Carbohydrates are the principal source of energy for the organism. In plants, carbohydrates are synthesized from carbon dioxide and water by using sunlight by a process called photosynthesis. But animals mostly depend on plants for their carbohydrate needs.
Glucose is the major fuel of most living forms. Also under normal conditions glucose is the exclusive source of energy to the brain.
Animals obtain different forms of carbohydrates from a dietary source but all the carbohydrates mostly absorb in the form of glucose. The entry of glucose into cells is mediated by two families of proteins
1. Sodium-Glucose symport
2. Uptake by glucose transporters (GLUT) mainly GLUT 4 which is directly dependent on insulin.
GLYCOLYSIS :
Def. : The pathway of glucose breakdown is called glycolysis. It is the sequence of reactions metabolising one molecule of glucose to one 2 molecules of pyruvate(aerobic) or lactate(anaerobic)
1. Glycolysis is the major pathway for the utilization of glucose and occurs in almost all the cells.
2. Glycolysis occurs in both aerobic and anaerobic conditions. The end product of glycolysis in the aerobic condition is pyruvate and in the anaerobic condition is lactate.
3. Tissues such as RBC, cornea, and the lens do not contain mitochondria so aerobic oxidation is absent these tissues so they depend on anaerobic glycolysis for their energy needs.
Steps of the glycolysis :
Site: Cytosol
Glycolysis is a sequence of 10 enzymatic reactions.
1. Phosphorylation: This step is an irreversible
Transfer of phosphoryl group from ATP to glucose(6c) to form glucose 6 phosphate(6c).
Enzyme: Hexokinase(phosphorylates any hexose) / Glucokinase(phosphorylates only glucose)
Glucokinase is functional only in the liver and it is an isoenzyme of hexokinase.
2. Isomerization:
Glucose 6 phosphate(6c) undergoes isomerization to form fructose 6 phosphate(6c).
Enzyme: Phosphohexose isomerase
3. Phosphorylation: This step is an irreversible and regulatory step of glycolysis
Transfer of phosphoryl group from ATP to fructose 6 phosphate(6c) to form fructose 1,6 bisphosphate(6c).
Enzyme: Phosphofructokinase(PFK) - It is an allosteric enzyme.
4. Cleavage:
Splitting of fructose 1,6 bisphosphate(6c) into two trioses viz. glyceraldehyde 3 phosphate(G3P) and dihydroxyacetone phosphate. G3P and DHAP are 3 carbon compounds.
Enzyme: Aldolase
5. Isomerisation:
Glyceraldehyde 3 phosphate(G3P) and dihydroxyacetone phosphate(DHAP) both are interconvertible. So DHAP isomerized to GAP thus forming 2 molecules of GAP.
Enzyme: Phosphotriose isomerase.
6. 0xidation:
Glyceraldehyde 3 phosphate(G3P) is converted to 1,3 bisphosphoglycerate. The origin of 2 molecules of NADPH+H+ occurs during this step.
Enzyme: glyceraldehyde-3-phosphate dehydrogenase.
7. Dephosphorylation: substrate-level phosphorylation.
1,3 biphosphoglyceradyhyde(1,2 BPG) is converted to 3-phosphoglycerate.
In this reaction, the high-energy phosphate group in 1 position of 1,2 BPG is captured as ATP such that 2 molecules of ATP are generated for 1 molecule of glucose.
Enzyme: Phosphoglycerate kinase.
8. Isomerisation:
3-phosphoglycerate is isomerised to 2-phosphoglycerate.
Enzyme: Phosphoglycerate mutase.
9. Dehydration:
2-phosphoglycerate is converted to phosphoenolpyruvate. In this reaction is the elimination of water occurs.
Enzyme: Enolase.
10. Dehphosphorylation: This step is irreversible and substrate-level phosphorylation.
In this reaction, the final product of glycolysis Pyruvate is formed from phosphoenolpyruvate.
In this reaction, the high-energy phosphate is transferred from phosphoenolpyruvate to ADP resulting in the formation of ATP.
Enzyme: Pyruvate kinase.
Conversion of pyruvate to lactate:
Site: RBC, Cornea, the lens, and also in skeletal muscles during intense workouts.
When oxygen is not available, Pyruvate is reduced to lactic acid utilizing NADH+H+ and this extension of glycolysis in the absence of oxygen is called anaerobic glycolysis.
Enzyme: Lactate dehydrogenase.
Energetics of glycolysis:
In glycolysis, there is a generation of 7 ATPs in aerobic glycolysis and 2 ATPs in anaerobic glycolysis.
1. There is a generation of 2 molecules of NADH+H+ in reaction 6 during oxidation. NADH thus produced in the cytosol is transported into mitochondria by one of the shuttle pathways where it is further oxidised in ETC, yielding energy by oxidative phosphorylation producing 2.5 ATP from each NADPH+H+ molecule thus producing 5 ATP molecules from 2 NADPH+H+.
2. There is a generation of 4 molecules of ATP in reaction 7 and 10 during substrate-level phosphorylation.
3. Two molecules of ATP are utilized in reactions 1 and 3 during phosphorylation.
We can now write the energetics in the form of the equation below,
2NADPH+H+(5 ATP) + 4 ATP - 2 ATP = 7 ATP
4. In anaerobic glycolysis there is the utilization of 2 NADPH+H+ during the conversion of pyruvate to lactate thus generating a net gain of 2 ATP.
Inhibitors of glycolysis:
1. Arsenate and iodoacetate inhibit the enzyme glyceraldehyde-3-phosphate catalysing step 6.
2. Fluoride inhibits the enzyme enolase catalysing step 9.
Regulation of glycolysis:
As mentioned earlier reaction 3 catalysed by enzyme phosphofructokinase(PFK) is the rate-limiting step. PFK is the key regulatory enzyme of glycolysis.
Phosphofructose kinase is regulated both by allosteric effectors and hormones. AMP, Fructose 2,6 bisphosphate, ADP are allosteric activators whereas ATP, Citrate, Acidic pH are allosteric inhibitors. Under hormonal regulation, this enzyme is activated by insulin and inhibited by glucagon.
Hexokinase is present in most of the tissues and Glucokinase is present hepatocytes of the liver and beta cells of pancreas. Compared to glucokinase, hexokinase has a lower Km (higher binding affinity) and lower Vmax (lower capacity). Glucokinase is in under hormonal regulation and is inhibited by glucogon and activated by insulin. Hexokinase is competitively inhibited by glucose-6-phosphate.
Pyruvate kinase is also under hormonal regulation. It is activated by insulin and inhibited by glucagon.
Rapaport-Leubering cycle:
Site: Erythrocytes
One quarter of glucose undergoes an altered pathway of glycolysis in which reaction 7 is bypassed instead of dephosphorylation 1,3 bisphosphoglycerate is converted into 2,3 bisphosphoglycerate by enzyme 2,3 bisphosphoglycerate mutase and 2,3 bisphosphoglycerate is then converted to 3 phosphoglycerate bt enzyme 2,3 bisphosphoglycerate phosphatase.
1. In RBC, 2,3 BPG combines with hemoglobin and reduces its affinity of oxygen. Thus enabling oxyheamoglobin to unload oxygen to the tissues.
2. It plays a vital role during hypoxia, anemic conditions and life at high altitudes.
The fate of Pyruvate:
Pyruvate is transported into mitochondria by a symport mechanism where it is converted into acetyl CoA by oxidative decarboxylation catalysed by Pyruvate dehydrogenase complex(PDH). This reaction is called the Link reaction.
PDH complex is dependent on 5 coenzymes - TPP, Lipoamide, CoenzymeA, FAD, and NAD+
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