Chapter 16

Hemal Biochemistry
The biochemistry department of SYMC

Quaternary Structure of hemoglobin

O2 transporter in
RBC.
4
subunits Each
subunit contains
one heme group.

1 Heme Synthesis

Sites:
Mitochondria and cytosol
Precursors:
Glycine, succinyl CoA, Fe2+
ferri
ion

1. Synthetic pathway of heme

(1) The formation of -amino levulinic acid
(ALA)
levulinic=Acetyl propionic acid
COOH

COOH
H2C
CH2

CSCoA
O

CH2NH2
COOH

HSCoA + CO2
ALA synthase
(pyridoxal
phosphate)

ALA synthase is the key enzyme

In the mitochondria

H2C
CH2
C

CH2NH2

(2) The formation of porphobilinogen (PBG)

COOH
O

CH2

OH

CH2

HO

ALA
O
H dehydratase

2H2O
H2N

In the cytosol

N
H

(3) The formation of uroporphyrinogen

(UPG) and coproporphyrinogen
(CPG)
4 Porphobilinogen

CPG
In the cytosol

Deaminase

UPG
decarboxylase

Linear
tetrapyrrol
UPG
isomerase

UPG

(4) The formation of heme

CPG

Heme

CPG
oxidase

Protoporphyrinogen

Protoporphyrinogen

ferrochelatase
oxidase
Protoporphyrin

In the mitochondria

PBG

Heme

Gly
succinyl CoA

Linear
tetrapyrrol

Protoporphyrin

Protoporphyrinogen

CPG

UPG

2. Regulation of heme biosynthesis

(1) ALA synthase
Rate-limiting enzyme
Feedback-inhibition by heme
Intensity inhibition by Ferriheme
Inducing by some drugs and
hormones (eg. testosterone)

(2) ALA dehydrase and ferrochelatase

Inhibited by heme, and heavy metals.

(3) Erythropoietin (EPO) can increase

synthesis of heme and hemoglobins.

2
Metabolism of Bile
Pigment and Jaundice

bile pigment is the main catabolic

product of iron porphyrin compound in
the body, consisting of bilirubin,
biliverdin, bilinogen and bilin.

1. Formation and transport of

bilirubin
The source of bilirubin
The compounds involving iron
prophyrin in the body are
hemoglobin, myoglobin, cytochrome,
peroxidase, and catalase, etc.

 Formation of bilirubin
site
In the microsome and cytosol of
monokaryon- macrophage system of
the liver, spleen, and bone marrow.

 process

Ketoform enol form

H
N

NADP+ O

H
N

Fe2+
N

NADPH+H+

Fe3+ CO
heme oxygenase

H
N

biliverdin
NADPH+H+
biliverdin reductase

HOOC

NADP+

heme
O

Reduce reduction

P P

2O2

COOH

H
N

H
N

H
N

P P
bilirubin

H
N

 property
hydrophobic

O
H
O

N
H

C
O

color

NH
O

The spatial structure of bilirubin

H
O
C
HO

 Transport of Bilirubin

Form of Transport
Bilirubin-albumin complex

2. Bilirubin conversion in liver

Uptake
Transport
Combine with ligandin

Smooth Endoplasmic reticulum


Conjugation

bilirubin UDPGA
UDPglucuronyl
transferase

UDP

Bilirubin
monoglucuronide
UDPGA

UDPglucuronyl
transferase

UDP

Bilirubin
diglucuronide

structure of bilirubin diglucuronide

O

H
N

H
N

H2C

H
OH

CH2

CO

CO

HO

COOH
O
H

H
H

CH2

OH

H
N

H
N

CH2
COOH
O

H
OH

OH
HO

 Excretion
Conjugated bilirubin is secreted
into the bile and then excreted into the
intestine.

3. Metabolism bilirubin in the

intestine
process
Conjugated
bilirubin

coliform

Free bilirubin

Glucuronic acid

Bilin

oxidized

reduced
bilinogen

Bilinogen enterohepatic circulation

In the terminal ileum and large
intestine, a small fraction of the
bilinogens is reabsorbed and
reexcreted through the liver to
constitute the enterohepatic cycle of
bilinogen.

monokaryon-macrophage cell

liver cell

blood

Hb

bilirubin
globin

heme

bilirubin-albumin
complex

cytosol

bilirubin-ligandin
complex

ligandin

NADPH+H+

2O2
Fe3+

UDPGA
NADP+

ER

H2O
+CO
biliverdin

UDP
bilirubin glucuronide

NADPH+H+

a large fraction

NADP+

bilirubin

bilinogen (a little)
a small
fraction

kidney
bilinogen

O2

urine

bilin
feces

bilinogen
O2
bilin

bilirubin
glucuronide

bilirubin

intestine

glucuronic
acid

4. Serum bilirubin and jaundice

Serum bilirubin
1 16mol/l (0.1 1mg/dl)
Conjugated bilirubin is also called
direct reacting bilirubin or
hepatobilirubin.
Free bilirubin is also called indirect
reacting bilirubin or hemobilirubin.

difference of two bilirubins

free
bilirubin

conjugated
bilirubin

Binding with Glucuronic

acid

no

Reacting with the diazo

reagent

Slow and
indirect

Rapid and
direct

small

large

Discharged via kidney

no

yes

Pass through the

membrane of cell

yes

no

solubility in water

yes

Jaundice
Hemolytic (prehepatic) jaundice
Hepatocellular (hepatic) jaundice
Obstructive (posthepatic) jaundice

Laboratory results in patients with jaundice

normal

Hemolytic
jaundice

< 1mg/dl

> 1mg/dl

Hepatocellular
jaundice

Obstructive
jaundice

Serum bilirubin
total
direct

0~ 0.8mg/dl

indirect

<1

> 1mg/dl

> 1mg/dl

Urine bile pigments

urobilirubin

++

++

urobilinogen

A few

uncertainty

urobilin

A few

uncertainty

Color of feces

normal

dark

Simple or normal Clay color

monokaryon-macrophage cell

liver cell

blood

Hb

bilirubin
globin

heme

bilirubin-albumin
complex

cytosol

bilirubin-ligandin
complex

ligandin

NADPH+H+

2O2
Fe3+

UDPGA
NADP+

ER

H2O
+CO
biliverdin

UDP
bilirubin glucuronide

NADPH+H+

a large fraction

NADP+

bilirubin

bilinogen (a little)
a small
fraction

kidney
bilinogen

O2

urine

bilin
feces

bilinogen
O2
bilin

bilirubin
glucuronide

bilirubin

intestine

glucuronic
acid