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



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



Hemoglobin in blood



Blood cells development



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)



Hemoglobin structure



Hemoglobin function



• 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



• 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



• 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



• 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)



• 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)



• 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



• 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



• 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

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



Heme



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



Biosynthesis of heme



Protoporphyrin IX



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.



Synthesis Of Porphobilinogen and Heme

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



Globin

• a polypeptide chain (protein)

• Various types of polypeptide chain:

• Alpha 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-





2 21 1 1

Globin Genes :

5' 3'

Chromosome #16

2 22 22 2Hb types :

Embryo

(Gower-I) (Portland) (Gower-II)

Chains Synthesized



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



50

% of totalglobinsynthesis

10

6 18 30 6 18 30 42

prenatal age (wks)

birth

postnatal age (wks)



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



Catabolism of Heme



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.



• 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.



• 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).



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.



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



Pathway for the

degradation ofheme 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;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.



• 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.



• 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.



• 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.



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.



• 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.



• 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).



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

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

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



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


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


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


, some, some

neurovisceralneurovisceral



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2.2. Biosintesis Hemoglobin