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Heme biosynthesis & porphyria
- 1. HEME BIOSYNTHESIS & PORPHYRIAS in short Dr. Deepa Anantha Laxmi N.V
- 2. MITOCHONDRIA CYTOSOL HEME BIOSYNTHESIS 4 STEPS IN MITOCHONDRIA AND 4 STEPS IN CYTOSOL
- 3. HEME • HEME Or iron porphyrin IX is a part of many compounds • Hemoglobin • Myoglobin • Respiratory cytochromes • Peroxidase • Cytochromes P450 • Catalase • Tryptophan pyrrolase, and • Nitric oxide synthase
- 4. HEME BIOSYNTHESIS PATHWAY AND PORPHYRIAS • The eight enzymatic steps involved in heme biosynthesis pathway • The 1st and last three- 6th, 7th and 8th steps in the pathway are carried out in the mitochondria while the intermediate four steps are performed in the relatively reducing environment of the cytosol. • Pathology in heme biosynthesis leads to disorders known as Porphyrias (8 in number). • The name porphyria is from the Greek term πορφύρα, porphyra, meaning "purple“, • Descriptively used to refer to the colour of urine in these disorders.
- 5. HEME BIOSYNTHESIS PATHWAY AND PORPHYRIAS
- 6. TYPES OF PORPHYRIAS Type Name Inheritance Gene affected Chromosom al location Comments Acute or Inducible Porphyrias ALA DEFICIENCY PORPHYRIA AR Pbgs 9q34 Very rare severe disease in infancy ACUTE INTERMITTENT PORPHYRIA AD Hmbs 11q23.3 Most severe form HERIDITARY COPROPORPHYRIA AD Cpox 3q12 May also have cutaneous features VARIEGATED PORPHYRIA AD Ppox 1q22 May also have cutaneous features
- 7. TYPES OF PORPHYRIAS Type Name Inheritance Gene affected Chromosomal location Comments Cutaneous Chronic Porphyrias CEP AR Uro3 10q26.1-q26.2 Rare usually manifests itself in infancy/childhood HEP AR Urod 1p34.1 Rare usually manifests itself in infancy/childhood PCT (Type I) Acquired None Diseases of adults PCT (Type II) AD Urod 1p34.1 Requires additional defects EPP AR Fech 18q21.31 Common; onset in infancy XLPP X-linked Alas1 Xp11.21 Gain of function mutations
- 8. TYPES OF PORPHYRIAS Type Name Inheritance Gene affected Chromosomal location Comments Acute Hepatic Porphyrias ALADP AR Pbgs 9q34 Very rare severe disease in infancy AIP AD Hmbs 11q23.3 Most severe form HCP AD Cpox 3q12 May also have cutaneous features VP AD Ppox 1q22 May also have cutaneous features
- 9. TYPES OF PORPHYRIAS Type Name Inheritance Gene affected Chromosomal location Comments Chronic Hepatic Porphyrias PCT (Type I) Acquired None Diseases of adults PCT (Type II) AD Urod 1p34.1 Requires additional defects HEP AR Urod 1p34.1 Rare usually manifests itself in infancy/childhood Erythropoietic Porphyrias CEP AR Uro3 10q26.1-q26.2 Rare usually manifests itself in infancy/childhood EPP AR Fech 18q21.31 Common; onset in infancy
- 10. DIAGNOSIS OF PORPHYRIA Type of porphyria Enzyme defect Urine Stool Plasma Rbcs X-linked protoporphyria ALA synthase-2 (gain of function) Normal PROTO PROTO Zn PROTO ALA dehydratase deficiency (ADP) ALA dehydratase COPRO ALA Normal ALA Zn PROTO Acute intermittent porphyria (AIP) PBG deaminase ALA, PBG, URO I Normal COPRO I ALA, PBG, URO I ↓PBGD Congenital erythropoietic porphyria (CEP) Uroporphyrinog en III synthase (cosynthase) COPRO I URO I COPRO I COPRO I URO I COPRO I URO I
- 11. DIAGNOSIS OF PORPHYRIA Type of porphyria Enzyme defect Urine Stool Plasma Rbcs Porphyria cutanea tarda (PCT) and Hepatoerythropo ietic porphyria (HEP) Uroporphyrinoge n III decarboxylase Uroporphyrin, heptacarboxyl porphyrin Heptacarboxyl porphyrin ISOCOPRO Uroporphyrin, heptacarboxyl porphyrin Zn PROTO Hereditary coproporphyria (HCP) Coproporphyrino gen III oxidase ALA, PBG, COPRO III COPRO III COPRO Normal Variegate porphyria (VP) Protoporphyrino gen oxidase ALA, PBG, COPRO III PROTO COPRO III Porphyrin peptide conjugate Normal Erythropoietic protoporphyria (EPP) Ferrochelatase COPRO III with hepatopathy PROTO PROTO PROTO
- 12. REFERENCES • Harrison’S Internal Medicine • Articles: • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279155/ • https://www.sciencedirect.com/science/article/abs/pii/S1096719218 305869
- 13. THANK YOU