A compele text of heme synthesis and the diseases associated with the process. Diseases have been discussed under the points of clinical featues, lab findings and treatment.

1. Heme
Metabolism
Dr Abhra Ghosh

2. STRUCTURE OF HEME
- Conjugated protein
- Derivative of porphyrin
- Cyclic compounds formed by fusion of 4 pyrrole rings
- Linked by methenyl (=CH-) bridges

3. • The pyrrole rings are named as I, II, III, IV
• The bridges as alpha, beta, gamma and delta
• The possible areas of substitution are denoted as 1 to 8

5. BIOSYNTHESIS OF PORPHYRINS:
SITES:
Partly mitochondria, partly cytoplasm (developing erythrocytes and
hepatic cells
STAGES:
Stage I: Synthesis of δ - ALA - in mitochondria
Stage II: Synthesis of coproporphyrinogen III (major series) and
coproporphyrinogen I (minor series) - in cytosol
Stage III: Synthesis of protoporphyrin IX – in mitochondria

6. Stage I: Synthesis of δ - ALA
• Condensation of ‘succinyl CoA’ (“active” succinate) and glycine
• Form ‘α-amino-β-Ketoadipic acid”.
• α-amino-β-ketoadipic acid undergoes decarboxylation to produce
δ-ALA

7. δ-ALA Synthetase Enzyme and its Regulation
• Erythropoietic substances including stimulate haem synthesis by
inducing the production of the enzyme
• End product ‘haem’ inhibits the enzyme by “feedback” inhibition
• Haem causes a repression of the synthesis of the enzyme

8. Stage II: Synthesis of coproporphyrinogen III and I
1. Formation of Porphobilinogen –
• Two molecules of δ-ALA condense to form a molecule of
porphobilinogen
• Catalysed by δ-ALA dehydratase (Zn Containing enzyme), Cu
as a cofactor
• Inhibited by lead

9. 2. Formation of Uroporphyrinogen I and III
• 4 mol. of porphobilinogens condense, losing 4 mol. of NH3
• Forms uroporphyrinogen I (minor series)
• Enzyme responsible porphobilinogen deaminase or
uroporphyrinogen-I synthetase

10. • Reversal of one porphobilinogen residue form uroporphyrinogen III
• Enzyme - an isomerase: uroporphyrinogen III cosynthetase
• In IVth pyrrole ring, acetic acid and propionic acid side chains are
“reversed” (cf. uroporphyrinogen I)

11. 3. Formation of
Coproporphyrinogen I
and III
• Four acetic acid side
chains get
decarboxylated
• Form methyl groups
• Enzyme–
Uroporphyrinogen
decarboxylase

12. Stage III: Formation of Protoporphyrin IX
• An oxidative decarboxylase system converts coproporphyrinogen
III to protoporphyrinogen IX
• Flavin acts as co-enzyme
• Protoporphyrinogen IX is converted to protoporphyrin IX another
oxidase enzyme
• The above steps require the presence of molecular O2

14. Formation of Haem and Haemoproteins
• Insertion of an atom of Fe++ into central position of protoporphyrin
IX
• Catalysed by haem synthetase (ferrochelatase)
• Requirement:
– Anaerobiosis
– Reducing agents such as glutathione

16. Regulation of Heme synthesis:
1. Effect of O2
- In vivo: Stimulated by low O2 tension
- In vitro: Conversion of porphobilinogen to uroporphyrinogen and
protoporphyrin to haem - inhibited by O2
- Decarboxylation of coproporphyrinogen – promoted by O2
2. Drugs: Many compound cause increase in hepatic δ-ALA
synthetase, leading to increased porphyrins
3. Hypoxia: increases δ-ALA synthetase activity
4. Steroids: drug meditated ‘derepression’ of δ-ALA synthetase
5. Iron: induction of δ-ALA synthetase.

17. 6. Enzyme Inhibition: Haem, the end-product of the metabolic
sequence, inhibits the activity of synthetase.
7. Lead: Inhibits δ-ALA synthetase, δ-ALA dehydratase and haem
synthetase
8. Glucose: Prevent induction of δ-ALA synthetase
9. Haematin: prevent the drug-mediated ‘derepression’ of δ-ALA
synthetase.

18. PORPHYRIAS
When the blood levels of coproporphyrins and uroporphyrins are
increased above normal level and excreted in urine/faeces, the
condition is called porphyria

20. I. Hereditary (Inherited) Porphyrias
A. Congenital Erythropoietic Porphyrias
Site of Lesion
- Expressed in erythropoietic tissues and affects red bone marrow
Inheritance
- Autosomal recessive
Enzyme Deficiency
- Deficiency of isomerase enzyme

21. Clinically
- Photosensitivity and skin lesions
- Porphyrins accumulate under the skin, normoblasts and erythrocytes.
- Teeth and bones may be brownish or pink due to porphyrin
deposition
Biochemically
- Increased amounts of porphyrins of type I
Urinary findings
- Portwine’ or ‘red’ coloured urine
- Contains type I isomers, oxidised to uroporphyrin I and
coproporphyrin I

22. Mast cell activation by complement activation induced by
protoporphyrin and irradiation
Release of preformed mediators from mast cells
Causes erythema, edema, and urticaria
Interaction of mast cells with fibroblasts, along with protoporphyrin
and irradiation contribute to the waxy thickening of skin

23. B. Hepatic porphyrias
a) Intermittent acute porphyria (IAP)
- Known as Paroxysmal porphyria
Inheritance:
Autosomal dominant
Enzyme deficiency:
Partial deficiency of deaminase (uroporphyrinogen I synthetase),
expressed in hepatic cells only
Race:
Found in Swedish family

24. Clinical features:
- GI symptoms
- CV abnormalities and neuropsychiatric signs and symptoms.
- Photosensitivity absent
- Increase in serum protein bound iodine
- Hypercholesterolaemia and diabetic type of Glucose tolerance curve
Urinary findings:
- On standing in sunlight urine turns to red wine colour.
- Increased quantities of porphobilinogen and δ-ALA
Biochemically: There is always associated catalase deficiency

25. b) Porphyria Cutanea Tarda
Race:
South African whites
Inheritance:
- Autosomal dominant
- Associated with hepatic injury, particularly alcohol or iron overload
Enzyme deficiency:
Partial deficiency of uroporphyrinogen decarboxylase
Clinical features:
Characterised principally by skin photosensitivity

26. Photoactivation of the complement and presence of uroporphyrin results in
activation of dermal mast cells
Results in dermal-epidermal separation, clinically as skin fragility and
vesicles
Uroporphyrin stimulates collagen biosynthesis by fibroblasts (independent
of irradiation)
Sclerodermoid lesions seen at sun-exposed as well as sun-protected areas

27. Urinary findings:
Contains uroporphyrins and coproporphyrins of both type I and type
III, as zinc complexes
Biochemically:
Frequent rise in serum iron

28. (c) Variegate Porphyria
Mixed or combined type porphyria
Inheritance:
Autosomal dominant.
Enzyme deficiency:
Partial block of enzymatic conversion of protoporphyrin IX to haem
Enzymes deficiency:
• Protoporphyrinogen oxidase, and
• Ferrochelatase (haemsynthetase)

29. Clinical features:
Mixed presentation.
Acute attacks of pain in abdomen, nausea and vomiting, constipation
Neuropsychiatric signs and symptoms
Cutaneous photosensitivity
Urinary findings:
Excretes δ-ALA, porphobilinogen and type I and III isomers

30. II. Acquired Porphyrias
a. Coproporphyrin type III
- Exposure to certain toxic chemicals and heavy metals
- Acute alcoholism
- Cirrhosis of the liver
- Conditions like poliomyelitis, aplastic anaemia, Hodgkin’s disease.
b. Coproporphyrin type I:
Abnormally large quantities of coproporphyrin type I found in the urine
- Obstructive jaundice
- Cirrhosis in non-alcoholics
- Haemolytic anaemia, pernicious anaemia and leukaemias.

31. Fluorescence of Porphyrins:
- Porphyrins dissolved in strong mineral acids or in organic solvents
- Illuminated by UV light
- Emit a strong red fluorescence
- The fluorescence is characteristic of free porphyrins.
The double bonds joining the pyrrole rings in the porphyrins are
responsible for the characteristic absorption and fluorescence of
these compounds

32. Cancer Phototherapy:
- Tumours often take up more porphyrins than do normal tissues
- Haematoporphyrins or other related compounds are administered to
a patient with appropriate tumour
- The tumour is then exposed to an argon laser, which excites the
porphyrins producing cytotoxic effects

33. 1. Which of the following steps in the biosynthesis of porphyrins is the
rate-controlling?
a. Uroporphyrinogen I synthetase
b. Uroporphyrinogen decarboxylase
c. δ-amino laevulinate synthetase
d. Protoporphyrinogen oxidase
e. None of the above
2. Substrates required for haemoglobin biosynthesis are:
a. ‘Active acetate’ and glycine
b. Glycine and ‘formate’
c. ‘Active succinate’ and lysine
d. ‘Active succinate and glycine
e. Formate and lysine

34. 3. Which of the porphyrins go into the formation of protoporphyrin IX?
a. Type I series b. Type II series
c. Type III series d. None of the above
e. All of the above
4. In the biosynthesis of porphyrins, which of the coenzyme is required for
δ-ALA formation:
a. FAD b. NAD+
c. NADP+ d. B6 – PO4
e. FMN

35. 5. δ-ALA dehydratase enzyme requires for its activity:
a. Fe++ b. Cu++
c. Mn d. Co
e. Mg
6. Oxidative decarboxylase system which converts coproporphyrinogen
III to protoporphyrinogen IX requires
which of the coenzyme:
a. NAD+ b. B6 – PO4
c. TPP d. Flavins
e. CoA-S

36. 7. The enzyme which catalyses the synthesis of Haem from
protoporphyrin IX is:
a. Ferroreductase b. Ferrochelatase
c. Ferro oxidase d. None of the above
e. All of the above
8. In mammalian liver, conversion of coproporphyrinogen III to
protoporphyrinogen IX requires the presence of:
a. ATP b. Molecular oxygen
c. Mg++ d. B6 – (P)
e. NAD+

37. 9. Uroporphyrin and coproporphyrin of which series is excreted in
urine in congenital erythropoietic porphyria:
a. Type I series b. Type II series
c. Type III series d. None of the above
e. All of the above