Uroporphyrinogen III - Formation of Coproporphyrinogen III - Formation of Protoporphyrinogen - Formation of Protoporphyrin IX - Formation of Heme Each stage of the process is labeled with the following enzyme names: - ALA synthase - ALA dehydratase - Hydroxymethylbilane synthase - Uroporphyrinogen III synthase - Uroporphyrinogen decarboxylase - Protoporphyrinogen oxidase - Coproporphyrinogen Oxidase - Ferrochelatase The overall reaction requires both mitochondria and cytoplasm components. - Heme biosynthesis in the erythroid cells of the bone marrow is affected: - Congenital erythropoietic porphyria: Uroporphyrinogen III synthase deficiency. - Erythropoietic protoporphyria: deficiency of ferrochelatase. - Congenital erythropoietic porphyria - Uroporphyrinogen III synthase deficiency. - HMB accumulation leads to spontaneous formation of uroporphyrinogen I and coproporphyrinogen I which accumulate in the urine. - Dark urine, pink/red fluorescence under UV light. - Patients are photosensitive. ### Chronic hepatic porphyria The image shows a diagram of the heme biosynthesis process with the following steps: - Formation of Aminolevulinic acid - Formation of Porphobilinogen - Formation of Hydroxymethylbilane - Formation of Uroporphyrinogen III - Formation of Coproporphyrinogen III Each stage of the process is labeled with the following enzyme names: - Hydroxymethylbilane synthase - Uroporphyrinogen III synthase - Uroporphyrinogen decarboxylase - Coproporphyrinogen oxidase - Accumulation of hydroxymethylbilane leads to the spontaneous (non-enzymatic) formation of uroporphyrinogen I & coproporphyrinogen I. - Uroporphyrinogen I & coproporphyrinogen I undergo oxidation and are elevated in the urine. Urine is therefore pink to red under UV light. - Occurrence of porphyria cutanea tarda is further aggravated by factors such as: - Hepatic iron overload - Alcohol abuse - Hepatitis (B or C) or HIV infections - Light exposure (high photosensitivity) ### Porphyria Cutanea Tarda - Porphyria Cutanea Tarda - A chronic porphyria, most common type - Liver and erythroid tissues - Deficiency in uroporphyrinogen decarboxylase - Often no symptoms until 4th or 5th decade - Clinical expression determined by many factors: - Hepatic iron overload - Exposure to sunlight - Hepatitis B or C, - HIV - Symptoms include: - Cutaneous rashes, blisters - Urine that is red to brown in natural light, or pink to red in UV light ### Chronic hepatic porphyria The image shows a diagram of the heme biosynthesis process with the following steps: - Formation of Aminolevulinic acid - Formation of Porphobilinogen - Formation of Hydroxymethylbilane - Formation of Uroporphyrinogen III - Formation of Coproporphyrinogen III Each stage of the process is labeled with the following enzyme names: - Hydroxymethylbilane synthase - Uroporphyrinogen III synthase - Uroporphyrinogen decarboxylase - Coproporphyrinogen oxidase - Porphyria cutanea tarda (PCT): a chronic condition of the liver & the most common porphyria. - Caused by a deficiency of the enzyme uroporphyrinogen decarboxylase. - Clinical onset is late: typically during the fourth or fifth decade of life. - Accumulation of uroporphyrinogen III (a cyclic tetrapyrrole) leads to: - Red to brown colored urine. - Skin eruptions. ### Porphyrins - Porphyrins are the obligate intermediates on the haem synthetic pathway. ### Porphyria The image shows a chart summarising the different types of porphyria and the enzymes involved in the biosynthesis of heme. The following types of porphyria are listed: - ALAD porphyria - Acute intermittent porphyria - Congenital erythropietic porphyria - Porphyria cutanea tarda - Hereditary coproporphyria - Variegate porphyria - Erythropoietic protoporphyria The chart also highlights enzymes in the heme biosynthesis pathway: - ALA synthase - PBG deaminase - Uroporphyrinogen cosynthase - Uroporphyrinogen decarboxylase - Coproporphyrinogen oxidase - Protoporphyrinogen oxidase - Ferrochetalase The chart highlights the following intermediates: - ALA - PBG - Uroporphyrinogen - C7-porphyrinogen - C6-porphyrinogen - C5-porphyrinogen - Coproporphyrinogen - Protoporphyrinogen - Protoporphyrin - Haem ### Porphyria The image shows a chart summarising the different types of porphyria and the enzymes involved in the biosynthesis of heme. The following enzymes are listed: - ALA synthase - ALA synthase 2 (in erythrocytes) - ALA dehydratase - PBG deaminase/HMB synthase - Uroporphyrinogen III synthase - Uroporphyrinogen decarboxylase - Coproporphyrinogen oxidase - Protoporphyrinogen oxidase - Ferrochelatase The chart also highlights the following steps in heme biosynthesis: - Glycine + Succinyl-CoA - 8-Aminolaevulinic acid (ALA) - Porphobilinogen (PBG) - Hydroxymethylbilane (HMB) - Uroporphyrinogen III - Coproporphyrinogen III - Protoporphyrinogen X - Protoporphyrin X - Haem - Haemoglobin - Myoglobin The chart also highlights the following types of porphyria: - X-linked protoporphyria - ALA dehydratase deficiency - Acute Intermittent porphyria - Congenital erythropoletic porphyria - Porphyria cutanea tarda - Hepato-erythropoietic porphyria - Hereditary coproporphyria - Variegate porpyhria - Erythropoletic protoporphyria - The product of heme biosynthesis is haemoglobin. - Haem is also used to make other proteins like myoglobin, cytochromes, peroxidases, catalases, tryptophan pyrrolase