Heme Metabolism: Professor Sit Kim Ping 2009
Heme Metabolism: Professor Sit Kim Ping 2009
Heme Metabolism: Professor Sit Kim Ping 2009
METABOLISM
1
1 2
II
8 3
IV
IV II
II
7 4
III
III
6 5
PORPHYRIN 2
Biosynthesis of Heme
Mitochondria Cytosol
TCA Cycle
Succinyl CoA
ALA
synthase Glycine
ALA ALA
(δ-aminolevulinic acid)
3
Cytosol
ALA
Porphobilinogen
(PBG)
Uroporphyrinogen I
Coproporphyrinogen4 III
Mitochondria
Coproporphyrinogen III
Decarboxylase/
oxidase
Protoporphyrinogen IX
oxidase
Protoporphyrin IX
Fe++ Ferrochelatase
Protoheme or Heme
protein
Heme proteins (Hb, Mb, cytochromes, enzymes) 5
Biosynthetic pathway
• Regulation
• Action of Lead
• Porphyria
6
Heme-containing proteins
• Hemoglobin
• Myoglobin
• Cytochromes
• Enzymes (catalase, peroxidase,
tryptophan pyrrolase)
7
β1
α2
β2 α1
8
V M
V
M
M M
P P
His
Oxyhemoglobin Globin
9
M V
α
M M
p
Fe++
V
p M
Heme Degradation 10
DEGRADATION OF HEME
Heme
O2 + NADPH
Heme oxygenase
H2O + NADP+
cyt P450
Fe++
II III IV I CO
OH
OH
Biliverdin 11
Biliverdin
Biliverdin reductase
Bilirubin
12
Biliverdin
Color of bruise
Bilirubin
13
Products of Heme oxygenase (HO)
Cytotoxicity
CO competes with O2 for Hb
Bilirubin: Neurotoxic (basal ganglia)
(neonatal jaundice and bilirubin
encephalopathy)
14
Cytoprotective
Bilirubin (at low nanomolar concns) a
potent antioxidant, scavenger of free
radicals
Bilirubin: cytotoxic
and cytoprotective
15
Conjugation &
Degradation
of Bilirubin
16
BILIRUBIN GLUCURONIDE
17
Degradation of Bilirubin
Myoglobin
Cytochrome HEME
UCB = Fe++ CO
UCB
unconjugated
bilirubin Bilirubin-albumin
UDPGA
Albumin
Bilirubin glucuronide
Bile
Stercobilin (feces)
Bacteria
Urobilin (urine) 19
BLOOD Bilirubin-Albumin
HEPATOCYTE Bilirubin
Neonatal jaundice
CONJUGATION Crigler-Najjar syndrome
Gilbert’s disease
Bilirubin glucuronide
Transporter
Dubin-Johnson syndrome
SECRETION
(MRP2)
BILE Bilirubin glucuronide
DUCTULE 20
Normal
Urobilin Stercobilin
Hemolytic Jaundice 22
Bilirubin
Glucuronide
secretion
Urobilin Stercobilin
Hepatic Jaundice 23
Urobilin (absent) Stercobilin
Bilirubin present (absent or trace)
Obstructive jaundice
24
Bilirubin + UDPGA
UDPGlucuronyl
transferase
(UDPGT)
Bilirubin Glucuronide
Neonatal Jaundice 25
Phototherapy