الفريق االكاديمي الطبي HLS/ Biochemistry Sheet Porphyrin and Heme metabolism By: Shatha Khtoum

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1 الفريق االكاديمي الطبي HLS/ Biochemistry Sheet Porphyrin and Heme metabolism By: Shatha Khtoum اا

2 Today we will take about heme metabolism: -Heme is iron (Fe +2 ) with 4 pyrrole rings. -Its function it works as a prosthetic group for many proteins, and without heme these proteins (Hemoproteins) cannot do their functions. These are examples for some proteins that considered as hemoproteins: 1. Hemoglobin heme contains the iron which O 2 binds to it; so heme group is very important here and the protein cannot transport O 2 in the blood without it. 2. Myoglobin also important protein which carries the O 2 to muscle tissues. 3. Cytochrome Cytochrome P450 enzymes also function to metabolize toxic compounds, found in the liver. 4. Catalase 5. Some peroxidase These two proteins are hemoproteins that hydrolyze peroxide to O 2 and water The Structure of Heme: This is the heme structure which contains: - 4 heterocyclic rings. -has some side chains like methyl and ethyl. -linked with each other by methenyl bridges. -in the middle there is an iron atom in a ferrous state (Fe +2 )

3 Heme synthesis: ** Amino acid (building blocks of protein) synthesized in your body It s a long pathway, we will start 2 simple precursors: one is Glycine (amino acid) and the other one is succinyl CoA (one of the intermediate of the citric acid cycle). In order to synthesis the heme we need 8 molecules of Succinyl CoA and 8 molecules of Glycine which give us heme. Heme synthesis

4 -Most of the heme synthesis takes place in the red blood cell (about 85%). Here the doctor didn t really mean the red blood cells itself, he means in the cells that form the red blood cells (erythroblast). -And about 15% takes place in liver. -Ceases when RBC s mature. -Erythroid-specific ALA synthase is regulated by an IRE in the mrna binding of IRBP inhibits mrna translation (will be discuss at page 5) Wherever the heme synthesis takes place, some of the synthesis process happens in the mitochondria and some in the cytosol. We will start from the mitochondria condensation of Succinyl CoA and Glycine will produce important intermediate molecule called Aminolaevulinic acid.

5 Then in the cytosol 2 molecules of Aminolaevulinic acid condensed with each other to give porphobilinogen. Aminolaevulinic acid synthase is very important enzyme in regulation of heme biosynthesis. It inhibited by heme which serves as feedback. Porphobilinogen synthase is also important enzyme, sometimes it s called aminolaevulinic acid dehydratase, because there is a dehydration (removal of water), so 2 H 2 O are removed along the condensation of the 2 molecules of Aminolaevulinic acid. This enzyme could be inhibited by heavy metals like lead (lead toxicity or lead poisoning) which causes a severe disease. If someone eats a contaminated food with lead, the lead will bind with some hydro groups in the active site of the enzyme which causes inhibition. After this step 4 molecules of porphobilinogen will be condensed and it will deaminated by enzyme called Porphobilinogen Deaminase. It will produce this molecule that called uroporphyrinogen Ⅲ. This uroporphyrinogen Ⅲ subjected to decarboxylation (removal of CO 2 ) and gives corporphyrinogen Ⅲ. Back to the mitochondria then by oxidative decarboxylation it will give protoporphyrin Ⅸ. And the last step by the enzyme Ferrochelatase which inhibited by lead. Iron in the ferrous state (Fe +2 ) is linked to the protoporphyrin which ends up with heme. So, protoporphyrin is a heme iron. -Any deficiencies in the previous enzymes will cause disorders of heme metabolism called Porphyrias. -heme synthesis is regulated by the enzymes ferrochelatase and porphobilinogen deaminase. HEME SYNTHESIS: Liver The liver is the main non-rbc source of heme synthesis

6 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. In live, the first enzyme is subjected to regulation by: the enzymes I ve mentioned before (ferrochelatase and porphobilinogen deaminase), also it s subjected by iron and RBCs that will be very important to balance the synthesis of heme and polypeptide chain. It was found that heme will activate the synthesis of polypeptide chain the glob part of hemoglobin. So, in order to make balance between the amount of globin polypeptide chain and the amount of heme, it s controlled by the first enzyme which is called the aminolaevulinic acid synthase. And this enzyme is controlled by hemin which is a derivative of heme and hemin will inhibit the aminolaevulinic acid synthase and the synthesis of heme will stop. So, if we have a lot of heme synthesis hemin will inhibit this enzyme and stop synthesis of heme and at the same time high amount of heme will activate synthesis of more globin polypeptide synthesis in order to compensate and make balance between the excess heme and globin polypeptide chain. Regulation of ALA Synthase -Level of enzyme synthesis: Enzyme synthesis, as well as its transport to the mitochondria, is inhibited by elevated levels of heme and hemin, the Fe 3+ oxidation product of heme. Enzyme synthesis is upregulated by a large number of drugs including barbiturates, steroids with a 4,5-double bond (e.g. testosterone) and some oral contraceptives: These drugs are metabolized by the microsomal cytochrome P 450 mono-oxygenase system, a heme-containing protein.

7 - Level of enzyme activity Heme and hemin inhibit ALA synthase activity Requires pyridoxal phosphate (Vitamin B6) as a coenzyme. Also at the level of mrna, iron controls the synthesis of aminolaevulinic acid synthase enzyme via a sequence on the mrna called iron response element and iron response element binding protein. If you don t have enough iron that protein will bind to iron response element at the 5 region and will inhibit the translation of mrna to produce more aminolaevulinic acid synthase enzyme to synthesis more heme. Disorders of Heme Synthesis: - Acquired: Lead poisoning that will inhibit Ferrochelatase enzyme and porphobilinogen synthase enzyme. - Congenital: Porphyrias there are enzymes in the heme biosynthesis pathway that genetically deficient; complete deficiency or partly deficiency. - Deficiency of heme has far-reaching effects (hemoglobin, cytochromes, etc.) LEAD TOXICITY: Symptoms Irritability Lethargy Sleeplessness Headaches Poor appetite Abdominal pain (with or without vomiting) Constipation Pathophysiology Binds to any compound with a sulfhydryl group Inhibits multiple enzyme reactions including those involved in heme biosynthesis (PBG synthase & ferrochelatase) One symptom of lead toxicity is increases in 5-ALA without concomitant increases in PBG.

8 PORPHYRIAS A group of rare disorders caused by deficiencies of enzymes of the heme biosynthetic pathway. The majority of the porphyrias are inherited in autosomal dominant fashion - thus, affected individuals have 50% normal levels of the enzymes, and can still synthesize some heme. Affected individuals have an accumulation of heme precursors (porphyrins), which are toxic at high concentrations. Attacks of the disease are triggered by certain drugs, chemicals, and foods, and also by exposure to sun. Treatment involves administration of hemin, which provides negative feedback for the heme biosynthetic pathway, and therefore, prevents accumulation of heme precursors. Highly famous porphyria Presents on the skin, patients are photosensitive and have many ulcers and irritations in the skin. This is the heme pathway synthesis, and these are the enzymes that catalyze each reaction in the pathway. And also these are the different types of porphyrias and indicates which enzyme is deficient in this step.

9 When heme is degraded the end product will be bilirubin, and we will take more about it in the GI system. There is only one corner of the universe you can be certain of improving, and that s your own self