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BIOSYNTHESIS & CATABOLISM OF

HEMOGLOBIN
Abdul Salam M. Sofro
Faculty of Medicine
YARSI University Jakarta

Learning objectives
By the end of learning, students are
expected to understand:
Molecular structure and function of
hemoglobin
Biosynthesis of hemoglobin
Catabolic process and the fate of
hemoglobin catabolic products

Hemoglobin in blood

Blood cells development

General
Hemoglobin (four subunits) and its similar
molecule myoglobin (one subunit) are ironcontaining heme proteins consists of
apoprotein & non-protein heme
These heme proteins function in oxygen
binding, oxygen transport, electron transport &
photosynthesis carried out by heme (a cyclic
tetrapyrrole) & its ferrous iron (at the center of
the planar ring)

Hemoglobin structure

Hemoglobin function

The Molecular structure is similar to


Myoglobin :
MW 17,000 ; a monomer of protein with
153 AA residues
stores oxygen in red muscle tissue will be
released under condition of oxygen
deprivation (eg. Severe exercise) and used
by muscle mitochondria for ATP synthesis

75% of the AA residues are present in 8 helix (helix A to H)


Histidin F8 and E7 perform unique roles in
oxygen binding
Oxygen-binding curve for myoglobin is
hyperbolic

Hemoglobin:
Transports oxygen, CO2 & protons
Its allosteric properties results from its
quaternary structures
A tetramer composed of pairs of different
polypeptides/subunits (, , , etc.
globin chains) a pair of globin chain
product of gene cluster in chromosome 11
& a pair of globin chain product of gene
cluster in chromosome 16

Hb binds 2 protons for every 4 oxygen


molecules released & thus contributes
significantly to buffering capacity of blood
increase in proton concentration promotes
oxygen release, while increase in PO2
promotes proton release.
At the lungs, oxygenation of Hb is
accompanied by expulsion and subsequent
expiration of CO2 Bohrs effect (a reversible
phenomenon with that in the peripheral
tissues)

2,3-Bisphosphoglycerate (BPG) in Hb
Formed from glycolytic intermediate 1,3bisphosphoglycerate
One molecule of BPG is bound per Hb
tetramer in the central cavity the space
is wide enough when Hb is in the T form
(deoxygenated)

Binds more weakly to fetal Hb than to


adult Hb
Increase concentration of BPG lowers
the affinity of Hb for oxygen (decreases
P50) increasing the ability of Hb to
release oxygen at the tissues

As CO2 is absorbed in the blood, the carbonic


anhydrase (CA) in erythrocyte catalyzes the
formation of carbonic acid, which in turn
rapidly dissociate into bicarbonate and a
proton. To avoid increasing the acidity of blood,
a buffering system must absorb these excess
protons this is carried out by Hb
CA

spontaneous

CO2 + H2O H2CO3 HCO3- + H+

Mutant human Hb
Causes hemoglobinopathy (when biologic
function is altered)
Due to mutations in the gene that code for
globin chains:
Structurally abnormal Hb (HbM, HbS, HbE,
HbC etc)
Reduced synthesis of Hb (thalassemias)
Diagnosed by special method (e.g. molecular
diagnosis)

Batak
Minahasa

1,5 0

Melayu
5,2 4,3

Minang

Bangka

3,7 2,9

5,4 4,5

Palembang
9,2 6,5

= trait hemoglobin-E

Palu

3,1 1,5

Banjar
0

1,2 3,7

1,2 6,1

2,9

Toraja
0

Tengger
0 10,6
Bali
Jawa
3,2 4,8

= trait thalassemia-

0 1,7

Dayak

4*

Sumbawa
5,1 6,8

Alor
0

Sasak
4,3 Sumba
2,5 36,6

Gambar . Pola distribusi dan prevalensi trait thalassemia- dan hemoglobin-E


pada berbagai populasi di Indonesia. * adalah hemoglobin OIna.

Heme

In addition to the heme b found in hemoglobin,


there are three different forms of heme found in
cytochromes such as those involved in the
process of oxidative phosphorylation.
Cytochromes of the c type contain a modified iron
protoporphyrin IX known as heme c. In heme c
the 2 vinyl (C=C) side chains are covalently
bonded to cysteine sulfhydryl residues of the
apoprotein. Only cytochromes of the c type
contain covalently bound heme. Heme a is also a
modified iron protoporphyrin IX. Heme a is found
in cytochromes of the a type and in the
chlorophyll of green plants

Biosynthesis of heme

Protoporphyrin IX

The sythesis of heme is a


complex process that
involves multiple
enzymatic steps. The
process begins in the
mitochondrion with the
condensation of succinylCoA and glycine to form 5aminolevulinic acid. A
series of steps in the
cytoplasm produce
coproporphrynogen III,
which re-enters the
mitochondrion. The final
enzymatic steps produce
heme.

Synthesis Of Porphobilinogen and Heme

http://themedicalbiochemistrypage.org/heme-porphyrin.html

Globin
a polypeptide chain (protein)
Various types of polypeptide chain:
Alpha globin
Beta globin
Gamma globin
Delta globin
Epsilon globin
Zetta globin
Teta globin

Globin Genes
Chromosome 11
(- cluster):
-G-A- --
Chromosome 16
(-cluster):
2-1-2-1-2-1-

Chromosome #16
5'

Globin Genes :
Chains Synthesized
Hb types :

2 2
(Gower-I)

2 2
(Portland)
Embryo

2 2
(Gower-II)

3'

Chromosome #11
5'

3'

Globin Genes :
Chains Synthesized
Hb types :

G
A
2 2 2 2
(Hb-F)
Fetus

2 2 2 2
(Hb-A2) (Hb-A)
Adult

% of total
globin
50
synthesis

30

10
6

18

30

prenatal age (wks)

birth

18

30

postnatal age (wks)

42

Types of Hemoglobin

Hb Gower 1
Hb Portland
Hb Gower 2
Hb Fetal (HbF)
Hb Adult (HbA)
Hb Adult minor (HbA2)

= 22
= 22
= 22
= 22
= 22
= 22

Catabolism of Heme

Heme Breakdown
During its 120 day life span the
erythrocyte has traveled 200-300 miles.
The process of aging is called
senescence.
Enzyme activity decreases (esp.
glycolytic enzyme which helps break
down glucose, the source of
erythrocyte energy), and the cell looses
its deformability.

MCHC (mean corpuscular hemoglobin


concentration) increases, the cell
becomes rounder, and the MCV mean
corpuscular volume) decreases.
90% of destruction of senescent
Erythrocytes occurs by extravascular
hemolysis. Macrophages of the
mononuclear phagocyte system remove
them from circulation.

Macrophages of the spleen are especially


active in removing aging, dead and abnormal
erythrocytes (e.g. cells containing Heinz
bodies or Howell-Jolly bodies, siderocytes,
target cells, schistocytes, tear drop cells and
antibody-coated erythrocytes).

Normally, Senescent Red Blood Cells and Heme


from other Sources are Engulfed by Cells of the
Reticuloendothelial System. The Globin is
Recycled or Converted into Amino Acids,
Which in turn are Recycled or Catabolized as
Required.

Heme is Oxidized, with the Heme Ring


Being Opened by the Endoplasmic
Reticulum Enzyme, Heme Oxygenase.
The Oxidation Step Requires Heme as
a Substrate, and any Hemin (Fe3+) is
Reduced to Heme (Fe2+) Prior to
Oxidation by Heme Oxygenase

Pathway for the


degradation of
heme to
bilirubin.
Substituents:
M = methyl,
P = proprionic,
V = vinyl

In individuals with abnormally high red cell


lysis, or liver damage with obstruction of
the bile duct, the bilirubin and its
precursors accumulate in the circulation;
the result is hyperbilirubinemia, the cause
of the abnormal yellowish pigmentation of
the eyes and tissues known as jaundice.

The protoporphyrin ring of heme is


disassembled. Its alpha carbon is
exhaled in the form of CO2. The opened
tetrapyrrole, biliverdin, is converted to
bilirubin which is then carried to the
liver by the plasma protein, albumin.

In the liver bilirubin is conjugated to


glucuronide to make it water soluble and
excreted along with bile into the intestines.
In the intestines it is converted by bacteria
into stercobilinogen and excreted in the
stool; some is eliminated as urobilinogen in
the urine.
Stercobilinogen and urobilinogen give feces
and urine their color.

Unconjugated bilirubin (prehepatic) and


conjugated bilirubin (posthepatic) are
measured in serum as indirect
(unconjugated) and direct (conjugated)
bilirubin; used to monitor amount of
hemolysis.
Bilirubin and its catabolic products are
collectively known as the bile pigments.

Intravascular Hemolysis
About 10% of normal erythrocyte
destruction occurs by intravascular
hemolysis.
In circulation the red cell is subjected to
metabolic and mechanical stresses:
turbulence, endothelial damage and fibrin
deposition, incompatibility due to
transfusion errors resulting in red cell
fragmentation (schistocytes) and/or
intravascular hemolysis.

When the erythrocyte ruptures,


hemoglobin is released into the blood. The
hemoglobin dissociates into alpha-beta
dimers and is picked up haptoglobin, a
protein carrier, to prevent renal excretion
of hemoglobin.
Haptoglobin carries the hemoglobin to the
liver for further catabolism where the
process proceeds as with extravascular
hemolysis.

As haptoglobin is depleted, unbound


hemoglobin dimers appear in the plasma
(hemoglobinemia) and are reabsorbed by
the kidney up to a certain level and
converted to hemosiderin; beyond this level
hemoglobin shows up in the urine
(hemoglobinuria)
Intravascular hemolysis results in pink, red or
brown plasma (hemoglobinemia). Urine may
also show red color (hemoglobinuria).

http://diaglab.vet.cornell.edu/clinpath/modules/chem/images/bilirubin%20metabolism.jpg

Clinical Aspect of Heme Metabolism


Clinical problems associated with heme
metabolism are of two types.
Disorders that arise from defects in the
enzymes of heme biosynthesis are termed
the porphyrias and cause elevations in the
serum and urine content of intermediates
in heme synthesis.
Inherited disorders in bilirubin metabolism
lead to hyperbilirubinemia

Porphyria

Enzyme Defect

Primary Symptom

-aminolevulinic acid
synthase 2, ALAS2

progressive iron
accumulation, fatal if not
treated

Erythroid Class

X-linked sideroblastic
anemia, XLSA

Congenital
erythropoietic
porphyria, CEP

Erythropoietic
protoporphyria, EPP

uroporphyrinogen III
cosynthase

photosensitivity

ferrochelatase

photosensitivity

Hepatic Class
ALA dehydratase deficient porphyria,
porphyria,
ADP

ALA dehydratase: also called


porphobilinogen synthase

neurovisceral

Acute intermittent porphyria,


porphyria, AIP

PBG deaminase: also called


hydroxymethylbilane
synthase or rarely
uroporphyrinogen I synthase

neurovisceral

coproporphyrinogen oxidase

neurovisceral,
some
photosensitivity

protoporphyrinogen oxidase

neurovisceral,
some
photosensitivity

Hereditary coproporphyria,
coproporphyria, HCP

Variegate porphyria,
porphyria, VP
Porphyria cutanea tarda type I, PCT
type I, also called the sporadic type
PCT

hepatic uroporphyrinogen
decarboxylase

Porphyria cutanea tarda type II, PCT


type II, also called the familial type
PCT, may also be referred to as
hepatoerythropoietic porphyria, HEP

uroporphyrinogen
photosensitivity
decarboxylase in nonnon-hepatic , some
tissues
neurovisceral

photosensitivity

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