Heme Metabolism: Professor Sit Kim Ping 2009

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HEME

METABOLISM

Professor Sit Kim Ping 2009

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1 2

II
8 3
IV
IV II
II
7 4
III
III

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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

Mitochondria Uroporphyrinogen III

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
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Heme-containing proteins

• Hemoglobin
• Myoglobin
• Cytochromes
• Enzymes (catalase, peroxidase,
tryptophan pyrrolase)
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β1
α2

β2 α1
8
V M
V
M

M M

P P

His
Oxyhemoglobin Globin
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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)

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Cytoprotective
Bilirubin (at low nanomolar concns) a
potent antioxidant, scavenger of free
radicals

Bilirubin: cytotoxic
and cytoprotective
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Conjugation &
Degradation
of Bilirubin
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BILIRUBIN GLUCURONIDE
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Degradation of Bilirubin

Bilirubin glucuronide LIVER

Bilirubin glucuronide BILE


β-glucuronidase
Bilirubin GUT
reduction
Mesobilirubin GUT
reduction
Mesobilirubinogen GUT
reduction
Urobilinogen Stercobilinogen

Urobilin(1-2 mg/day in urine) Stercobilin ( ≈ 250 mg/day in18 feces)


RBC Hemoglobin

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

UPTAKE Gilbert’s disease

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

Bilirubin absent Stercobilin:


0-4 mg urobilin/day 40-280 mg/day
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Bilirubin formation

Urobilin Stercobilin

Hemolytic Jaundice 22
Bilirubin
Glucuronide
secretion

Urobilin Stercobilin

Hepatic Jaundice 23
Urobilin (absent) Stercobilin
Bilirubin present (absent or trace)

Obstructive jaundice
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Bilirubin + UDPGA

UDPGlucuronyl
transferase
(UDPGT)

Bilirubin Glucuronide

Neonatal Jaundice 25
Phototherapy

Absorption spectrum of bilirubin-albumin


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Photo-
isomerization
products of
bilirubin
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(Z,Z) Bilirubin,
present naturally 28
(Z,E) Bilirubin 29
Lumirubin
Cyclization product 30

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