2.2. Biosintesis Hemoglobin
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Transcript of 2.2. Biosintesis Hemoglobin
7/23/2019 2.2. Biosintesis Hemoglobin
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BIOSYNTHESIS & CATABOLISM OF
HEMOGLOBIN
Abdul Salam M. Sofro
Faculty of MedicineYARSI University Jakarta
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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 ofhemoglobin catabolic products
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Hemoglobin in blood
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Blood cells development
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General
• Hemoglobin (four subunits) and its similarmolecule myoglobin (one subunit) are iron-
containing heme proteins consists ofapoprote n non-prote n eme
• These heme proteins function in oxygenbinding, oxygen transport, electron transport &
photosynthesis carried out by heme (a cyclictetrapyrrole) & its ferrous iron (at the center ofthe planar ring)
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Hemoglobin structure
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Hemoglobin function
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• The Molecular structure is similar toMyoglobin :
• 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 usedby muscle mitochondria for ATP synthesis
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• 75% of the AA residues are present in 8 -
helix (helix A to H)
• Histidin F8 and E7 perform unique roles inoxygen n ng
• Oxygen-binding curve for myoglobin is
hyperbolic
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• Hemoglobin:
• Transports oxygen, CO2 & protons
• Its allosteric properties results from its
quaternary structures
• A tetramer composed of pairs of differentpolypeptides/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
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• Hb binds 2 protons for every 4 oxygen
molecules released & thus contributessignificantly to buffering capacity of blood
increase in proton concentration promotes
oxygen release, while increase in PO2
.
• At the lungs, oxygenation of Hb is
accompanied by expulsion and subsequent
expiration of CO2Bohrs effect (a reversiblephenomenon with that in the peripheral
tissues)
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• 2,3-Bisphosphoglycerate (BPG) in Hb
• Formed from glycolytic intermediate 1,3-bisphosphoglycerate
• One molecule of BPG is bound per Hbtetramer in the central cavity the spaceis wide enough when Hb is in the T form(deoxygenated)
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• Binds more weakly to fetal Hb than toadult Hb
• Increase concentration of BPG lowers
P50) increasing the ability of Hb torelease oxygen at the tissues
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• 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,
protons this is carried out by Hb
CO2 + H2O H2CO3HCO3- + H+CA spontaneous
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• 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)
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Batak
Melayu
Minang
Bangka
Dayak
Banjar
Palu
Minahasa
Toraja
1,5 0
3,7
5,2
2,9
4,3
5,4 4,5
3,1 1,5
0 1,7
1,2 3,7
Palembang
Jawa
Tengger
SumbawaBali
Sumba
Sasak
Alor
Gambar . Pola distribusi dan prevalensi trait thalassemia- dan hemoglobin-E
pada berbagai populasi di Indonesia. * adalah hemoglobin OIna
.
9,2 6,5
3,2 4,8
0 10,6
0 0 0 4*
1,2 6,1
2,9 4,32,5 36,6
5,1 6,8 0 0
= trait thalassemia-
= trait hemoglobin-E
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Heme
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In addition to the heme b found in hemoglobin,
there are three different forms of heme found incytochromes 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 vin l C=C side chains are covalentl
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 foundin cytochromes of the a type and in the
chlorophyll of green plants
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Biosynthesis of heme
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Protoporphyrin IX
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The sythesis of heme is a
complex process thatinvolves multiple
enzymatic steps. The
process begins in the
mitochondrion with the
condensation of succinyl- -
aminolevulinic acid. A
series of steps in the
cytoplasm produce
coproporphrynogen III,which re-enters the
mitochondrion. The final
enzymatic steps produce
heme.
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Synthesis Of Porphobilinogen and Heme
http://themedicalbiochemistrypage.org/heme-porphyrin.html
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Globin
• a polypeptide chain (protein)
• Various types of polypeptide chain:
• Alpha globin
•
• Gamma globin
• Delta globin
• Epsilon globin• Zetta globin
• Teta globin
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Globin Genes
• Chromosome 11
(- cluster):
-G -A - --
• Chromosome 16
(-cluster):
2-1-2-1-2-1-
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2 21 1 1
Globin Genes :
5' 3'
Chromosome #16
2 22 22 2Hb types :
Embryo
(Gower-I) (Portland) (Gower-II)
Chains Synthesized
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3'5'G A
Globin Genes :
Chromosome #11
2 2 222 2 2 2
Fetus Adult
(Hb-F)(Hb-A ) (Hb-A)2
G
G
A
A
Hb types :
Chains Synthesized
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50
% of totalglobinsynthesis
10
6 18 30 6 18 30 42
prenatal age (wks)
birth
postnatal age (wks)
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Types of Hemoglobin
• Hb Gower 1 = 22
• Hb Portland = 22 • ower =
• Hb Fetal (HbF) = 22
•Hb Adult (HbA) =
2
2
• Hb Adult minor (HbA2) = 22
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Catabolism of Heme
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Heme Breakdown
• During its 120 day life span the
erythrocyte has traveled 200-300 miles.
The process of aging is calledsenescence.
• Enzyme activity decreases (esp.
glycolytic enzyme which helps break
down glucose, the source of
erythrocyte energy), and the cell looses
its deformability.
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• MCHC (mean corpuscular hemoglobinconcentration) increases, the cell
becomes rounder, and the MCV mean
corpuscular volume) decreases.
•
Erythrocytes occurs by extravascular
hemolysis. Macrophages of the
mononuclear phagocyte system removethem from circulation.
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• 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,, ,
antibody-coated erythrocytes).
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Normally, Senescent Red Blood Cells and Heme
from other Sources are Engulfed by Cells of the
Reticuloendothelial System. The Globin isRecycled or Converted into Amino Acids,
Which in turn are Recycled or Catabolized as
Required.
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Heme is Oxidized, with the Heme Ring
Being Opened by the Endoplasmic
Reticulum Enzyme, Heme Oxygenase.
a Substrate, and any Hemin (Fe3+) is
Reduced to Heme (Fe2+) Prior to
Oxidation by Heme Oxygenase
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Pathway for the
degradation ofheme to
bilirubin.
Substituents:
M = methyl,
P = proprionic,
V = vinyl
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• 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;t e resu t s yper ru nem a, t e cause
of the abnormal yellowish pigmentation of
the eyes and tissues known as jaundice.
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• The protoporphyrin ring of heme isdisassembled. 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.
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• 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 thestool; some is eliminated as urobilinogen in
the urine.
• Stercobilinogen and urobilinogen give feces
and urine their color.
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• Unconjugated bilirubin (prehepatic) and
conjugated bilirubin (posthepatic) are
measured in serum as indirect
(unconjugated) and direct (conjugated)ru n; use to mon tor amount o
hemolysis.
• Bilirubin and its catabolic products are
collectively known as the bile pigments.
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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 totransfusion errors resulting in red cell
fragmentation (schistocytes) and/or
intravascular hemolysis.
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• When the erythrocyte ruptures,hemoglobin is released into the blood. Thehemoglobin dissociates into alpha-betadimers and is picked up haptoglobin, a
protein carrier, to prevent renal excretiono emog o n.
• Haptoglobin carries the hemoglobin to theliver for further catabolism where the
process proceeds as with extravascularhemolysis.
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• 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
hemo lobin shows u in the urine(hemoglobinuria)
• Intravascular hemolysis results in pink, red or
brown plasma (hemoglobinemia). Urine mayalso show red color (hemoglobinuria).
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http://diaglab.vet.cornell.edu/clinpath/modules/chem/images/bilirubin%20metabolism.jpg
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Clinical Aspect of Heme Metabolism
• Clinical problems associated with heme
metabolism are of two types.
• Disorders that arise from defects in the
the porphyrias and cause elevations in the
serum and urine content of intermediates
in heme synthesis.• Inherited disorders in bilirubin metabolism
lead to hyperbilirubinemia
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Porphyria Enzyme Defect Primary Symptom
Erythroid Class
X-linked sideroblastic
anemia, XLSA
δ-aminolevulinic acid
synthase 2, ALAS2
progressive iron
accumulation, fatal if nottreated
Congenital
erythropoietic
porphyria, CEP
uroporphyrinogen III
cosynthasephotosensitivity
Erythropoietic
protoporphyria, EPPferrochelatase photosensitivity
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Hepatic ClassHepatic Class
ALA dehydratase deficient porphyria ALA dehydratase deficient porphyria,,
ADP ADP
ALA dehydratase: also called ALA dehydratase: also called
porphobilinogen synthaseporphobilinogen synthaseneurovisceralneurovisceral
Acute intermittent porphyria Acute intermittent porphyria, AIP, AIP
PBG deaminase: also calledPBG deaminase: also calledhydroxymethylbilanehydroxymethylbilane
synthase or rarelysynthase or rarely
uroporphyrinogen I synthaseuroporphyrinogen I synthase
neurovisceralneurovisceral
Hereditary coproporphyriaHereditary coproporphyria, HCP, HCP coproporphyrinogen oxidasecoproporphyrinogen oxidase
neurovisceral,neurovisceral,
somesome
photosensitivityphotosensitivity
Variegate porphyriaVariegate porphyria, VP, VP protoporphyrinogen oxidaseprotoporphyrinogen oxidase
neurovisceral,neurovisceral,
somesome
photosensitivityphotosensitivity
Porphyria cutanea tardaPorphyria cutanea tarda type I, PCTtype I, PCT
type I, also called the sporadic typetype I, also called the sporadic type
PCTPCT
hepatic uroporphyrinogenhepatic uroporphyrinogendecarboxylasedecarboxylase
photosensitivityphotosensitivity
Porphyria cutanea tardaPorphyria cutanea tarda type II, PCTtype II, PCT
type II, also called the familial typetype II, also called the familial type
PCT, may also be referred to asPCT, may also be referred to as
hepatoerythropoietic porphyria, HEPhepatoerythropoietic porphyria, HEP
uroporphyrinogenuroporphyrinogen
decarboxylase in nondecarboxylase in non--hepatichepatic
tissuestissues
photosensitivityphotosensitivity
, some, some
neurovisceralneurovisceral
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