metabolism of tetrapyrrols pavla balnov. tetrapyrrols circular compounds binding a metal ion (most...
DESCRIPTION
Where can we find a heme?? Hemoproteins Hemoglobin (Hb) Myoglobin (Mb) Cytochrome c Catalases (decomposition of H 2 O 2 to H 2 O and O 2 ) Figure was assumed fromTRANSCRIPT
![Page 1: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/1.jpg)
Metabolism of tetrapyrrols
Pavla Balínová
![Page 2: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/2.jpg)
Tetrapyrrols• circular compounds
binding a metal ion (most frequently Fe2+ and Fe3+)
• consist of 4 pyrrol rings interconnected via methine bridges
Examples:• heme (Fe2+)• chlorophyll (Mg2+)• vitamin B12 (Co2+)
Figure was assumed from http://en.wikipedia.org/wiki/Porphyrin
![Page 3: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/3.jpg)
Where can we find a heme??
Hemoproteins• Hemoglobin (Hb)• Myoglobin (Mb)• Cytochrome c • Catalases
(decomposition of H2O2 to H2O and O2)
Figure was assumed from http://en.wikipedia.org/wiki/Heme
![Page 4: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/4.jpg)
Heme structure
pyrrol
methine bridge
Figure was assumed from a book T. M. Devlin et al.: Textbook of Biochemistry With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
![Page 5: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/5.jpg)
Biosynthesis of heme• Organ location: bone marrow 85% and liver • Subcellular location: mitochondria and cytosol
• Substrates: succinyl-CoA and glycine
• Important intermediates: δ-aminolevulinic acid (ALA), porphobilinogen, uroporphyrinogen III, protoporphyrin IX
• Key regulatory enzyme: ALA synthase
![Page 6: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/6.jpg)
Heme biosynthesis
Figure was assumed from http://www.porphyrin.net/mediporph/_netbiochem/synthesis/_synthmain.html
![Page 7: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/7.jpg)
Delta-aminolevulinic acid (ALA)• synthesis of heme starts in mitochondria• succinyl-CoA and glycine (Gly) undergo
condensation → δ-aminolevulinic acid (ALA)• reaction is catalyzed by enzyme ALA synthase
-OOC-CH2-CH2-CO-S-CoA + NH3+-CH2-COO-
CO2 -OOC-CH2-CH2-CO-CH2-NH3
+
![Page 8: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/8.jpg)
Porphobilinogen (PBG)• ALA leaves the mitochondria → cytoplasm• 2 molecules of ALA condense to form porphobilinogen• reaction is catalyzed by enzyme porphobilinogen
synthase
Figure was assumed from http://en.wikipedia.org/wiki/Porphobilinogen
pyrrol ring
![Page 9: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/9.jpg)
Uroporphyrinogen III
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
![Page 10: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/10.jpg)
Uroporphyrinogen → coproporphyrinogen III
• enzyme hydroxymethylbilane synthase catalyzes the linkage of 4 PBG molecules and cleavage of 4 NH4
+ to yield uroporphyrinogen III• 4 acetate residues are decarboxylated into
methyl groups → coproporphyrinogen III returns to the mitochondria again
![Page 11: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/11.jpg)
Protoporphyrinogen IX
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
![Page 12: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/12.jpg)
Protoporphyrinogen IX → protoporphyrin IX
• oxidation of protoporphyrinogen IX produces the conjugated π-electron system of protoporphyrin IX
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
![Page 13: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/13.jpg)
Heme
• Fe2+ is incorporated into protoporhyrin IX• reaction is catalyzed by enzyme ferrochelatase
Figure was assumed from http://www.porphyrin.net/mediporph/_netbiochem/synthesis/ferrochelatase.html
![Page 14: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/14.jpg)
Regulation of heme biosynthesisALA synthase is a key regulatory enzyme• it is an allosteric enzyme that is inhibited by heme = feedback inhibition• requires pyridoxal phosphate• certain drugs and steroid hormones can increase heme synthesis
Porphobilinogen synthase is inhibited by lead ions Pb2+ in case of lead poisoning.
Ferrochelatase can be also inhibited by Pb2+. Its activity is influenced by availability of Fe2+ and ascorbic acid.
![Page 15: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/15.jpg)
Porphyrias• are hereditary or acquired disturbances of heme synthesis
• in all cases there is an identifiable abnormality of the enzymes which synthesize heme
• this leads to accumulation of intermediates of the pathway and a deficiency of heme → excretion of heme precursors in feces or urine, giving them a dark red color
● accumulation of porphyrinogens in the skin can lead to photosensitivity • the neurological symptoms
![Page 16: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/16.jpg)
Heme degradation• around 100 – 200 million aged erythrocytes per hour are broken down in the human organism• Organ location: RES (reticuloendothelial cells) in the spleen, liver and bone marrowHb is degraded to:● globin → AAs → metabolism● heme → bilirubin● Fe2+ → transport with transferrin and used in the next heme biosynthesis
Not only Hb but other hemoproteins also contain heme groups which are degraded by the same pathway.
![Page 17: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/17.jpg)
Conversion of heme to bilirubin
Figure was assumed from http://web.indstate.edu/thcme/mwking/heme-porphyrin.html
![Page 18: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/18.jpg)
BilirubinBilirubin (Bil) is released from RES into the blood. BUT! Bil is only poorly soluble in plasma, and therefore during transport it is bound to albumin. ↓ LIVERIn the hepatocytes, Bil is conjugated by 2 molecules of glucuronic acid → bilirubin diglucuronide (soluble in water, „conjugated Bil“). Conjugation is catalyzed by UDP-glucuronosyltransferase.
![Page 19: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/19.jpg)
Bilirubin diglucuronide
Figure was assumed from http://web.indstate.edu/thcme/mwking/heme-porphyrin.html
![Page 20: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/20.jpg)
Bile pigments bilirubin diglucuronide ↓ BILE ↓ INTESTINEBil is reduced to urobilinogen and stercobilinogen by bacteria → oxidation to urobilin and stercobilinBile pigments are mostly excreted in feces, but a small proportion is resorbed (enterohepatic circulation).Small amount of urobilinogen is excreted with urine.
![Page 21: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/21.jpg)
Determination of bilirubin in serum
Blood tests • Bil reacts directly when dyes are added to the
blood sample → conjugated bilirubin = direct
• free Bil does not react to the reagents until alcohol (methanol) or caffeine is added to the solution. Therefore, the measurement of this type of bilirubin is indirect → unconjugated bilirubin = indirect
• Total bilirubin measures both unconjugated and conjugated Bil (normal value up to 20 µmol/L).
![Page 22: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/22.jpg)
Hyperbilirubinemias• Hyperbilirubinemia = an elevated bilirubin level
(> 10 mg/L) → Bil can diffuses from the blood into peripheral tissues and gives it a yellow color (jaundice = icterus)
Jaundice can have various causes: • Increased erythrocyte degradation – hemolytic
jaundice• Impaired conjugation of bilirubin in the liver –
hepatocellular jaundice• Disturbance of bile drainage (gallstones) –
obstructive jaundice
In the urine, only conjugated bilirubin can be present.
![Page 23: Metabolism of tetrapyrrols Pavla Balnov. Tetrapyrrols circular compounds binding a metal ion (most frequently Fe 2+ and Fe 3+ ) consist of 4 pyrrol](https://reader035.vdocument.in/reader035/viewer/2022062909/5a4d1b977f8b9ab0599c42dd/html5/thumbnails/23.jpg)
IcterusIcterus is the yellow coloration of skin and mucus membranes of jaundice (hyperbilirubinemia with various ethiology) • Hemolytic icterus: elevated level of unconjugated Bil in blood
• Neonatal jaundice usually appears after a few days after birth (elevated hemolysis, decreased activity of UDP-glucuronosyltransferase → ↑ unconjugated Bil)In severe cases, unconjugated Bil can cross the blood-brain barrier and lead to brain damage (kernicterus).