HEMOGLOBIN ppt _ HÓA SINH

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“tài liệu ngành dược hay nhất” ;

https://123doc.net/users/home/user_home.php?use_id=7046916

 is a hemoprotein only found in the

cytoplasm of erythrocytes (ery)

 normal concentration of Hb in the blood:

adult males 13.5 – 16.5 g/dL

adult females 12 – 15 g/dL

 In fact if the body had to depend upon dissolved oxygen in the plasma to

supply oxygen to

the cells –

 The heart would

have to pump 140 liters per minute - instead of 4 liters per minute

 Hemoglobin is made from two similar

proteins that "stick together"

 Both proteins must be present for the

hemoglobin to pick up and release oxygen normally

 One of the component proteins is called alpha, the other is beta

 Blood cells are made up of two components

 The hemoglobin is in solution inside the cell

 The cell is surrounded by a membrane that holds in the hemoglobin

STRUCTURE OF HEMOGLOBIN

• Hb is a spherical molecule consisting of 4 peptide

subunits (globins) = quartenary structure

• Hb of adults (Hb A) is a tetramer consisting of 2

- and 2 β-globins → each globin contains 1 heme group with a central Fe 2+ ion (ferrous

ion)

 1 iron cation (Fe 2+ )

→ bound in the middle

of tetrapyrrole skelet

by coordination

covalent bonds methine bridge pyrrole ring

STRUCTURE OF HAEM

PROPERTIES OF IRON IN HEME

IRON AND HEMOGLOBIN

 The mineral, iron,

plays an important

role in the body’s

delivery and use of

IRON AND HEMOGLOBIN

 Generally, the more

oxygen there is

being delivered, the

greater the body’s

exercise, and it has

been postulated that

a lack of iron in the

body can reduce

aerobic capacity and

impair endurance

performance

IRON AND HEMOGLOBIN

 Iron deficient red

blood cells

 Low number or cells

 Note the hollow and

blanched

appearance of the

red blood cells

IN WHICH COMPOUNDS CAN WE FIND A HEME GROUP?

binding of the first O 2 to Hb enhances the binding futher

O2 molecules → allosteric effect → S-shaped (sigmoidal)

saturation curve of Hb

PROCESS OF O2 BINDING TO HB

 Hb can exist in 2 different forms: T-form and R-form.

T-form (T = „tense“) has a much lower oxygen affinity than the

R-form The subunits of Hb are held together by electrostatic

interactions The binding of the first O 2 molecule to subunit of the form leads to a local conformational change that weakens the

T-association between the subunits → R-form („relaxed“) of Hb.

Increasing of oxygen partial pressure causes the conversion

of T-form to R-form

 T  R

 Hb + ↑pO 2  HbO 2

PROCESS OF O2 BINDING TO HB

 Hemoglobin is a remarkable molecular machine that uses motion and small structural changes to regulate its action

 Oxygen binding at the four heme sites in

hemoglobin does not happen simultaneously

 Once the first heme binds oxygen, it introduces small changes in the structure of the

corresponding protein chain

PROCESS OF O2 BINDING TO HB

 These changes nudge the neighboring chains into

a different shape, making them bind oxygen more easily

 Thus, it is difficult to add the first oxygen

molecule, but binding the second, third and fourth oxygen molecules gets progressively easier and easier

 This provides a great advantage in hemoglobin

function

PROCESS OF O2 BINDING TO HB

 When blood is in the lungs, where oxygen is

plentiful, oxygen easily binds to the first subunit and then quickly fills up the remaining ones

 Then, as blood circulates through the body, the oxygen level drops while that of carbon dioxide increases

PROCESS OF O2 BINDING TO HB

 In this environment, hemoglobin releases its

bound oxygen As soon as the first oxygen

molecule drops off, the protein starts changing its shape

 This prompts the remaining three oxygens to be quickly released

 In this way, hemoglobin picks up the largest

possible load of oxygen in the lungs, and delivers all of it where and when needed

The heme group of one subunit, shown in the little circular window, is kept in one place so that you can see how the protein moves

around it when oxygen binds

As it binds to the iron atom in the center of the heme, it pulls a histidine amino acid upwards

on the bottom side of the heme

This shifts the position of an entire alpha helix, This motion is propagated throughout the

protein chain and on to the other chains,

ultimately causing the large rocking motion of the two subunits

AGENTS THAT INFLUENCE OXYGEN BINDING



● 2,3-bisphosphoglycerate (2,3-BPG) only binds to deoxyHb

 (β-chains) → deoxyHb is thus stabilized

 ● H + ions (lower pH) – binding of H+ by Hb lowers its affinity for O 2 → Bohr effect

 ● CO 2 – high CO2 levels in the plasma also result in a right shift of saturation curve = Bohr effect

OXY & DEOXYHAEMOGLOBIN

HB-OXYGEN DISSOCIATION CURVE

HB-OXYGEN DISSOCIATION CURVE

 The normal position of curve depends on

 Concentration of 2,3-DPG

 H + ion concentration (pH)

 CO 2 in red blood cells

 Structure of Hb

HB-OXYGEN DISSOCIATION CURVE

 Right shift (easy oxygen delivery)

Hb A Hb A2 Hb F

ADULT HAEMOBLOBIN

TYPES OF HEMOGLOBIN

 Adult Hb (Hb A) = 2 α and 2 β subunits

HbA 1 is the major form of Hb in adults and in children over 7 months.

HbA 2 (2 α, 2 δ) is a minor form of Hb in adults It forms only 2 – 3% of a total Hb A.

 Fetal Hb (Hb F) = 2 α and 2 γ subunits

- in fetus and newborn infants Hb F binds O2 at lower

tension than Hb A → Hb F has a higher affinity to O 2

After birth, Hb F is replaced by Hb A during the first few months of life.

 Hb S – in β-globin chain Glu is replaced by Val

= an abnormal Hb typical for sickle cell anemia

DERIVATIVES OF HEMOGLOBIN

 Oxyhemoglobin (oxyHb) = Hb with O2

 Deoxyhemoglobin (deoxyHb) = Hb without O2

 Methemoglobin (metHb) contains Fe 3+ instead of Fe 2+ in heme groups

 Carbonylhemoglobin (HbCO) – CO binds to Fe 2+ in heme in

case of CO poisoning or smoking CO has 200x higher affinity to Fe 2+

than O 2

 Carbaminohemoglobin (HbCO2) - CO2 is non-covalently bound to

globin chain of Hb HbCO 2 transports CO 2 in blood (about 23%).

 Glycohemoglobin (HbA1c) is formed spontaneously by

nonenzymatic reaction with Glc People with DM have more HbA1c

than normal (› 7%) Measurement of blood HbA1c is useful to get

info about long-term control of glycemia.

Mutations in hemoglobin (hemoglobinopathies:

1- Sickle cell anemia (Hb S disease):

It is a genetic disorder of blood caused by mutation in globin chain resulting in the formation of Hb S The

acid is replaced by valine (non polar) Valine residues aggregate together by hydrophobic interactions leading to precipitation of Hb within RBCs RBCs assume sickle- shaped leading to fragility of their walls and high rate of hemolysis

Such sickled cells frequently block flow of blood in narrow capillaries and block blood supply to tissue (tissue anoxia) causing pain and cell death.

Note: The lifetime of erythrocyte in sickle cell is less than

20 days, compared to 120 days for normal RBCs.

Patients may be :

- Heterozygotes (Hb AS): mutation occurs only in one globin chain These patients have sickle cell trait with no clinical symptoms and can have normal life span.

β-globin chain with apparent anemia and its symptoms

2- Hb C disease: Like HbS, Hb C is a mutant Hb

in which glutamic acid in 6th position of β-chain is

replaced by lysine

RBCs will be large oblong and hexagonal

The heterozygous form (HbAC) is asymptomatic.The homozygous form (Hb CC) causes anemia, tissue anoxia and severe pain

3- Thalassemia: A group of genetic diseases in which a defect occur in the rate of synthesis of one

or more of Hb chains, but the chains are structurally normal This due to defect or absence of one or more of genes responsible for synthesis of α or β chains leading to premature death of RBCs

decreased or absent There are two copies of the gene responsible for synthesis of β chains Individuals with β globin gene defects have either :

: when the synthesis of only one β –globin gene is defective or absent Those individuals make some β chains and usually not need specific treatment

both genes are defective

-Babies will be severely anemic during the first or second year of life and so require regular blood transfusion Bone marrow replacement is more safe treatment

-α-thalassemia: in which synthesis of α globin

chain is defective or absent There are four copies

of gene responsible for synthesis of α globin chains

so patients may have:

i - Silent carrier of α-thalassemia with no

symptoms:

if one gene is defective

Minor anemia present

Moderate anemia present

survive till birth then dies