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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
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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)
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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
Carbon monoxide poisoning
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:
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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
Carbon monoxide poisoning