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BIOSYNTHSIS OF HEME
“Believe In Yourself”
Know that there is something
inside you
That is greater than any
obstacles.
Dr. Santhosh Kumar N
Associate Professor
Department of Biochemistry
PRIMS, Hanamkonda, TS
Functions of Heme
• Heme is the prosthetic group of several proteins & enzymes
– Transport of gases (Hemoglobin & Myoglobin)
– Electron transfer (cytochrome-c,a,a3,b, involve ETC)
– Chemical catalysis (tryptophan pyrrolase)
– Detoxification (cytochrome-P450)
– Antioxidant defence (Catalase, Peroxidase)
• Heme production:
• Bone marrow (80%) & The liver (20%)
• In heme synthesis:
• The first & last 3 reactions occurs in mitochondria &intermediate
reactions takes place in cytosol
• Heme is a derivative of porphyrin
(Ferroprotoporphyrin).
• Porphyrin are cyclic compounds formed by
fusion 4 pyrrole rings linked by methenyl
(=CH-) bridges, with iron atom.
• Starting material of the heme synthesis-
Glycine & Succinyl CoA.
M: Methyl, V: Vinyl, P: Propionyl
Coordination bonds of Iron
Heme Biosynthesis
• Heme synthesis: all most all the tissues
– In normoblast but not in the matured erythrocytes
• Partly cytoplasmic and partly mitochandrial
Step -1: ALA Synthesis
In mitochondria:
• Condensation of Succinyl-CoA and
glycine in the presence of PLP to form
delta amino levulinic acid (δ-ALA) by
ALA synthase.
• Rate-limiting enzyme of the pathway.
PLP: Pyridoxal phosphate
Step 2: Formation of PBG
In the cytoplasm:
• 2 moles of ALA are condensed to form
porphobilinogen (PBG) by ALA
dehydratase (zinc contain)
• Inhibited by lead.
Step 3: Formation of UPG
In the cytoplasm:
• Condensation of 4 PBG, forms Uroporphyrinogen (UPG)
• Condensation occurs in a head-to-tail manner, so that a
linear tetra pyrrole is produced (OH- methyl bilane
(HMB). By PBG-deaminase (otherwise called
Uroporphyrin -I synthase or HMB synthase).
• HMB will cyclise spontaneously to form
uroporphyrinogen –I further converted to
uroporphyrinogen -III by uroporphyrinogen -III
synthase.
Step 4: Synthesis of CPG
In the cytoplasm:
• UPG-III is next converted to
coproporphyrinogen (CPG-III) by
uroporphyrinogen decarboxylase.
• Four moles of CO2 are eliminated.
• The acetate groups (CH2–COOH) are
decarboxylated to methyl (CH3) groups.
Step 5: Synthesis of PPG
In mitochondria:
• CPG is oxidized to proto-porphyrinogen- III
by coproporphyrinogen oxidase.
• This enzyme specifically acts only on type -
III series, and not on type I series.
• Two propionic acid side chains are oxidatively
decarboxylated to vinyl groups.
Step 6: Generation of Protoporphyrin
In mitochondria:
• The proto-porphyrinogen-III is oxidized by
proto-porphyrinogen oxidase to form proto
porphyrin-III.
• The methylene bridges (–CH2) are oxidized to
methenyl bridges (–CH=) and colored
porphyrins formed.
• Protoporphyrin-IX is thus formed.
Step 7: Generation of Heme
In mitochondria
• Formation of heme is the attachment of ferrous
iron to the protoporphyrin by heme synthase or
ferrochelatase.
• When the ferrous iron (Fe++) in heme gets
oxidized to ferric (Fe+++) form – hematin
• Which loses the property of carrying the oxygen.
• Heme is red in color, but hematin is dark brown.
Regulation of Heme synthesis
1. ALA synthase is regulated by repression mechanism.
• Heme inhibits the synthesis of ALA synthase by acting as a co-repressor.
2. ALA synthase is also allosterically inhibited by hematin.
• Excess of heme, the Fe++ is oxidized to Fe+++ (ferric), thus forming hematin.
3. The compartmentalization of the enzymes in the synthesis of heme makes it
easier for the regulation.
• The rate-limiting enzyme is in the mitochondria.
• The steps 1,5,6, and 7 are taking place inside mitochondria, while the steps 2,3 and 4 are in
cytoplasm.
4. Drugs like barbiturates induce heme synthesis.
– Barbiturates require the heme containing cytochrome p450 for their metabolism.
– Out of the total heme synthesized, two thirds are used for cytochrome p450
production.
5. Lead inhibits ferrochelatase and ALA dehydratase .
6. INH (Isonicotinic acid hydrazide)
 Decreases the availability of pyridoxal phosphate may also affect heme synthesis.
Disorders of Heme Biosynthesis
(Porphyrias)
• Porphyrias are rare inherited (autosomal) or acquired disorder due to deficiencies of
enzymes in heme synthesis.
• This leads to accumulation & increased excretion of porphyrins or porphyrin precursors
(ALA & PBG) in the urine & feces.
• Porphyrin precursors are also excreted in urine under normal conditions,
– PBG - 2mg in urine/ day.
– ALA - 1.7mg in urine/ day.
Classification
• The porphyrias are classified as
– Erythropoietic porphyria &
– Hepatic porphyrias,
Depending on whether the enzyme deficiency occurs in the
erythropoietic cells of the bone marrow or in the liver.
Acute intermittent porphyria
– Inherited as an autosomal dominant trait
» Pass from one parent onto their child
» Pass from both parents onto their child -autosomal recessive trait
– ALA & PBG are elevated in blood & urine
» PBG deaminase (UPG-I synthase) defect
– On standing – urine turns colorless to more color
» Due to photo-oxidation of PBG to porphobilin
• No photosensitivity.
– Porphyrin are not excreted or elevated in blood
• Most common patient with acute abdominal pain & vomiting
• More frequency in female than in males
– Female sex hormones have a stimulatory effect on ALA synthase
• Neuropsychiatric manifestation
– Fluctuating BP & may present sensory & motor disturbances, confusion.
Diagnosis of Porphyrias
• UV fluorescence is the best technique to demonstrate porphyrins.
• The presence of porphyrin precursor in urine is detected by Ehrlich's test.
• When urine is observed under UV light; porphyrins if present, will emit
strong red fluorescence.
Soret Band
• All porphyrins will have an absorption band near 400nm; this distinguishing
band is called the Soret band.
• UP, CP and PP show Soret bands at 406, 400 and 408 respectively.
• Heme does not possess this property.
Urinary Excretion of Prophyrins
Urinary Excretion Disorder
ALA (δ- amino levulinic acid )
PBG (Porphobilinogen )
Acute intermittent porphyria (AIP)
CP (coproporphyrinogen) Erythropoeitic porphyria
UP (Uroporphyrinogen) Acquired porphyrias
PP (Protoporphyrin ) Acquired porphyrias
Over thinking is the biggest waste of
human energy.
Trust yourself, make a decision & gain
more experience.
There is no such thing as perfect. You
cannot think your way into perfection.
Just take action
Thank Q

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HM-01 HEME BIOSYNTHESIS & Porphyrias .pptx

  • 1. BIOSYNTHSIS OF HEME “Believe In Yourself” Know that there is something inside you That is greater than any obstacles. Dr. Santhosh Kumar N Associate Professor Department of Biochemistry PRIMS, Hanamkonda, TS
  • 2. Functions of Heme • Heme is the prosthetic group of several proteins & enzymes – Transport of gases (Hemoglobin & Myoglobin) – Electron transfer (cytochrome-c,a,a3,b, involve ETC) – Chemical catalysis (tryptophan pyrrolase) – Detoxification (cytochrome-P450) – Antioxidant defence (Catalase, Peroxidase)
  • 3. • Heme production: • Bone marrow (80%) & The liver (20%) • In heme synthesis: • The first & last 3 reactions occurs in mitochondria &intermediate reactions takes place in cytosol
  • 4. • Heme is a derivative of porphyrin (Ferroprotoporphyrin). • Porphyrin are cyclic compounds formed by fusion 4 pyrrole rings linked by methenyl (=CH-) bridges, with iron atom. • Starting material of the heme synthesis- Glycine & Succinyl CoA. M: Methyl, V: Vinyl, P: Propionyl
  • 7. • Heme synthesis: all most all the tissues – In normoblast but not in the matured erythrocytes • Partly cytoplasmic and partly mitochandrial
  • 8. Step -1: ALA Synthesis In mitochondria: • Condensation of Succinyl-CoA and glycine in the presence of PLP to form delta amino levulinic acid (δ-ALA) by ALA synthase. • Rate-limiting enzyme of the pathway. PLP: Pyridoxal phosphate
  • 9. Step 2: Formation of PBG In the cytoplasm: • 2 moles of ALA are condensed to form porphobilinogen (PBG) by ALA dehydratase (zinc contain) • Inhibited by lead.
  • 10. Step 3: Formation of UPG In the cytoplasm: • Condensation of 4 PBG, forms Uroporphyrinogen (UPG) • Condensation occurs in a head-to-tail manner, so that a linear tetra pyrrole is produced (OH- methyl bilane (HMB). By PBG-deaminase (otherwise called Uroporphyrin -I synthase or HMB synthase). • HMB will cyclise spontaneously to form uroporphyrinogen –I further converted to uroporphyrinogen -III by uroporphyrinogen -III synthase.
  • 11. Step 4: Synthesis of CPG In the cytoplasm: • UPG-III is next converted to coproporphyrinogen (CPG-III) by uroporphyrinogen decarboxylase. • Four moles of CO2 are eliminated. • The acetate groups (CH2–COOH) are decarboxylated to methyl (CH3) groups.
  • 12. Step 5: Synthesis of PPG In mitochondria: • CPG is oxidized to proto-porphyrinogen- III by coproporphyrinogen oxidase. • This enzyme specifically acts only on type - III series, and not on type I series. • Two propionic acid side chains are oxidatively decarboxylated to vinyl groups.
  • 13. Step 6: Generation of Protoporphyrin In mitochondria: • The proto-porphyrinogen-III is oxidized by proto-porphyrinogen oxidase to form proto porphyrin-III. • The methylene bridges (–CH2) are oxidized to methenyl bridges (–CH=) and colored porphyrins formed. • Protoporphyrin-IX is thus formed.
  • 14. Step 7: Generation of Heme In mitochondria • Formation of heme is the attachment of ferrous iron to the protoporphyrin by heme synthase or ferrochelatase.
  • 15. • When the ferrous iron (Fe++) in heme gets oxidized to ferric (Fe+++) form – hematin • Which loses the property of carrying the oxygen. • Heme is red in color, but hematin is dark brown.
  • 16.
  • 17. Regulation of Heme synthesis 1. ALA synthase is regulated by repression mechanism. • Heme inhibits the synthesis of ALA synthase by acting as a co-repressor. 2. ALA synthase is also allosterically inhibited by hematin. • Excess of heme, the Fe++ is oxidized to Fe+++ (ferric), thus forming hematin. 3. The compartmentalization of the enzymes in the synthesis of heme makes it easier for the regulation. • The rate-limiting enzyme is in the mitochondria. • The steps 1,5,6, and 7 are taking place inside mitochondria, while the steps 2,3 and 4 are in cytoplasm.
  • 18. 4. Drugs like barbiturates induce heme synthesis. – Barbiturates require the heme containing cytochrome p450 for their metabolism. – Out of the total heme synthesized, two thirds are used for cytochrome p450 production. 5. Lead inhibits ferrochelatase and ALA dehydratase . 6. INH (Isonicotinic acid hydrazide)  Decreases the availability of pyridoxal phosphate may also affect heme synthesis.
  • 19. Disorders of Heme Biosynthesis (Porphyrias)
  • 20. • Porphyrias are rare inherited (autosomal) or acquired disorder due to deficiencies of enzymes in heme synthesis. • This leads to accumulation & increased excretion of porphyrins or porphyrin precursors (ALA & PBG) in the urine & feces. • Porphyrin precursors are also excreted in urine under normal conditions, – PBG - 2mg in urine/ day. – ALA - 1.7mg in urine/ day.
  • 21. Classification • The porphyrias are classified as – Erythropoietic porphyria & – Hepatic porphyrias, Depending on whether the enzyme deficiency occurs in the erythropoietic cells of the bone marrow or in the liver.
  • 22. Acute intermittent porphyria – Inherited as an autosomal dominant trait » Pass from one parent onto their child » Pass from both parents onto their child -autosomal recessive trait – ALA & PBG are elevated in blood & urine » PBG deaminase (UPG-I synthase) defect – On standing – urine turns colorless to more color » Due to photo-oxidation of PBG to porphobilin
  • 23. • No photosensitivity. – Porphyrin are not excreted or elevated in blood • Most common patient with acute abdominal pain & vomiting • More frequency in female than in males – Female sex hormones have a stimulatory effect on ALA synthase • Neuropsychiatric manifestation – Fluctuating BP & may present sensory & motor disturbances, confusion.
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  • 26. Diagnosis of Porphyrias • UV fluorescence is the best technique to demonstrate porphyrins. • The presence of porphyrin precursor in urine is detected by Ehrlich's test. • When urine is observed under UV light; porphyrins if present, will emit strong red fluorescence.
  • 27. Soret Band • All porphyrins will have an absorption band near 400nm; this distinguishing band is called the Soret band. • UP, CP and PP show Soret bands at 406, 400 and 408 respectively. • Heme does not possess this property.
  • 28. Urinary Excretion of Prophyrins Urinary Excretion Disorder ALA (δ- amino levulinic acid ) PBG (Porphobilinogen ) Acute intermittent porphyria (AIP) CP (coproporphyrinogen) Erythropoeitic porphyria UP (Uroporphyrinogen) Acquired porphyrias PP (Protoporphyrin ) Acquired porphyrias
  • 29. Over thinking is the biggest waste of human energy. Trust yourself, make a decision & gain more experience. There is no such thing as perfect. You cannot think your way into perfection. Just take action Thank Q