NEET MDS Lessons
Biochemistry
Erythrocytes and the Pentose Phosphate Pathway
The predominant pathways of carbohydrate metabolism in the red blood cell (RBC) are glycolysis, the PPP and 2,3-bisphosphoglycerate (2,3-BPG) metabolism (refer to discussion of hemoglobin for review of the synthesis and role role of 2,3-BPG).
Glycolysis provides ATP for membrane ion pumps and NADH for re-oxidation of methemoglobin. The PPP supplies the RBC with NADPH to maintain the reduced state of glutathione.
The inability to maintain reduced glutathione in RBCs leads to increased accumulation of peroxides, predominantly H2O2, that in turn results in a weakening of the cell wall and concomitant hemolysis.
Accumulation of H2O2 also leads to increased rates of oxidation of hemoglobin to methemoglobin that also weakens the cell wall.
Glutathione removes peroxides via the action of glutathione peroxidase.
The PPP in erythrocytes is essentially the only pathway for these cells to produce NADPH.
Any defect in the production of NADPH could, therefore, have profound effects on erythrocyte survival.
Glycolysis Pathway
The reactions of Glycolysis take place in the cytosol of cells.
Glucose enters the Glycolysis pathway by conversion to glucose-6-phosphate. Initially, there is energy input corresponding to cleavage of two ~P bonds of ATP.
1. Hexokinase catalyzes: glucose + ATP → glucose-6-phosphate + ADP
ATP binds to the enzyme as a complex with Mg++.
The reaction catalyzed by Hexokinase is highly spontaneous
2. Phosphoglucose Isomerase catalyzes:
glucose-6-phosphate (aldose) → fructose-6-phosphate (ketose)
The Phosphoglucose Isomerase mechanism involves acid/base catalysis, with ring opening, isomerization via an enediolate intermediate, and then ring closure .
3. Phosphofructokinase catalyzes:
fructose-6-phosphate + ATP → fructose-1,6-bisphosphate + ADP
The Phosphofructokinase reaction is the rate-limiting step of Glycolysis. The enzyme is highly regulated.
4. Aldolase catalyzes:
fructose-1,6-bisphosphate → dihydroxyacetone phosphate + glyceraldehyde-3-phosphate
The Aldolase reaction is an aldol cleavage, the reverse of an aldol condensation.
5. Triose Phosphate Isomerase (TIM) catalyzes
dihydroxyacetone phosphate (ketose) → glyceraldehyde-3-phosphate (aldose)
Glycolysis continues from glyceraldehydes-3-phosphate
The equilibrium constant (Keq) for the TIM reaction favors dihydroxyacetone phosphate, but removal of glyceraldehyde-3-phosphate by a subsequent spontaneous reaction allows throughput.
6. Glyceraldehyde-3-phosphate Dehydrogenase catalyzes:
glyceraldehyde-3-phosphate + NAD+ + Pi → 1,3,bisphosphoglycerate + NADH + H+
This is the only step in Glycolysis in which NAD+ is reduced to NADH
A cysteine thiol at the active site of Glyceraldehyde-3-phosphate Dehydrogenase has a role in catalysis .
7. Phosphoglycerate Kinase catalyzes:
1,3-bisphosphoglycerate + ADP → 3-phosphoglycerate + ATP
This transfer of phosphate to ADP, from the carboxyl group on 1,3-bisphosphoglycerate, is reversible
8. Phosphoglycerate Mutase catalyzes: 3-phosphoglycerate → 2-phosphoglycerate
Phosphate is shifted from the hydroxyl on C3 of 3-phosphoglycerate to the hydroxyl on C2.
9. Enolase catalyzes: 2-phosphoglycerate → phosphoenolpyruvate + H2O
This Mg++-dependent dehydration reaction is inhibited by fluoride. Fluorophosphate forms a complex with Mg++ at the active site .
10. Pyruvate Kinase catalyzes: phosphoenolpyruvate + ADP → pyruvate + ATP
This transfer of phosphate from PEP to ADP is spontaneous.
Balance sheet for high energy bonds of ATP:
- 2 ATP expended
- 4 ATP produced (2 from each of two 3C fragments from glucose)
- Net Production of 2~ P bonds of ATP per glucose
Functions of lipids
1. They are the concentrated fuel reserve of the body (triacylglycerols).
2. Lipids are the constituents of membrane structure and regulate the membrane permeability (phospholipids and cholesterol).
3. They serve as a source of fat soluble vitamins (A, D, E and K).
4. Lipids are important as cellular metabolic regulators (steroid hormones and prostaglandins).
5. Lipids protect the internal organs, serve as insulating materials and give shape and smooth appearance to the body.
PHOSPHORUS
Serum level of phosphate is 3-4 mg/dl for adults and 5-6 mg/dl in children. Consumption of calcitriol increases phosphate absorption.
Functions of phosphorus
(a) Plays key role in formation of tooth and bone
(b) Production of high energy phosphate compounds such as ATP, CTP, GTP etc.,
(c) Synthesis of nucleotide co-enzymes such as NAD and NADP
(d) Formation of phosphodiester backbone structure for DNA and RNA synthesis
Hypophosphatemia is the condition which leads to decrease in absorption of phosphorus. it leads to hypercalcamia
Hyperphosphatemia, increase in absorption of phosphate was noticed. Hyperphosphatemia leads to cell lysis, hypocalcemia and thyrotoxicosis.
Function of Calcium
The major functions of calcium are
(a) Excitation and contraction of muscle fibres needs calcium. The active transport system utilizing calcium binding protein is called Calsequestrin. Calcium decreases neuromuscular irritability.
(b) Calcium is necessary for transmission of nerve impulse from presynaptic to postsynaptic region.
(c) Calcium is used as second messenger in system involving protein and inositol triphosphate.
(d) Secretion of insulin, parathyroid hormone, calcium etc, from the cells requires calcium.
(e) Calcium decrease the passage of serum through capillaries thus, calcium is clinically used to reduce allergic exudates.
(f) Calcium is also required for coagulation factors such as prothrombin.
(g) Calcium prolongs systole.
(h) Bone and teeth contains bulk quantity of calcium.
The Hemoglobin Buffer Systems
These buffer systems are involved in buffering CO2 inside erythrocytes. The buffering capacity of hemoglobin depends on its oxygenation and deoxygenation. Inside the erythrocytes, CO2 combines with H2O to form carbonic acid (H2CO3) under the action of carbonic anhydrase.
At the blood pH 7.4, H2CO3 dissociates into H+ and HCO3 − and needs immediate buffering.
Thyroid Hormones
Thyroid hormones (T4 and T3) are tyrosine-based hormones produced by the follicular cells of the thyroid gland and are regulated by TSH made by the thyrotropes of the anterior pituitary gland, are primarily responsible for regulation of metabolism. Iodine is necessary for the production of T3 (triiodothyronine) and T4 (thyroxine).
A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as goitre.
Thyroid hormones are transported by Thyroid-Binding Globulin
Thyroxine binding globulin (TBG), a glycoprotein binds T4 and T3 and has the capacity to bind 20 μg/dL of plasma.
Diseases
1. Hyperthyroidism (an example is Graves Disease) is the clinical syndrome caused by an excess of circulating free thyroxine, free triiodothyronine, or both. It is a common disorder that affects approximately 2% of women and 0.2% of men.
2 Hypothyroidism (an example is Hashimoto’s thyroiditis) is the case where there is a deficiency of thyroxine, triiodiothyronine, or both.