Biochemistry: TCA Cycle and Fatty Acid Metabolism

Metabolic Pathways Overview

• Metabolism in the fed state involves storing nutrients.
• In the fasting state, nutrients are oxidized for energy production.
• Food is broken down into carbohydrates, fats, and proteins during digestion and absorption.
• Glucose, fatty acids and glycerol, and amino acids are the resulting products.
• Glycolysis is the metabolic pathway for glucose.
• Beta-oxidation is the pathway for fatty acids.
• Transamination is the pathway for amino acids.
• Glycogen and fats are storage forms of glucose and fatty acids.
• Other compounds can be synthesized from these molecules.
• Acetyl-CoA is a key intermediate in all three pathways.
• The Krebs cycle (also known as the citric acid cycle or TCA cycle) is crucial for ATP production.
• ATP is generated through the Krebs Cycle (in the mitochondria).
• ATP fuels the body's functions

Cellular Respiration

• Cellular respiration includes glycolysis, link reaction, Krebs cycle, and chemiosmosis.
• Glycolysis occurs in the cytosol.
• Glucose is broken down to pyruvate.
• 2 ATP molecules are generated.
• The link reaction connects glycolysis to the Krebs cycle.
• Acetyl CoA is formed.
• The Krebs cycle (citric acid cycle) occurs in the mitochondria.
• Acetyl CoA enters the Krebs cycle.
• 2 ATP, 6 NADH, and 2 FADH2 are produced.
• Chemiosmosis produces ATP from NADH and FADH2.

Glycolysis

• Glycolysis is a metabolic pathway that breaks down glucose into pyruvate.
• It's a crucial step in cellular respiration, occurring in the cytosol.
• Different enzymes catalyze stepwise reactions from glucose to pyruvate.
• 2 ATP and 2 NADH are the overall net products of glycolysis.

Glycolysis in Full Detail

• Glucose is phosphorylated by hexokinase or glucokinase to glucose-6-phosphate.
• An isomerization to fructose-6-phosphate occurs.
• Phosphofructokinase phosphorylates the fructose-6-phosphate.
• Fructose-1,6-bisphosphate is the resulting product.
• Aldolase cleaves the fructose-1,6-bisphosphate into GAP and DHAP.
• Triose phosphate isomerase converts DHAP to GAP.
• Further reactions result in 2 pyruvate molecules.
• NADH and 4 ATP are produced throughout the process.
• The net gain is 2 ATP and 2 NADH molecules.

Gluconeogenesis

• Gluconeogenesis is the formation of glucose from non-carbohydrate precursors like lactate, glycerol, and amino acids.
• It's a reversal of glycolysis, but not completely reversible.
• It involves a different set of 8 enzymes.
• Precursors for gluconeogenesis include lactate, glycerol, alanine, and glutamine.

Aerobic Respiration

• Aerobic respiration utilizes oxygen as the final electron acceptor in the electron transport chain (ETC) within the mitochondria.
• The ETC is a series of protein complexes transferring electrons, producing an H+ gradient.
• The H+ gradient drives ATP synthesis by ATP synthase.
• Oxygen is the terminal electron acceptor, forming water in the process.

TCA Cycle

• The TCA cycle is a series of 8 enzymatic reactions converting pyruvate to CO2 generating ATP, NADH, and FADH2.
• The cycle starts with Acetyl coA entering and generates 2 GTP, 6 NADH, 2 FADH2
• Isocitrate dehydrogenase, and alpha-ketoglutarate dehydrogenase regulates the cycle via allosteric enzymes.
• These molecules carry energy used to produce ATP.

Electron Transport Chain (ETC)

• The ETC is a series of protein complexes in the inner mitochondrial membrane.
• It transports electrons from NADH and FADH2.
• The energy from electrons drives proton pumping, creating a proton gradient.
• ATP synthase uses the gradient to generate ATP molecules.

FOF1 ATP Synthase

• ATP synthase is an enzyme complex responsible for ATP synthesis during oxidative phosphorylation.
• It consists of F0 and F1 subunits.
• F0 is embedded in the mitochondrial inner membrane to create a proton channel and F1 in the matrix (where ATP synthesis occurs).
• The rotation of the F0 subunit drives the formation of ATP from ADP + Pi.

Beta-Oxidation

• Beta-oxidation is a metabolic pathway for degrading fatty acids into acetyl-CoA.
• It involves four steps that repeat for each two-carbon unit.
• Acyl-CoA dehydrogenase, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase.
• Fatty acids are broken down into acetyl-CoA units for energy.
• It occurs in the mitochondria.

Lipid Catabolism

• Lipids are broken down into glycerol and fatty acids.
• Glycerol enters glycolysis, and fatty acids undergo beta-oxidation to produce Acetyl-CoA.
• Fatty acids are transported into the mitochondria via carnitine shuttle.

Fatty Acid Activation

• Fatty acids are activated to acyl-CoA esters and transported into the mitochondrial matrix.
• ATP is used in this process.

Mitochondrial Transport

• Fatty acyl-CoA enters the mitochondrial matrix after transport via the carnitine shuttle.

Summary of Carbon Fates

• The number of acetyl-CoA molecules produced in fatty acid breakdown is half the number of carbon atoms.
• The number of NADH and FADH2 molecules formed is also related to the number of carbons in the fatty acids.
• The products from fatty acid breakdown enter the TCA Cycle or ETC for further energy production.

Amino Acid Catabolism

• Proteins are broken down into amino acids.
• Amino acids can be converted into intermediates in the TCA cycle or used to synthesize new proteins.
• Transamination and Deamination are crucial steps.
• Nitrogen is removed and either excreted as Urea or used to synthesize other compounds including other amino acids.
• Key molecules like Urea cycle and Glutamate are vital for nitrogen removal.

Carbohydrates vs Lipids

• Carbohydrates are quickly available for energy, readily digested, oxidize more quickly, and readily dissolve in water.
• Lipids require more energy to release, are digested slower, and dissolve less easily in water and have more carbon and hydrogen.