Mod.A. Bio Lec6: Hemoglobin Flashcards
basic structure of Hb
1- four globin polypeptide chains
(بس خلي بالك two pairs of dissimilar globins.) * أي أنه : * heterotetramer (α2β2)
Each polypeptide chain has a helical structure, each with heme group.
2- The iron ((Fe2+ to bind O2 reversibly ) of each heme group is bound by
coordination bonds to nitrogen atoms of imidazole rings of histidine amino acids
where is Hb present ?
weight
count
only found in the cytoplasm of erythrocytes (RBCs)
comprise almost one third of the weight of a red cell
280 million Hb molecules are carried in one RBC
main function
1- transport O2 from lungs to tissues and CO2 from the tissues to the lungs.
2- Hemoglobin Buffering system
Haem & globin produced at two different sites in the cells:
haem in mitochondria
globin in ribosomes
Steps of heme synthesis:
1- Synthesis of ALA
2- Synthesis of porphobilinogen
3-incorprating iron
ALA synthesis (site ,substrate used enzyme, co enzymes)
in mitochondria ( لماذا ؟؟؟ ) السبب This reaction is energy dependent
* Two starting materials : succinyl-CoA (citric acid cycle) and Glycine
* الإنزيم المستخدم : ALA
synthase
need pyridoxal phosphate as activator of glycin
What is the rate limiting step of heme synthesis ?
ALA synthase
Porphobilinogen synthesis (site, how, used enzyme)
لمكان : ALA leaves the mitochondria → cytoplasm
* ما يتم في التفاعل : 2x ALA condense together to form porphobilinogen (PBG)
- الإنزيم المستخدم : porphobilinogen synthase (=ALA dehydratase)
incorporating iron
By ferrochelatase
Heme synthesis (location , substrate , mediated by, regulatory enzyme)
Organ location: in bone marrow (85% of Hb) and
liver (mainly for the synthesis of the cytochrome P450 class of enzymes that
are involved in detoxification )
*intracellular location: mitochondria/cytoplasm/mitochondria
مهم synthesis of heme starts in mitochondria
- substrates: succinyl-CoA + glycine + Fe2+
- Mediated by : erythropoietin ( EPO ) and vitamin B6
- key regulatory enzyme : ALA synthase
regulation of ALA synthase
inhibited by
1- an end product-heme
(feedback inhibition) ,
2- glucose and steroids
activated by:
stimulated by certain drugs as phenobarbital and iron.
ALA dehydratase (porphobilinogen synthase) is inhibited by
lead
ferrochelatae is inhibited and activated by
inhibited by lead ions Pb2+.
- Its activity is influenced by availability of Fe2+ and ascorbic acid.
Lead poisoning (type, result, symptoms)
Acquired
Inhibits enzyme involved in heme biosynthesis (PBG synthase & ferrochelatase).
Irritability , Poor appetite, Lethargy, Abdominal pain
Porphyrias (type, cause, result. symptoms)
(hereditary
abnormality of the enzymes which synthesize heme
(e.g., PBG Synthase, Porphobilinogen Deaminase, etc…)
1- leads to accumulation of intermediates of the pathway (“porphyrins” or “porphyrin precursors” ) خاصة Elevated 𝛿-aminolevulinic acid (ALA)
2- a deficiency of heme → 3- excretion of heme precursors in feces or urine, giving them a dark 4- red color accumulation of porphyrinogens in the skin can lead to photosensitivity
5- affected primarily in liver or in developing erythrocytes. 6-the neurological symptoms
7- abdominal pain 8- nerve damage and even death 9- formation of superoxide radicals.
Photosensitivity, abdominal pain, neuropsychiatric symptoms
The binding of the first O2
to Hb enhances the binding
futher O2 molecules
allosteric affect?
Hb binds O2 weakly at low oxygen pressures
Hb binds O2 tightly at high pressures
Hb can exist in 2 different forms:
R-form and T-form.
Oxyhemoglobin exists in
the R state
increased affinity for O2 = Oxygen causes rupture of some bonds.
Deoxyhemoglobin exist in
T state
reduced affinity for O2 = 4subunits are packed by ionic and H-bond
Carbaminohemoglobin is formed when
T-state Hb react with CO2
15% of CO2 are transported to the lungs as
hemoglobin carbamate
85% of CO2
transported as bicarbonate
2,3diphosphoglycerate (formation, functon)
Formation of 2,3diphosphoglycerate in RBCs by the enzyme 2,3-BPG mutase
binds with greater affinity to deoxygenated hemoglobin
fetal HB has high O2 affinity, why ?
Fetal Hb has less 2,3-diphosphoglycerate than adult HB
What is HbA1C
Non-enzymatic glycated adult Hb-form
constitutes
has glucose residues attached to
β-globin chains يعني is glycosylated (5-8%)
increased amount of HbA1C is found in
patients with diabetes (reaches 12%)
importance of HbA1C
could be used as a monitor for
the control of the blood glucose level during the
last 2 months for diabetic patients.
Abnormal derivative of Hb:
1- Methemoglobin (Met-Hb) : It is an oxidized Hb ,where Fe is present in the ferric state. بمعنى contains Fe3+ instead of Fe2+ in heme groups. It Binds O2 irreversibly, is unable to act as an O2 carrier,
oxidation (Fe2+Fe3+) caused by H2O2, free radical, drugs, and pollution
2-Carboxylhemoglobin (COHb):
– CO binds to Fe2+ in heme in case of CO poisoning or smoking.
- CO has 200x higher affinity to Fe2+ than O2left-shifted O2-Hb curve.
- Conc of COHb above 40% unconsciousness fatal
3-Sulfhemoglobin (S-Hb) Hb:
- combining with sulfur, results from exposure of Hb to the toxic effects of certain
drugs as sulfonamides.
- S-HB produces anoxia because it can not act as O2 carrier
4- Hematin: is Hb without iron (i.e. protoporphyrin combining with globin).
