Citric Acid Cycle (Krebs Cycle)

• The Citric Acid Cycle is also known as the Tricarboxylic Acid Cycle or Krebs' Cycle.

Tricarboxylic Acid Cycle (Krebs Cycle)

• It is the final common pathway for oxidizing carbohydrates, lipids, and proteins.
• All of these substances are metabolized to acetyl-CoA.
• Acetyl-CoA is then completely oxidized.
• It occurs in the mitochondrial matrix near the respiratory chain and oxidative phosphorylation enzymes.

Metabolic Pathways

• Carbohydrates, lipids, and proteins are broken down to monosaccharides, glycerol + fatty acids, and amino acids respectively.
• They are then broken down to Acetyl-CoA.
• Acetyl-CoA enters the Krebs Cycle
• Krebs Cycle produces CO2, Reduced Coenzymes
• Reduced Coenzymes are oxidized to Oxidized Coenzymes
• H2O + ATP + Free Energy and [O] + ADP + Pi are produced from the Oxidized Coenzymes, which enters the Electron Transport Chain (ETC)

Citric Acid Cycle Products

• 1 ATP, produced through substrate-level phosphorylation.
• 1 FADH2, which yields 2 ATP.
• 3 NADH, which yields 9 ATP.
• In total, one cycle yields 12 ATP.

Importance of the Citric Acid Cycle

• Functions as a common pathway for oxidizing carbohydrates and fats.
• Produces energy, specifically 12 ATP.
• Intermediates are produced, giving rise to amino acids.
• α-ketoglutarate gives rise to Glutamic acid
• Oxaloacetate gives rise to Aspartic acid
• Pyruvate gives rise to Alanine
• Succinyl CoA is produced

Regulation

• NAD+ supply and ATP/ADP ratio regulate the cycle
• ATP inhibits citrate synthase, isocitrate dehydrogenase, and alpha-ketoglutarate dehydrogenase.
• Malic acid can become oxaloacetate via malic dehydrogenase
• Pyruvic acid can become Pyruvate Carboxylase via Pyruvate carboxylase
• Oxalo-acetate is used to form both Citrate Lyase and Transaminase.

Key Enzymes

• Malic dehydrogenase.
• Pyruvate carboxylase.
• Citrate Lyase.
• Transaminase

Gluconeogenesis

• Gluconeogenesis happens mainly in the liver and, to a lesser extent, in the kidneys.
• It is the synthesis of glucose or glycogen from non-carbohydrate precursors.

Gluconeogenic Substances

• Glucogenic amino acids.
• Glycerol.
• Pyruvate.
• Lactate.
• Propionate.

Gluconeogenic Substance

• Lactate and Pyruvate combine
• Glucogenic amino acids combine
• Glycerol are utilized
• Odd chainfatty acids propionate are utilized

Other Facts About Gluconeogenesis

• It meets the body's glucose needs when glycogen reserves are insufficient to provide glucose (prolonged fasting and starvation).
• Glucose is necessary for the proper functioning of the nervous system & erythrocytes
• Hypoglycemia causes brain dysfunction, which can lead to coma and death.
• Glucose is important for maintaining levels of citric acid cycle intermediates
• Includes pyruvate, which provides oxaloacetate and acetyl-CoA for the citric acid cycle
• Fatty acids are the main source of acetyl CoA in tissues.
• Clears lactic acid produced during anaerobic glycolysis (severely exercising muscle).
• Clears glycerol from adipose tissue.

Glycolytic and Gluconeogenic Key Enzymes

• Glucose 6-phosphatase is the key gluconeogenic enzyme, unlike Glucokinase.
• Fructose 1,6-bisphosphatase is the key enzyme, unlike Phosphofructokinase-1.
• Pyruvate carboxylase and Phosphoenolpyruvate carboxykinase (PEPCK) are used, unlike Pyruvate kinase.
• All gluconeogenic key enzymes exist in the cytosol besides mitochondrial pyruvate carboxylase.

Cori Cycle Importance

• The Cori Cycle prevents the loss of lactate as a waste product in urine
• It maintain blood glucose levels
• Muscle is specific for pyruvate because pyruvate → lactate.
• The liver is specific for lactate, because lactate → pyruvate

Glucogenic Amino Acids

• Glucogenic amino acids are convertible to glucose.
• All amino acids can give glucose except leucine and lysine
  • Leucine and Lysine are 100% ketogenic.

Fructose 1,6 Bisphosphatase

• The presence denotes that triose phosphates like dihydroxyacetone phosphate or glyceraldehyde 3-p can synthesize glucose .
• It can be present in the liver, kidneys, and muscles
• It is absent from the heart and smooth muscles

Glycerol

• Two molecules of glycerol can be used for the synthesis of one molecule of glucose.

Conversion of Propionyl CoA into Glucose

• Propionyl CoA can be converted to glucose

Fructose 2,6-bisphosphate Role

• It has a unique role in gluconeogenesis.
• It's the most potent allosteric activator for PFK1 and inhibitor for F1,6Bpase.
• F2,6BP relieves ATP allosteric inhibition on PFK1
• F2,6 BP increases the Km of the F1,6bp and inhibit it.
• PFK2 is a bifunctional enzyme that act as both a kinase and phosphatase
• F-6-P allosteric activator for the kinase and inhibitor for the phosphatase activity'

Regulation of Gluconeogenesis

• Anti-Insulin hormones like Glucagon, epinephrine, cortisol, growth hormone, and thyroid hormones regulates the activity of gluconeogenic key enzymes.

Inherited Enzyme Deficiences

• Inherited aldolase A & pyruvate kinase deficiency affects glycolysis.
• Glycolysis is inhibited in red blood cells (RBCs)
• No ATP is produced
• The Na+/K+ ATPase pump stops
• Na+ accumulates inside RBCs
• RBCs swell due to osmosis.
• RBCs rupture, leading to hemolytic anemia.

Clinical Aspects of Pyruvate Metabolism

• Arsenite & mercuric ions react with the lipoate groups, inhibiting the PDH complex.
• Dietary deficiency of thiamine resulting from high alcohol intake inhibits the PDH complex.
• These factors cause accumulation of pyruvate, leading to fatal lactic acidosis.

Inherited PDH Deficiency

• It happens due to the relationship on glucose.
• Neurological disturbances are caused by this deficiency

Pentose Phosphate Pathway (PPP)

• The Pentose Phosphate Pathway is also known as the Pentose Shunt, or Hexose Monophosphate Pathway shunt.
• The pentose phosphate pathway (PPP) is an alternative pathway for glucose oxidation
• Glucose is converted to pentose and NADPH, but doesn't yield ATP.
• NADPH is required for fatty acid synthesis, steroid hormone synthesis, and glutathione reductase function.
• Ribose (a pentose) is used for nucleotide and nucleic acid synthesis (DNA/RNA).

Favism

• Favism is erythrocyte hemolysis as a result of G-6-P dehydrogenase (G-6-PD) deficiency.
• It is common in Mediterranean and Afro-Caribbean populations.

Hemolysis Triggers:

• Oxidants such as:
• Antimalarial drugs (primaquine).
• Anti-inflammatory drugs (aspirin).
• Antibiotics (sulfonamides).
• Fava beans.