Hemoglobin Flashcards
structure of heme
Blood is about 150g of Hb/Liter. Hb carries O2 through oxygenation using a heme prosthetic group that contains a set of 4 5-membered pyrrole rings called protoporphyrin IX. * There is an Fe that forms 4 bonds with nitrogens within the 4 pyrrole rings as well as a 5th bond with the proximal histidine. Fe forms a 6th bond with O2 and transitions from the ferrous state (Fe2+) to the ferric state (Fe3+)
Structure of Hb/Mb
Mb binds the Fe though 4 bonds to the Nitrogens of the pyrrole rings and a 5th bond to the F8 Histidine (proximal histidine. There is another histidine (HisE7) that forms perfect pocket for oxygen to bind to Fe. When oxygen binds to Fe, the Fe shifts more into the plain of the pyrrole rings, causing the HisF8 (and the entire F helix along with it) to be pulled toward the ring as well. This causes the shift between the T and R states in the tetrameric Hb.
HbA
the major adult Hb, is a tetrameric protein consisting of 2 α and 2 β subunits.
HbA2
the minor adult Hb with δ subunits instead of β
HbF
has γ subunits instead of β subunits
T and R states
Hb interconverts from the T state to the R state by breaking its 8 salt bonds and creating more H-bonds (salt bonds stronger than H-bonds- why the states are designated tense (T) and relaxed (R)). When O2 binds, the Fe moves closer in plane to the nitrogens of the pyrrole rings and pulls the F8 proximal His and its α-helix, causing the subunit to change to the R conformation. The R conformation increases the subunit affinity for O2 by 150-300 times. Hb is considered an allosteric protein because it can interconvert between structures. This occurs spontaneously, but the equilibrium is affected by the binding of the ligand.
Anemia
defined as Hb below the normal range of 12%-17%. This can be due to an impairment in Hb synthesis, a condition called microcytic hypochromic anemia, usually caused by an Fe deficiency. Can also be genetic like in thalassemia where the synthesis of Hb α and β chains is disrupted.
Methemoglobinemia
Methemoglobinemia is a condition where iron is oxidized from the ferrous to the ferric state, so it cannot transport oxygen. Normally methemoglobin (oxidized Hb) is present at 1% concentration due to the activity of methemoglobin reductase, but a deficiency in this enzyme leads to congenital methemoglobinemia. This condition is treated with methylene blue, a dye that is reduced to leucomethylene blue, which then reduces the ferric iron back to ferrous iron.
2, 3-bisphosphglycerate (BPG)
2, 3-bisphosphglycerate (BPG) is a negative allosteric inhibitor of Hb. Each Hb molecule has one BPG in the central area between the subunits. BPG only binds to the T form and stabilizes it, so it decreases the overall affinity of Hb for oxygen. [BPG] increases in lung diseases, which barely affects oxygenation in the lungs, but increases oxygen delivery to peripheral tissues. BPG forms salt bonds with Lys EF6 and His H21. In HbF γ chains, the His H21 is replaced with series, so BPG binds less efficiently, so HbF has a higher affinity for oxygen.
CO poisoning
CO poisoning is due to 200x affinity for Hb of CO than O2 called competitive antagonism. CO binding also increases O2 affinity of the other subunits, so decreases oxygen delivery. Normal nonsmokers have 2% CO-Hb, but each pack of cigarettes increases this by 2.5%. Hookah smoke is especially high in CO and can cause acute CO poisoning, also seen in car-related suicide attempts. 70% is fatal
Bohr effect
Hb affinity for oxygen decreases in acidic environments such as those high in carbonic or lactic acid. CO2 also can covalently, spontaneously, reversibly bind to Hb, forming carbaminohemoglobin, which also decreases the Hb affinity for oxygen.
