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Heme Biosynthesis and Regulation in Hepatic and Erythroid Tissues: Biochemistry

Heme Biosynthesis and Regulation

Biological Importance of Heme 

- Oxygen transport (Hemoglobin) & Storage (Myoglobin)
- Electron carrier in Electron Transport Chain  (Cytochromes)
- Prosthetic group of various enzyme
- Deficiency of the enzyme causes porphyria

Biosynthetic Pathway for the Synthesis of Heme 

Figure 1: Pathway for Heme Synthesis (Source: NEJM).  

Steps of the pathway:

1. Formation of Delta Aminolevulinic Acid (ALA):

- catalyzed by enzyme ALA synthase, rate limit step for the biosynthesis of Heme
- ALA synthase (ALAS) is a mitochondrial enzyme consisting of two isozymes
- ALAS1 is a housekeeping gene present in the cells consisting of mitochondria
- ALAS2 is the erythroid form of the ALA synthase
- Succinyl CoA and Glycine are the precursors that undergo condensation to form ALA
- ALAS require pyridoxal-5-phosphate as a cofactor
- The deficiency of ALA synthase causes X-Linked Sideroblastic Anemia 

2. Conversion of ALA to Porphobilinogen (PBG):

- catalyzed by enzyme a cytosolic enzyme ALA dehydratase
- the reactions occur in cytoplasm
- catalyzes the formation of the monopyrrole porphobilinogen from two molecules of ALA
- ALA dehydratase requires zinc into as a cofactor.

3. Conversion of Porphobilinogen to Hydroxymethylbilane 

- catalyzed by enzyme Porphobilinogen deaminase
- Porphyrin formation
- open tetrapyrrole ring is formed by from four hydroxymethylbilanes
- release four ammonia during the reaction
- inhibited by intermediates coproporphyrinogen III and protoporphyrinogen IX
- Deficiency of the enzyme causes Acute Intermittent Porphyria 

4. Conversion of hyroxymethylbilane to Uroporphyrinogen III

- catalyzed by enzyme Uroporphyrinogen III synthase
- cytoplasmic enzyme that rearranges and cyclizes HMB to form uroporphyrinogen III
- the deficiency of the enzyme causes Congenital Erythropoietic Porphyria 

5. Conversion of Uroporphyrinogen III to Coproporphyrinogen III

- Catalyzed by a cytosolic enzyme Uroporphyrinogen decarboxylase
- Coproporphyrinogen III is formed by the decarboxylation of four carboxymethyls groups from uroporphyrinogen III
- the deficiency of the enzyme causes Porphyria Cutanea tarda 

6. Conversion of Coproporphyrinogen III to Protoporphyrinogen IX

- catalyzed by enzyme Coproporphyrinogen oxidase
- Enzyme Coproporphyrinogen oxidase (CPOX) is present in the intermembrane space of mitochondria
- CPOX catalyzes the sequential decarboxylation of the carboxymethyl group to the vinyl group
- result in the formation of more lipid-soluble protoporphyrinogen
- the deficiency of the enzyme causes Hereditary coproporphyria 

7. Conversion of Protoporphyrinogen IX to Protoporphyrin IX

- Catalyzed by Protoporphyrinogen oxidase
- Protoporphyrinogen oxidase is a flavoprotein present in the inner mitochondrial membrane 
- the enzyme catalyzes the removal of six hydrogens to form protoporphyrin IX
- the deficiency of the enzyme causes Variegate Porphyria 

8. Conversion of Protoporphyrin IX to Heme (Iron incorporation)

- catalyzed by an inner-mitochondrial membrane enzyme ferrochelatase, an iron sulfur-containing protein
- the enzyme catalyzes the incorporation of Fe+2 into the protoporphyrinogen to form Heme
- the enzyme is sensitive to toxic metals such as lead 
- the deficiency of the enzyme causes protoporphyria 

Regulation of Heme Synthesis:

Regulation in Hepatocytes and other tissues 
- ALA synthase is the rate-limiting enzyme for the synthesis of heme 
- ALA synthase 1 is ubiquitously expressed in all tissue containing mitochondria
- Negatively regulated by heme, 
- Heme destabilizes mRNA for ALAS1, blocks mitochondrial import of ALAS1 etc.
- induced by drugs and chemical that induce cytochrome P450
- direct transcriptional activation by the drugs and chemicals 

Regulation in Erythroid tissue
- The ALAS2 is encoded by a gene on chromosome X121-22
- Mainly expressed in erythroid tissue
- Increased transcription during erythroid differentiation
- Iron level regulates the ALAS2 in erythroid tissues
- Low iron inhibits the translation of ALAS2 mRNA 
- The effect is exerted by the binding of the regulatory protein to the iron response element in the 5' UTR of ALAS2 mRNA (Click Here For Details: Iron Metabolism)
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