Heme Metabolism and Hemoproteins Quiz

Heme Metabolism Objectives

• Study Heme Synthesis
• Understand Heme Catabolism
• Examine the Biochemical Basis and Clinical Implications of Porphyrias
• Explore Heme Catabolism into Bilirubin

Hemoproteins

• Hemoglobin: Oxygen transport in blood
• Myoglobin: Oxygen storage in muscles
• Cytochromes: Electron transport in the respiratory chain
• Cytochrome P450: Hydroxylation reactions
• Catalase and peroxidases: Degradation of hydrogen peroxide
• Tryptophan pyrrolase: Oxidation of tryptophan
• Nitric oxide synthase: Synthesis of nitric oxide

Heme Structure

• Heme is a Metaloporphyrin
• Heme = porphyrin ring (Protoporphyrin IX) + iron
• Porphyrins are cyclic compounds formed by fusion of four pyrrole rings linked by methenyl bridges
• Porphyrins form complexes with metal ions

Heme Synthesis Sites

• Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic group of enzymes and electron transport chain
• Major sites of heme synthesis are the liver, and erythroid progenitor cells of the bone marrow
• Liver involves formation of hemoproteins (e.g., cytochrome P450) for detoxification
• Erythroid cells involve hemoglobin synthesis
• Steps 1, 6, 7, and 8 occur in mitochondria
• Steps 2, 3, 4, and 5 occur in cytoplasm

Overview of Heme Synthesis

• Heme synthesis involves 8 steps
• Succinyl CoA + Glycine → 8-aminolevulinic acid
• Step 1: Formation of 8-ALA
  • Occurs in the mitochondria
  • Requires Pyridoxal phosphate (B6)
  • Catalyzed by d-amino levulenic acid synthase
  • Condensation reaction of succinyl-CoA and glycine
• Step 2: Formation of Porphobilinogen (PBG)
  • Occurs in the cytoplasm
  • Catalyzed by ALA dehydratase
  • Inhibited by Lead (Acquired porphyria)
• Last Step: Formation of heme
  • Occurs in the mitochondria
  • Catalyzed by Ferrochelatase
  • Inhibited by Lead (Acquired porphyria)

Regulation of Heme Synthesis

• Heme biosynthesis is regulated differently in erythroid and liver cells
• Rate-controlling enzyme for heme biosynthesis is ALA synthase
• Heme or its Fe(III) oxidized (Hematin and Hemin) products control the enzyme's activity via feedback inhibition
• Inhibiting ALA synthase transport from the cytosol to the mitochondria
• Repressing ALAS synthesis

Effect of Drugs on ALA Synthase Activity

• Drugs like barbiturates and grisofulvin increase ALA synthase activity, leading to more heme consumption.
• Consequently, heme concentration reduced, stimulating ALA synthase

Porphyrias

• Porphyria is an inherited genetic defect in enzyme of heme synthesis resulting in accumulation of porphyrin precursors
• Precursors increase in blood and appear in urine.
• Porphyrias are classified as erythropoietic or hepatic, depending on the major site where the deficiency manifests
• Porphyrias exhibit autosomal dominant (AD) inheritance, except for congenital erythropoietic porphyrias (AR).

Types of Porphyria

• Many types with different defects and symptoms
  • Acute Intermittent Porphyria (AIP): Usually expresses after puberty, abdominal pain, neuropsychiatric disturbances;triggered by drugs, infections, menstrual cycle; not photosensitive.
  • Porphyria cutanea tarda (PCT): Chronic cutaneous hepatic porphyria, the most common; caused by deficiency of the enzyme uroporphyrinogen decarboxylase; increased excretion of uroporphyrins; cutaneous photosensitivity.

Degradation of Heme

• Red blood cells (RBCs) live for 120 days.
• RBC degradation occurs in the Reticulo-endothelial System (RES) in the liver and spleen.
• Heme is released from hemoglobin; Globin reused
• Heme -> Biliverdin -> Bilirubin -> Excreted by liver into Bile.