Heme synthesis

Describes the pathway of heme synthesis. Rate limiting step and negative feed back involved in heme synthesis is explained.

1. Heme synthesis Radhakrishna G Pillai

2. Heme –iron containing compound Gender-based difference in t he total body iron content in adult humans; approximately 50 mg/kg in men and 40 mg/kg in women Due to the decreased mass of red cells, muscle and liver in women Almost all iron in body is incorporated into heme -containing proteins, particularly hemoglobin, myoglobin and cytochromes The unique properties of heme allows it to function both as an electron carrier and a catalyst for redox reactions An iron molecule is coordinated within a tetrapyrrole ring

3. Heme synthesis B iochemical pathway with many steps, substrates, and enzymes A deficiency in an enzyme or substrate leads to accumulation of intermediates of heme synthesis in blood, tissues, and urine Leads to a group of disorders called porphyrias Porphyrias are hepatic or erythropoietic They can be acute or chronic Cause neurologic dysfunction, mental disturbance or photosensitivity Other symptoms: change in urine color, abdominal colic, highly agitated state, tachycardia, respiratory problems, nausea etc.  

4. Heme synthesis Heme synthesis is through a highly conserved pathway This involves both cytosolic and mitochondrial compartments Protoporphyrin IX is generated Protoporphyrin IX is an important compound in heme synthesis All of the heme biosynthetic genes are nuclear-encoded and translated in the cytoplasm

5. Location of heme synthesis Most of the heme synthesis takes place in developing red cells in the marrow About 15% of the daily production takes place in the liver for the formation of heme -containing enzymes In the liver, heme biosynthetic enzymes are turned over rapidly, enabling the liver to respond to changing metabolic requirements In erythroid progenitors the pathway is regulated to permit a high steady-state level of heme synthesis and Regulation is tied to the availability of iron

6. Porphyrins Large heterocyclic organic ring structures Composed of 4 modified pyrrole subunits connected by methine (=CH-) bridges Heme is an example of naturally occurring porphyrin Heme in biological system consists of Fe2 + ions complexed with 4N of porphyrin molecules Three structurally distinct hemes in human; heme a, b and c Heme is critical for biological functions of several enzymes – eg cytochromes of oxidative phosphorylation Cytochrome P450 family (CYP)

7. Heme synthesis First reaction occurs in mitochondria Condensation of one succinyl-coA & glycine by pyridoxal phosphate requiring enzyme (vitamin B6) – δ aminolevulinic acid synthase (ALAS) forming δ aminolevulinic acid (5 aminoleuvinic acid) This is the rate limiting reaction in heme synthesis There are both “housekeeping” and erythroid genes for aminolevulinate synthase

8. Formation of Porphobilinogen ALA is transported to cytosol ALA dehydratase (porphobilinogen synthetase ) dimerises 2 molcules of ALA Forms Porphobilinogen

9. Heme synthesis Head-tail condensation of four molecules of porphobilinogen (PBG) form the tetrapyrrole , hydroxymethylbilane (HMB) Enzyme for this condensation is porphobilinogen deaminase (PBG deaminase) Hydroxymethylbilane has two fates One due to enzymatic action Other due to non-enzymatic action

10. Heme synthesis Hydroxymethylbilane is enzymatically converted to uroporphyrinogen III Mediated by the enzyme uroporphyrinogen III synthase Uroporphyrinogen III is decarboxylated by uroporphyrinogen decarboxylase Forms coproporphyrinogens Coproporphyrinogen III is most important in heme synthesis Coproporphyrinogen III transported to the interior of the mitochondria

11. Formation of conjugated ring Propionate residues of Coproporphyrinogen III are decarboxylated Protoporphyrinogen IX formed Catalysed by coproporphyrinogen -III oxidase To protoporphyrin IX (PROTO IX)– By protoporphyrinogen IX oxidase This oxidation requires oxygen as the terminal electron acceptor Protoporphyrinogen IX protoporphyrin IX Coproporphyrinogen -III oxidase

12. Insertion of Fe 2+ Ring system -Loss of 6 protons and 6 electrons – produce a completely conjugated ring Final reaction in heme synthesis takes place on the inner surface of the inner mitochondrial membrane Insertion of Fe 2+ into the ring system Enzyme involved is ferrochelatase Responsible for the red colour of heme

13. Thank you [email protected] 0091 9495554891