heme catabolism
Post on 06-Jan-2016
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HEME CATABOLISM
Prof.Dr.Arzu SEVEN
HEME CATABOLISM
•In one day, 70 kg human turns over = 6 gr of Hb
•Hb heme iron_free porphyrin iron (reuse)
globulin amino acid (reuse)
~
• Heme is the source of bile pigments .• Iron free porphrin of heme is degraded in RES
(liver,spleen bone_marrow) by microsomal heme oxygenase system.
• Humans have at least 3 izoenzyems of heme oxygenase (HO).
• HO-1 highyl regulated, induced by a wide range of stress conditions (shear stress, angiogenesis, hypoxia, heat shock, UV light, H2O2)
• HO-2 MAİNLY İN BRAİN γ TESTES• HO-3 NOT WELL CHARACTERİZED• Iron is oxidized to ferric form HEMIN
• Hemin is reduced to heme by NADPH.• O2 is added to α_methenyl bridge
between pyroles I and II of the porphyrin.• Ferrous iron is again oxidized to ferric
form.
• O2 is added, Fe is released, CO is produced, tetrapyrole ring is split to form biliverdin (green).
+3
• In animals biliverdin reductase reduces the methenly bridge between pyrole III and IV to a methylene group to produce bilirubin. (yellow pigment)
• 1 gr Hb 35 mg biliburin • Daily bilirubin formation in human adults =
250-350mg (from Hb +ineffective erytropoiesis+cyt P450)
• The CO produced by heme oxygenase is toxic at high concentrations, however at very low concentrations generated during heme degradation, it has regulatory and/or signalling functions, it acts as a vasodilatator, less potent than NO.
• Low levels of CO have regulatory effects on neurotransmission .
• Bilirubin is the most abundant antioxidant in mammalian tissues and is responsible for the most of the antioxidant activity in serum.
• İts protective effects are important in the developing brain of newborn infants
• Bilirubin formed in peripheral tissues is transported to liver by albumin
• IN LIVER:
1)Uptake of bilirubin by liver paranchmal cells
2)conjugation of bilirubin with glucuronate in endoplasmic reticulum
3)secretion of conjugated bilirubin into bile
• Uptake of bilirubin by liver
• Bilirubin is only sparingly soluble in water
• İts solubility in plasma is increased by noncovalent binding to albumin
• Albumin has one high affinity site and one low affinity site for bilirubin
• In 100 ml plasma = 25 mg bilirubin can be tightly bound to albumin at high affinity site
• Antibiotics and other drugs compete with bilirubin to bind to high_affinity site of albumin.
• In liver, bilirubin is removed from albumin and taken up at the sinusoidal surface of hepatocytes by a facilated transport system.
• In the hepatocytes bilirubin binds to cytosolic proteins :
ligandin (a family of glutathione s-transferases) and protein γ_to be kept solubilized prior to conjugation.
Conjugation of bilirubin with glucuronic acid
• Bilirubin is non_polar.
• Hepatocytes convert bilirubin to a polar form by adding glucuronic acid to it (conjugation)
• Enzyme: glucuronosyl transferase
• Location:endoplasmic reticulum
• Glucuronosyl donor:UDP_GLUCURONİC ACİD
• Bilirubin monoglucuronide is an intermediate, subsequently converted to diglucuronide.
• Phenobarbital induces UDP_glucuronosyl_transferase activity
Secretion of conjugated bilirubin into bile
• Active transport mechanism• Rate-limiting for the entire hepatic bilirubin
metabolism • MRP_2 (multidrug resistance like protein 2) = MOAT(multi specific organic anion
transporter)Location:plasma membrane of the bile
canalicular membrane
• A member of the family of ATP_binding cassette (ABC) transporters
• Inducible by phenobarbital• Conjugation γ excretion systems behave as a
coordinated functional unit.• Conjugated bilirubin reaches the terminal ileum
and large intestine.• The glucuronides are removed by
β_glucuronidases (specific bacterial enzymes)
• The pigment is reduced by intestinal bacteria (fecal flora) to urobilinogen (colorless tetrapyrolic compound)
• A small portion of urobilinogen is reabsorbed and reexcreted through the liver: ENTEROHEPATİC UROBİLİNOGEN CYCLE
• Some urobilinogen is reabsorbed into the blood and transported to the kidney, where it is oxidized to urobilin(the compound that gives urine its yellow color).
• Urobilinogen remaining in the intestine is converted to stercobilin, which gives the red_brown color to feces .
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