Respiration and Metabolism: Biochemical Pathways in Human Physiology

Glycolysis and the Lactic Acid Pathway

Introduction to Glycolysis

Glycolysis is the initial metabolic pathway for the catabolism of glucose, occurring in the cytoplasm of cells. It is an anaerobic process that breaks down one molecule of glucose into two molecules of pyruvic acid, generating ATP and NADH in the process.

• Location: Cytoplasm

• Net ATP Yield: 2 ATP per glucose molecule

• Products: 2 pyruvic acid, 2 NADH, 2 ATP

• Key Enzymes: Kinases, phosphatases, isomerases, dehydrogenases

Equation:

$\mathrm{C_6H_{12}O_6} \rightarrow 2\ \mathrm{C_3H_4O_3} + 2\ \mathrm{NADH} + 2\ \mathrm{ATP}$

Physiological Significance: Glycolysis provides quick energy and intermediates for other metabolic pathways.

Decision Point: Fate of Pyruvic Acid

After glycolysis, pyruvic acid can enter one of two pathways depending on the presence of oxygen:

• Aerobic conditions: Pyruvic acid enters the mitochondria for further oxidation.

• Anaerobic conditions: Pyruvic acid is converted to lactic acid.

Lactic Acid Pathway (Anaerobic Metabolism)

When oxygen is absent, NADH donates electrons to pyruvic acid, forming lactic acid and regenerating NAD+. This process, called fermentation, allows glycolysis to continue but yields no additional ATP.

• Key Reaction: Pyruvic acid + NADH + H+ → Lactic acid + NAD+

• Significance: Provides energy in low-oxygen conditions, but is inefficient and can lead to acidosis.

• Special Cases: Red blood cells rely solely on lactic acid fermentation due to lack of mitochondria.

Example: During intense exercise, skeletal muscles produce lactic acid, which is transported to the liver for conversion back to pyruvic acid or glucose.

Aerobic Respiration: Citric Acid Cycle (TCA/Krebs Cycle)

Transition Step

In the presence of oxygen, pyruvic acid is transported into the mitochondrial matrix, where it is converted to acetyl CoA via the removal of CO2 and reduction of NAD+ to NADH.

• Location: Mitochondrial matrix

• Purpose: Links glycolysis to the citric acid cycle

Equation:

$\mathrm{Pyruvic\ acid} + \mathrm{CoA} + \mathrm{NAD^+} \rightarrow \mathrm{Acetyl\ CoA} + \mathrm{CO_2} + \mathrm{NADH} + \mathrm{H^+}$

Citric Acid Cycle (Krebs/TCA Cycle)

The citric acid cycle is a series of reactions that oxidize acetyl CoA to CO2, generating NADH, FADH2, ATP, and heat. It is a central pathway in aerobic metabolism.

• Key Steps: Acetyl CoA combines with oxaloacetic acid to form citric acid, which is then metabolized back to oxaloacetic acid.

• Products per cycle: 3 NADH, 1 FADH2, 1 ATP, 2 CO2

• Coenzymes: NAD+ and FAD

Equation:

$\mathrm{Acetyl\ CoA} + 3\ \mathrm{NAD^+} + \mathrm{FAD} + \mathrm{ADP} + \mathrm{Pi} \rightarrow 2\ \mathrm{CO_2} + 3\ \mathrm{NADH} + \mathrm{FADH_2} + \mathrm{ATP} + \mathrm{CoA}$

Aerobic Respiration: Electron Transport Chain (ETC) and Oxidative Phosphorylation

Electron Transport Chain

The ETC is located in the inner mitochondrial membrane and is responsible for converting the energy stored in NADH and FADH2 into ATP. Electrons are passed through a series of protein complexes, pumping protons to create a gradient used by ATP synthase.

• Final Electron Acceptor: Oxygen

• Byproduct: Water (H2O)

• ATP Yield: Theoretically 36-38 ATP per glucose; actual yield is 30-32 ATP

Equation:

$\mathrm{O_2} + 4\ \mathrm{e^-} + 4\ \mathrm{H^+} \rightarrow 2\ \mathrm{H_2O}$

ATP Calculation:

• Each NADH: 2.5 ATP (actual)

• Each FADH2: 1.5 ATP (actual)

Interconversion of Glucose, Lactic Acid, and Glycogen

Storing Glucose: Glycogenesis

Cells cannot store glucose directly due to osmotic effects. Instead, glucose is converted to glycogen for storage, primarily in the liver, skeletal muscle, and cardiac muscle.

• Glycogenesis: Formation of glycogen from glucose

• Enzyme: Glycogen synthase

• Storage Sites: Liver, skeletal muscle, cardiac muscle

Glycogenolysis

When glucose is needed, glycogen is broken down to glucose-1-phosphate, then to glucose-6-phosphate. Only the liver can release free glucose into the bloodstream due to the enzyme glucose-6-phosphatase.

• Glycogenolysis: Breakdown of glycogen to glucose

• Key Enzyme (Liver): Glucose-6-phosphatase

Cori Cycle and Gluconeogenesis

The Cori cycle describes the recycling of lactic acid produced by muscles during anaerobic metabolism. Lactic acid is transported to the liver, converted back to pyruvic acid, and then to glucose via gluconeogenesis.

• Location: Skeletal muscle and liver

• Function: Prevents lactic acid accumulation and provides glucose for muscle activity

• Gluconeogenesis: Formation of glucose from non-carbohydrate sources

Metabolism of Lipids and Proteins

Lipid Metabolism: Lipogenesis and Lipolysis

Excess glucose is converted to fatty acids and triglycerides (lipogenesis). When energy is needed, triglycerides are broken down into fatty acids and glycerol (lipolysis), which can be used for ATP production.

• Lipogenesis: Formation of lipids from acetyl CoA

• Lipolysis: Breakdown of triglycerides into fatty acids and glycerol

β-Oxidation of Fatty Acids

Fatty acids are broken down by β-oxidation to produce acetyl CoA, which enters the citric acid cycle. This process yields large amounts of ATP.

• Example: A 16-carbon fatty acid yields 8 acetyl CoA, producing up to 108 ATP.

Ketogenesis

When fatty acid breakdown exceeds utilization, the liver converts acetyl CoA into ketone bodies (ketogenesis). These water-soluble molecules can be used as energy sources but may cause ketosis if accumulated.

Amino Acid Metabolism

Amino acids are primarily used for protein synthesis. Excess amino acids can be converted to glucose (gluconeogenesis) or fat. Amino acids can also be synthesized from citric acid cycle intermediates by transamination.

Summary: Interchangeability of Energy Sources

Proteins, fats, and carbohydrates can be interconverted through various metabolic pathways, allowing the body to adapt to different energy demands.

Relative Importance of Energy Molecules in Different Organs

The preference for energy substrates varies by organ. The brain relies heavily on glucose, while muscles and the liver can utilize fatty acids, ketone bodies, and lactic acid.

Organ	Glucose	Fatty Acids	Ketone Bodies	Lactic Acid
Brain	+++	–	+	–
Skeletal muscles (resting)	+	+++	+	–
Liver	++	++	+	+
Heart	+	++	+	+