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Chapter 16
Hemal Biochemistry
The biochemistry and molecular biology department of CMU
• Composition of the blood
– The liquid element: plasma
– The formed elements: red blood cells (ery
throcytes), white blood cells (leukocytes),
and platelets (thrombocytes).
• Plasma --- The blood fraction obtained after
removal of the cellular components.
• Serum --- The liquid element obtained by allo
wing the blood to clot.
§1 Heme Synthesis
Sites:
Mitochondria and cytoplasm
Precursors:
Glycine, succinyl CoA, Fe2+
1. Synthetic pathway of heme
(1) The formation of -aminolevulinic acid (ALA)
+HSCoA + CO2
ALA synthase (pyridoxal phosphate)
In the mitochondria
COOH
H2C
CH2
C¡«SCoA
O
CH2NH2
COOH
COOH
H2C
CH2
C
CH2NH2
O
(2) The formation of porphobilinogen (PBG)
ALA dehydratase
2H2O
In the cytosol
NH
OH
O
OH
O
NH2
COOH
CH2
CH2
C
C
N
O
H H
H H
(3) The formation of uroporphyrinogen (UⅢPG ) and coproporphyrinogen (CPGⅢ Ⅲ
) Ⅲ
4× Porphobilinogen Linear tetrapyrrol
UPGⅢCPGⅢ
Deaminase
UPG Ⅲisomerase
UPGⅢdecarboxylase
In the cytosol
Protoporphyrinogen Ⅸ
Protoporphyrin ⅨHeme ferrochelatase
(4) The formation of heme
CPGⅢoxidase
CPGⅢ
Protopor- phyrinogen Ⅸoxidase
In the mitochondria
Heme
Protoporphyrin Ⅸ
Protoporphyrinogen Ⅸ CPGⅢ UPGⅢ
Linear tetrapyrrol
PBG
Gly
succinyl CoA
(1) ALA synthase
•Rate-limiting enzyme
•Feedback-inhibition by heme
•Intensity inhibition by Ferriheme
•Inducing by some drugs and hormones (eg. testosterone)
2. Regulation of heme biosynthesis
(3) Erythropoietin (EPO) can increase sy
nthesis of heme and hemoglobins.
(2) ALA dehydrase and ferrochelatase
Inhibited by heme, and heavy metals.
§2
Metabolism of Bile
Pigment and Jaundice
bile pigment is the main catabolic p
roduct of iron porphyrin compound in t
he body, consisting of bilirubin, biliver
din, bilinogen and bilin.
* The source of bilirubin
The compounds involving iron pr
ophyrin in the body are hemoglobin,
myoglobin, cytochrome, peroxidase,
and catalase, etc.
1. Formation and transport of bilirubin
* Formation of bilirubin
• site
In the microsome and cytosol of monokaryon- macrophage system of the liver, spleen, and bone marrow.
N N
NN
HOOC
Fe2+
COOH
2O2
NADPH+H+
NADP+
COFe3+
HN
HN
P
N
P
HNO O
NADPH+H+
NADP+
HN
HN
PP
HNO O
HH
heme
biliverdin
bilirubin
heme oxygenase
biliverdin reductase
HN
¦Ä
¢ô ¢ó
¢ò¢ñ
¦Ã
¦Â
¦Á
• process
The spatal structure of bilirubin
N
N H
N
N
O
CO
OO
H
C
O
H
HOH
H
• property
hydrophobic
* Transport of Bilirubin
•Form of Transport
Bilirubin-albumin complex
2. Bilirubin conversion in liver
* Uptake
* Transport
Smooth Endoplasmic reticulum
Combine with ligandin
* Conjugation
Bilirubin monoglucuronide
bilirubin
UDPUDP-glucuronyl transfe
rase
UDPGA
Bilirubin diglucuronide
UDPGA
UDPUDP-glucuronyl transfe
rase
structure of bilirubin diglucuronide
HN
HN
HN
HNO O
HH
H2C CH2
CH2
CO
O
CH2
CO
OO
H
HO
H
H
OH
COOH
HH
OH
O
H
OH
HO
H
H
H
OH
H
COOH
* Excretion
Conjugated bilirubin is secreted
into the bile and then excreted into the
intestine.
Conjugated bilirubin
bilinogen
coliform
Glucuronic acid
Bilinoxidized
* process
3. Metabolism bilirubin in the intestine
Free bilirubin
reduced
NHN
PP
NHO OHHH
bilirubin
H H
+8H
d-urobilinogen
+8H
HN
HN
HN
PP
NHO OHHHH
N
NHN
PP
NHO OHHHH
NH H H H
H HH HH
mesobilirubinogen
d-urobilin
HN
HN
PP
NHO OHHHH
NH HH HH
H HH H
stercobilinogen (l-urobilinogen)
+4H
stercobilin (l-urobilin)
H H
2H
2H
Bilinogen enterohepatic circulation
In the terminal ileum and large i
ntestine, a small fraction of the urob
ilinogens is reabsorbed and reexcret
ed through the liver to constitute the
enterohepatic cycle of urobilinogen.
Hb
globin
heme
NADPH+H+
NADP+
biliverdin
bilirubin
2O2
H2O
Fe3+
+CO
NADPH+H+
NADP+
bilirubin-albumincomplex
bilirubin
ligandin bilirubin-ligandincomplex
bilirubin glucuronide
UDPGA
UDPER
cytosol
liver cellmonokaryon-macrophage cell blood
intestine
glucuronic acid
bilirubin
bilinogen
bilinogen (a little)
bilin
feces
kidneya small fraction
a large fraction
bilinogenO2O2
bilin
urine
bilirubin glucuronide
4. Serum bilirubin and jaundice
• Conjugated bilirubin is also called dire
ct reacting bilirubin or hepatobilirubin.
* Serum bilirubin
1 ~ 16mol/l (0.1 ~ 1mg/dl)
• Free bilirubin is also called indirect re
acting bilirubin or hemobilirubin.
free bilirubi
n conjugated
bilirubin
Binding with Glucuronic acid
no yes
Reacting with the diazo reagent
Slow and indirect
Rapid and direct
solubility in water small large
Discharged via kidney no yes
Pass through the membrane of cell
yes no
difference of two bilirubins
Jaundice
• Hemolytic (prehepatic) jaundice
• Hepatocellular (hepatic) jaundice
• Obstructive (posthepatic) jaundice
Laboratory results in patients with jaundice
normalHemolyticjaundice
Hepatocellularjaundice
Obstructivejaundice
Serum bilirubin
total <1mg/dl >1mg/dl >1mg/dl >1mg/dl
direct 0~ 0.8mg/dl
↑
indirect < 1
Urine bile pigments
urobilirubin – – + + + +
urobilinogen A few ↑ uncertainty ↓
urobilin A few ↑ uncertainty ↓
Color of feces normal dark Simple or normal Clay color
↑↑ ↑
↑↑