2. All of the hetero-allosteric modulators of O2 binding to hemoglobin in mammal
ID: 74214 • Letter: 2
Question
2. All of the hetero-allosteric modulators of O2 binding to hemoglobin in mammals are produced as a result of glucose catabolism in glycolysis and the TCA cycle.
a. What are all of the allosteric modulators for O2 binding to human hemoglobin?
b. Write at least one net reaction in glycolysis or the TCA cycle that is involved in producing these hetero-allosteric modulators – show all reactants, products and co-enzymes.
c. Write the complete reactions for all 3 of the CO2 producing reactions involved in the complete combustion of glucose to CO2 and H20
d. When CO2 produced in the cell moves to the blood stream it contributes to the bicarbonate buffering system. Write this complete buffering system and predict what will happen to the pH as the partial pressure of CO2 increases in the blood stream as a result of the complete combustion of glucose – the pH will increase, decrease or remain the same.
e. Several enzymes in glycolysis and the TCA cycle are allosterically regulated. List the allosteric activators and inhibitors for phosphofructokinase, pyruvate kinase, citrate synthase and -ketoglutarate dehydrogenase. Explain the general purpose of these allosteric activators and inhibitors.
Explanation / Answer
a- Allosteric regulation of human hemoglobin (HbA) with two quaternary states T and R has been a paradigm of allosteric structural regulation of proteins. T state is the deoxy form of HbA while R state is the Oxygenated form.
2, 3-BPG (2, 3- BiPhosphoGlycerate) is one of the principal allosteric effectors of O2 binding to Hb.
b- 2, 3- BiPhosphoGlycerate is a product of glycolysis in the red blood cells.
2, 3-BPG is formed from1,3-BPG by the enzyme BPG mutase.
1,3- BiPhosphoGlycerate--------------------à 2,3- BPG-----------------------à 3-Phosphoglycerate (in presence of 2,3-BPG phosphatase)
Instead of the one step reaction 1,3- BPG to 3-Phosphoglycerate in presence of enzyme Phosphoglycerate kinase, the glycolytic reaction occurs in two steps in RBC, thereby generating 2,3-BPG as an intermittent product.
c- The 3 of the CO2 producing reactions involved in the complete combustion of glucose to CO2 and H20 are: (these reactions occur in the TCA cycle & are called oxidative decarboxylation)-
1. Pyruvate is oxidized to acetyl-CoA & CO2 by a multienzyme complex, pyruvate dehydrogenase (PDH) complex,in which a series of chemical intermediates remain bound to the enzyme molecules as a substrate is transformed into the final product. PDH complex catalyses oxidative decarboxylation, an irreversible oxidation process in which carboxyl group is removed from pyruvate (3C) as a molecule of CO2 & 2 remaining carbons become the acetyl group of acetyl-CoA.
2. Isocitrate dehydrogenase catalyzes oxidative decarboxylation of isocitrate ( a 6C compound) to form -ketoglutarate (a 5C compound), releasing CO2 in the process.
3. Another oxidative decarboxylation occurs where -ketoglutarate is converted to succinyl-CoA and CO2 by the action of the -ketoglutarate dehydrogenase complex.
d- The bicarbonate buffering system is an acid-base homeostatic mechanism that maintains pH in the blood (7.4). The enzyme Carbonic anhydrase plays a vital role in this buffering. The CO2 reacts with water in presence of enzyme Carbonic anhydrase to form Carbonic acid; which dissociates to form bicarbonate ions & hydronium ions.
H2O + CO2 ---> H2CO3-----> H3O++ HCO3-
The weak acid H2CO3 & its conjugate base HCO3- maintains the pH of the blood.
If the partial pressure of CO2 increases in the blood stream as a result of the complete combustion of glucose, then it may lead to lowering of the pH of the blood (from 7.4 to around 7.0)- thus causing acidosis.
However, in normal physiological conditions, such acidosis does not occur as the kidneys control the buffering system. If there is excess bicarbonate in the blood, kidneys will excrete it, thereby maintaining the normal buffering of the blood pH.
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