hemoglobin eng web

7/27/2019 Hemoglobin Eng Web

1/13

Structure, function, andmetabolism of hemoglobin

Vladimra Kvasnicov

Structure of hemoglobin

hemoprotein (complex protein:globin+ prosthetic group)

quaternary structure: 4 subunits

prosthetic group of each of the subunit = heme

4 polypetide chains4 molecules of heme

4 ferrous (Fe2+) ions

The figure is found athttp://dtc.pima.edu/~biology/202alpha/lesson1/hemoglobin.jpg(March 2007)

Mr = 64 500

The figures are found at http://www.virtuallaboratory.net/Biofundamentals/lectureNotes/AllGraphics/myoglobinSurface.jpgand http://courses.washington.edu/conj/protein/hemo.gif (March 2007)

hemoglobin

HEME

MYOGLOBIN

it has not a quarternary structure: only 1 polypeptide chain

found in muscles: binds O2 for storrage higher affinity to oxygen than hemoglobin


2/13

Types of hemoglobin and its subunits

adult hemoglobin:HbA1 = 22HbA2 = 22 (2% from total Hb of adults)

fetal hemoglobin

HbF = 22 ! higher affinity to O2 than HbA !

binds oxygen more firmly at lower pO2 (placenta!)The figure is found at http://www.labcorp.com/datasets/labcorp/html/img/fethgb.jpg (March 2007)

Structure of heme

cyclic tetrapyrrole

the pyrrols has different substituents belongs among porphyrins (heme = Fe-protoporphyrine IX)

it contains:

conjugated double bonds red color

4 nitrogen atoms (N)

1 ferrous ion (Fe2+) in the middle of the tetrapyrrole structure

by coordination-covalent bonds The figures are found at http://www.medical-definitions.net/images/hemoglobin.jpgand http://omlc.bme.ogi.edu/spectra/hemoglobin/hemestruct/heme-struct.gif (March 2007)

Pyrrole

hemoglobin


3/13

Pyrrole

The figures are found at http://www.medical-definitions.net/images/hemoglobin.jpgand http://omlc.bme.ogi.edu/spectra/hemoglobin/hemestruct/heme-struct.gif (March 2007)

1. What is the concentration of Hbin blood?

2. Describe the structure of Hb

3. Where is oxygen bound into Hb?

4. How many O2

can be bound to Hb?

5. Draw the saturation curve of Hb

Qiuz

Synthesis of hemoglobin

bone marrow

in erytroblasts, not in erythrocytes 4 individual subunits are connected by

noncovalent bonds to form tetramer of Hb

hemoglobin is an intracellular protein: within ery

concentration of Hb in blood:

female 120 162 g/l

male 135 172 g/l


4/13

Synthesis of hemoglobin

Disorders:

THALASSEMIA = group of genetically determineddisorders: absence or reduced synthesis of a globin chain

(orthalassemia)

ANEMIA (= decreased oxygen-carrier capacity of blood)

sideropenic anemia insufficient concentration of Fe

sickle cell anemia point mutationin the -globin gene forms abnormalHbS (Glu Val)

Synthesis of heme - REPETITION

mainly in the bone marrow (Hb) and in the liver

(cytochroms)

mitochondria / cytoplasm / mitochondria

substrates: succinyl-CoA + glycine

important intermediates:

-aminolevulinic acid (= 5-aminolevulinic, ALA)

porphobilinogen (PBG = pyrrol derivative)

uroporphyrinogen III (= 1st porphyrinogen precursor of heme)

protophorphyrine IX (= direct precursor of heme)

The figure is from: Color Atlas of Biochemistry / J. Koolman, K.H.Rhm. Thieme 1996. ISBN 0-86577-584-2

Synthesis of heme - regulation

ALA-synthase

the key regulatory enzyme in all tissues

pyridoxal phosphate dependent (vit. B6)

ALA-synthase 1 (liver)

inhibited by heme (feed back inhibition)

regulation of transcription and by allosteric mechanism

some drugs amount of ALA-synthase ( conc. of heme)

ALA-synthase 2 (erythroblasts)neither feed back inhibition nor induction by drugs

regulated on the level of iron availability


5/13

Disorders of hemesynthesis

PORPHYRIAS

inborn or acquired

classification by defect enzyme

accumulation of heme precursors in the body(skin) and their excretion with urine or feaces(dark color)

neurogical symptomps, photosensitivity

lead poisoning accumulation of ALA (blood, urine)(inhibition of porphobilinogen synthase)

Degradation of hemoglobin

cells of reticulo-endothelial system (RES) of

spleen, bone marrow, liver, and skin

Hb released from erythrocytes in blood vesels isbound by haptoglobin RES

free heme is transported by hemopexin

HEMOGLOBIN 4x globin + 4x heme

globins chains amino acids

heme Fe3+ + CO + biliverdinbile pigmentsfeaces

The figure is from: Color Atlas of Biochemistry / J. Koolman, K.H.Rhm. Thieme 1996. ISBN 0-86577-584-2

1. Where is Hb synthesized?

2. What failures of Hb synthesis do youknow?

3. What substrates are needed for thesynthesis of heme?

4. What is the source of iron for thesynthesis of heme?

5. What is the cause of jaundice during anexcessive degradation of erytrocytes?

Qiuz


6/13

Transport of blood gases

Air composition:

78% N2 21% O2 1% water, inert gases, CO2 (0,04%)

Air pressure:

1 atm = 101 325 Pa (~ 101 kPa) = 760 Torr (= mmHg)

1 mmHg = 0,1333 kPa

1 kPa = 7,5 mmHg

Transport of blood gases

arterial blood venose blood

pO2 13,33 kPa 5,33 kPa

100 mmHg 40 mmHg

pCO2 5,33 kPa 6,13 kPa

40 mmHg 46 mmHg

(alveols)

The figure is found at http://people.eku.edu/ritchisong/RITCHISO//301notes6.htm (March 2007)

Transport of blood gases- function of hemoglobin -

it transports O2 and part of CO2 (and CO)

it binds H+

(reacts as a buffer)

O2 and CO: bound to Fe2+ in heme 4 O2 / 1 Hb

oxyhemoglobin HbO2 /carbonylhemoglobin COHb

CO2 is bound to globin! (-NH2 of side chains of amino acids)

carbaminohemoglobin HbCO2

H+ is bound to residues of His

deoxyhemoglobin HHb


7/13

Transport of blood gases- transport of CO2 -

1. largely in a form of HCO3-

(~ 70%)CO2 + H2O H2CO3 HCO3- + H+

enzyme: carbonic anhydrase spontaneous dissociation

(in erytrocytes)

2. bound to hemoglobin (~ 23%)

3. freely dissolved (~ 7%)

The figure is found athttp://fig.cox.miami.edu/~cmallery/150/physiol/sf41x11.jpg(March 2007)

Transport of blood gases- reactions in erytrocytes -

tissues:

CO2 + H2O H2CO3 HCO3- + H+

H+ + HbO2 HHb + O2 aerobic metabolism

lungs:

HHb + O2 HbO2 + H+

H+ + HCO3- H2CO3 H2O + CO2 excreted

The figure is from http://science.kennesaw.edu/~jdirnber/Bio2108/Lecture/LecPhysio/42-29-BloodCO2Transport-AL.gif (March 07)

O2

O2


8/13

Hemoglobin saturation curve- saturation with oxygen -

The figure is found at http://employees.csbsju.edu/hjakubowski/classes/ch331/bind/MbHbbindcurve.gif(March 2007) The figure is found at http://dr-amy.com/rich/oxygen/fig1.gif(March 2007)

The figure is found at http://dr-amy.com/rich/oxygen/fig1.gif(March 2007)The figure is found athttp://www.biocrawler.com/encyclopedia/Fetal_hemoglobin(March 2007)

HbF is left-shifted(it has higher affinity to oxygen)


9/13

Saturation of hemoglobin by oxygen

quaternary structure of hemoglobin

allosteric effect

T-conformation: lower affinity to O2 (deoxy Hb)

R-conformation: higher affinity to O2 (oxyHb)

T R

Hb + O2 HbO2The figure is found at http://employees.csbsju.edu/hjakubowski/classes/ch331/bind/MbHbbindcurve.gif (March 2007)

The animation is found at http://en.wikipedia.org/wiki/Image:Hb-animation2.gif (March 2007)

Saturation of hemoglobin with oxygen

Factors affecting the saturation:

alkaline pH and pO2stabilize R-conformation

(IN LUNGS)

acidic pH, pCO2, temperature and 2,3-BPG

stabilize T-conformation, i.e. deoxyHb

(IN PERIPHERY)

shift of the saturation curve toward right


10/13

The figure is found at http://employees.csbsju.edu/hjakubowski/classes/ch331/bind/MbHbbindcurve.gif(March 2007)

Bohrs effect= the saturation of Hb by O

2drops because lowering pH

The figure is found at http://www.nd.edu/~aseriann/dpg.html(March 2007)

1. What is the % proportion of O2

and CO2

in air?

2. What is pO2

in arterial blood?

3. What is pCO2

in arterial blood?

4. How is CO2

transported in thehuman body?

5. Summarize factors decreasing

the affinity of Hb to oxygen

QiuzPatological forms of hemoglobin

1. methemoglobin (over 3%) metHb

Fe3+ instad of Fe2+

unable to transport oxygen !!!

2. glycohemoglobin (over 6%) HbA1c after long term increased glycemia

3. carbonylhemoglobin (over 2%) COHb

after CO poisoning

4. sulfhemoglobin, cyanhemoglobin

poisoning by H2S, HCN or by cyanides


11/13

1. Compare the fetal and adult Hb

2. What is methemoglobin?

3. What is glycohemoglobin?

4. What is carbonylhemoglobin?

5. What is carboxyhemoglobin?

QiuzCarbon monoxide poisoning

CO has 200x higher affinity to Hb than O2

it forms COHb = carbonyl hemoglobin(formerly called carboxyhemoglobin)

max. allowed concentration in the air: 0.003%

intoxication by CO depends on pCO and a timeof its exposition (0.04% strong headache, 2-3 hours:unconsciousness; 1% death after a few minutes)

The figure is found at http://www.orthosmoke.org/index.php/pt/Carbon%20Monoxide (March 2007)

CO binds

to Fe2+ instead ofoxygen

The figure is found at http://dr-amy.com/rich/oxygen/fig1.gif(March 2007)


12/13

Carbon monoxide poisoning

may result due to:

exposure to automobile exhaust

smoke inhalation

an improperly ventilated gas heater

or other appliance (incomplete burning)

CONSEQUENCES

decreased oxygen-carrying capacity of Hb

decreased delivery of oxygen to cells

CO prevents reversible displacement of O2 on Hb

CO shifts the O2-hemoglobin dissociation curve

to the left

CO inhibits the intracellular respiration

CO may bind directly to cardiac and skeletal muscleto cause direct toxicity and to components of thenervous system to cause demyelination and neurologicsymptoms


The figure is found at http://www.acsu.buffalo.edu/~lcscott/carbonmonoxide.html (March 2007)

cherry red coloration to the skin

Saturation ofhemoglobinwith CO

The figure is found athttp://www.uhseast.com/134221.cfm

(March 2007)

COHb / total Hb(ratio in %)

physiological value:


13/13

The figure is from http://www.coheadquarters.com/CORisk/figco32x.htm (March 2007)

Describe the first aid in case of anintoxication of a person by

carbon monoxide

Qiuz

TREATEMENT

fresh air

exposure to high concentrations of oxygen(the 100% oxygen is administered by a face mask)

it is recommended in patients who have a historyof loss of consciousness, carbonyl hemoglobinsaturation greater than 25%, metabolic acidosisand cerebellar findings on neurologic exam


hemoglobin eng web

Documents