The TCA cycle, also known as the Krebs cycle or citric acid cycle, is the final common pathway for the oxidation of carbohydrates, fats, and proteins. It generates energy through the oxidation of acetyl-CoA derived from these nutrients and provides precursors for amino acid, nucleotide, and lipid synthesis. The cycle takes place in the matrix of mitochondria and involves 8 steps that completely oxidize acetyl-CoA to produce carbon dioxide and water while generating reduced cofactors NADH and FADH2. These cofactors then transfer electrons to the electron transport chain to facilitate ATP production through oxidative phosphorylation.

1. TCA cycle (Tricarboxylic Acid Cycle)
Also known as Krebs cycle
TCA cycle essentially involves the oxidation of acetyl CoA to C02 and H20.
TCA cycle —the central metabolic pathway The TCA cycle is the final common oxidative pathway for carbohydrates,
fats, amino acids.
TCA cycle supplies energy & also provides many intermediates required for the synthesis of amino acids, glucose,
haem, etc.
TCA cycle is the most important central pathway connecting almost all the individual metabolic pathways.

3. Significance of TCA cycle
Complete oxidation of acetyl COA
ATP generation.
Final common oxidative pathway.
Integration of major metabolic pathways.
Fat is burned on the wick of carbohydrates.
Excess carbohydrates are converted as neutral fat
No net synthesis of carbohydrates from fat.
Carbon skeleton of amino acids finally enter the TCA cycle.
Requirement of 02 by TCA cycle
There is no direct participation of 02 in TCA cycle. Operates only under aerobic conditions. This is due to, NAD*
& FAD required for the operation of the cycle can be regenerated in the respiratory chain only in presence of 02.

4. Therefore, citric acid cycle is strictly aerobic.
Energetics of TCA Cycle
Oxidation of 3 NADH by ETC coupled with oxidative phosphorylation results in the synthesis of
9ATP.
• FADH2 leads to the formation of 2ATP.
• One substrate level phosphorylation.
Thus, a total of 12 ATP are produced from one acetyl COA.

6. Regulationof TCA cycle
• Three regulatory enzymes
1. Citrate synthase
2. Isocitrate dehydrogenase
3. a-ketoglutarate dehydrogenase
• Citrate synthase is inhibited by ATP, NADH, acyl COA & succinyl CoA.
• Isocitrate dehydrogenase is activated by ADP inhibited by ATP and NADH
• a-ketoglutarate dehydrogenase is inhibited by succinyl CoA & NADH.
• Availability of ADP is very important for TCA cycle to proceed.

7. Skeletal muscle

8. • Its cells, and particularly fast-twitch fibers contracting under low oxygen conditions, such as during intense
exercise, produce much lactate Structure of a Skeletal Muscle

9. require moderate amount of glucose uses oxygen faster than it can be supplied by the blood stream
Muscle that is vigorously exercising will enter anaerobiosis and show a decreasing NAD/NADH ratio, which favors
reduction of pyruvate to lactate.
• typically during intense muscular activity, energy must be released through anaerobic metabolism , the rate of
ATP production by anaerobic glycolysis is greater than that produced by the complete oxidation of glucose .
• But this could lead to an intracellular accumulation of lactate, and a consequent reduction in intracellular pH

12. In liver
• In the liver, glucogenesis occurs
• The lactate thus produced can be transported to the liver, where it is reoxidized by liver lactate dehydrogenase
to yield pyruvate, which is converted eventually to glucose.
in this way, the liver shares in the metabolic stress created by vigorous exercise
Energy cost of the Cori cycle
• The Cori cycle results in a net consumption of 4 ATP.
• The gluconeogenic leg of the cycle consumes 2 GTP and 4 ATP per molecule of glucose synthesized, that is, 6
ATP.
• the glycolysis part of the cycle produces 2 ATP molecules
As a result the cycle cannot be sustained indefinitely

13. Importance of cori cycle:
Red blood cells
These cells, lacking a nucleus, ribosomes, and mitochondria, are smaller than most other cells.
In skeletal muscle
• Prevent lactic acidosis in the muscle under anaerobic conditions and producing ATP, an energy source
during muscle activity
Cori cycle functions, more sufficiently when the muscle activity has ceased thus allowing the oxygen debt
to be repaid.

14. Gluconeogenesis
 Some tissues such as brain, kidney medulla, eyes, Testes and exercising muscles require continuous
supply of Glucose as metabolic fuel
 Liver Glycogen an essential postprandial source of Glucose
 During prolonged fast Glucose produced from non-carbohydrate sources
 Glucose synthesized denovo by special pathway Gluconeogenesis which requires both mitochondrial
and cytosolic enzymes
 Deficiency of gluconeogenesis enzymes causes hypoglycemia
 Glucose is produced in Liver, Kidneys
Precursors for gluconeogenesis:

15.  Molecules that can be used to produce a new synthesis of Glucose
 Most important precursors are Glycerol, Lactate and a-Ketoacids obtained from the metabolism of
glucogenic amino acids.
 All but two amino acids (Leucine & Lysine) are glucogenic.
 Acetyl COA and compounds giving rise to it cannot give rise to synthesis of glucose

17. STIOCHIOMETERY OF GLUCONEOGENESIS:
 Conversion of two pyruvate molecules to a glucose molecules couples the cleavage of six high
energy bonds and oxidation of two NADH
REGULATION
 Moment to moment regulation is determined primarily by the circulating level of Glucagon.
 Availability of gluconeogenic substrates