HemoglobinStructure and Function

Abbas A. A. Shawka

Introduction

• Hemoglobin is a protein ( Heme protein )• Types of proteins are

globular proteins ( functional proteins ) linear proteins ( structural proteins )

• Hb is considered of globular proteins.• Mature RBCs do NOT synthesis Hb, while

immature RBCs synthesis Hb.• Mitochondria is very important for Heme

synthesis

Hemoglobin = Heme + globin ( protein )

Note : globin is considered as a protein so that it synthesized by RER.

Heme synthesis

• Heme = Protoporphyrin + Iron • Protoporphyrin = Iron free Heme• Protoporphyrin consist of 4 pyrrol rings.• Iron have 6 coordination, 4 bind with these 4

pyrrol rings of protoporphyrin, 1 bind with histidine ( anino acid ) from globulin and 1 is free (bind to Oxygen , CO2 respectively)

Structure of heme

Each hemoglobin molecule ( Globular protein ) consists of 1. 4 Heme 2. 4 linear proteins each one bind to a Heme

1) Heme synthesis start with 2 simple molecules a. Glycine ( amino acid ) b. Succinyl Co-A (intermediate of citric acid cycle) 2) Reaction of these 2 simple molecule together

with a Co-Factor ( Vitamin B6 ) will produce aminolevulinic acid synthase ( ALA Synthase )

• This step also called ( regulatory step ) or ( rapid limited step )

• Regulatory step : When this step being enhanced , all other pathways will be enhaced ( fast ) and if this step have inhibitory action, all other pathways will be inhibited.

3. Then some steps will happened in the cytoplasm. ( NOT important )

4. Then this molecule will return to mitochondria, when a protoporphyrin formed.

5. Protoporphyrin will bind to Iron (ferrous)6. At same time, globulin is being

synthesized in RER.7. Protoporphyrin + ferrous + globulin will

form Hemoglobin.

Iron in Hemoglobin is ferrous or ferric ? Why ?

• Iron in ferrous form ( 6 coordination )1) 4 bind with protoporphyrin2) 1 bind to histidine ( globin )3) 1 free bind to O2 or CO2 respectively • Where in ferric form we well have one

bond missing ( malfunctional hemoglobin ) • Heme and globulin are not isolated, the

bind together by Iron,

Notes• When O2 bind to Iron this process is called “

oxygenation “ not “ oxydation “ and oxygen transport through circulation as a mloecular form ( O2 ).

• The oxidation stage of the iron does NOT change. Oxidation of Fe2+ to Fe3+ only occurs occasionally. The oxidized form, methemoglobin, is then no longer able to bind O2. The proportion of Met-Hb is kept low by reduction (see p. 284) and usually amounts to only 1–2%.

Types of HemoglobinNormal

• Different types of Hb due to different type of globin NOT Heme.

• Adult have HbA and small amount of HbA2.

• Fetus Have HbF.

Types of Hemoglobin

Type FormulaHbA α2β2

HbA2 α2δ2HbF α2γ2

HbF have more affinity to oxygen than HbA.

Gas Transportation• Why we use hemoglobin as a transporter for

oxygen ?1. Because of low solubility of oxygen in

water. 2. Hemoglobin have a regulatory effect on

oxygen concentration in lungs and tissues.Note : all tissue required of oxygen and 20% of CO2 from metabolic wastes transport via Hb.

Allosteric effect

• When an enzyme reacts to effectors with conformational changes that increase or reduce its activity, it is said to show allosteric behavior

• Many substances act on Hb as an allosteric substances.

• Although Hb is NOT an enzyme, but it have all the characteristics of enzymes

• Substances that have an allosteric effect on Hb are :

1. 2,3 DGP (intermediate factor in glycolysis)2. H+ ( i.e. ph affect on Hb )3. CO2

Forms of Hb• When Hb have high affinity to oxygen in

lung is called ( oxyhemoglobin ) and refereed to as R form ( R from Relax )

• When Hb have low affinity to oxygen in tissue is called ( deoxyhemoglobin ) and refereed to as T form ( T from Tense )

• Allosteric substances act as a stabilizer for T form of Hb.

• in other worsds, affecting on the saturation of Hb with oxygen.

• Myoglobin saturation curve do not show allosteric effect because of have NO affinity to 2,3 DGP.

• Hb saturation curve is sigmoidal ( S shape, means saturation changes ) due to allosteric effect.

Steps for O2- CO2 Transport

1. In lungs, Pressure of oxygen is high so it diffuse from outside the body to inside the body and bind with Hb. ( bond of one O2 to hemoglobin fascilate the binding of other O2 moleculse )

2. In tissues, hemoglobin bind to 2,3 DPG and that cause to decrease affinity of Hb to Oxygen and releasing Oxygen to the tissues.

3. In the same time, CO2 is being bind to Hb due to high pressure of CO2 inside tissues and that reducing Hb affinity to Oxygen ( allosteric effect )

Affect of allosteric effectors1. 2,3 DGP or ( BGP ) enters between two chains of β and convert Hb from R to T form, reduning affinity of Hb to oxygen and cause it to releas, also it referred to as ( shift to the right )

*Note : HbF have no affinity to 2,3DGP, So the affinity of HbF to oxygen is more than HbA that have affinity to 2,3DGP.

2. H+ or pH and CO2 form from metabolic reactions in tissue, bind to Hb and decrease the affinity of Hb to Oxygent ( allosteric effect ) ans specificly called ( Bohr effect ) .

Hemoglobinopathies

Quiz

Q1 : briefly, What we mean when we say a hemoglobin molecule is tetramer ?Q2 : if R form of Hb have high affinity to O2, How it can give this O2 to tissue ?.Q3 : Explain Cooperative behavior in gas transport inside the body.

Answers is just a few words ( do not overcome 2 lines )