Overview of Metabolic Pathways

• Glycolysis: Conversion of glucose to pyruvate, producing ATP and metabolic intermediates.
• Gluconeogenesis: Conversion of pyruvate to glucose.
• Glycogenolysis: Conversion of glycogen to glucose.
• Glycogenesis: Conversion of glucose to glycogen.

Glycolysis

• Definition: Conversion of glucose into pyruvate, producing ATP and intermediates.
• Location: Occurs in the cell membrane.
• Importance: Crucial for red-blood cells and muscle tissues under anaerobic conditions.
  • Preparatory Phase:
    • Primes glucose using ATP.
    • Two key irreversible steps: Glucose to glucose-6-phosphate & F6P to F1,6BP.
    • Glucose transportable across cell membrane; G6P is not.
    • Commitment step: Conversion into F1,6BP.
  • Payoff Phase:
    • Major energy generation phase.
    • Produces 8 ATP, 2 pyruvate, and 4 NADH per glucose.

Redox Reactions and NAD+/NADH

• Redox Reactions: Transfer of electrons (oxidation and reduction).
• Role in Glycolysis: NAD+ is oxidized to NADH during the payoff phase.
• Recycling: NADH must be recycled to NAD+ for glycolysis to continue.

The Warburg Effect

• Definition: Metabolic adaptation of cancer cells.
• Characteristics: High glycolysis reliance, NAD+ replenished through lactic acid fermentation.
• Detection: PET scan can detect increased glycolysis rate in cancer tissues.

Glycogen in Humans

• Storage: Mainly in liver and muscle.
• Energy Supply: Muscles have glycogen for ~1 hour, liver for 12-24 hours.
• Release: Glycogen phosphate releases glucose as glucose-1P.

Structure of Glycogen

• Composition: Chains/branches of glucose linked by a1-4 and a1-6 links.
• Breakdown: Glucose is released as glucose-1P.

Glycogenolysis and Enzymes

• Process: Phosphorylase adds phosphate, breaking the bond from glycogen.
• Debranching Enzyme: Moves glucose units and breaks a1-6 links.

Fate of Glucose-1P

• Muscle: Converted to G6P for glycolysis.
• Liver/Kidney: G6P can be dephosphorylated for glucose transport out of the cell.

Glycogenesis

• Precursor: ADP-glucose, a sugar nucleotide.
• Process: Glucose + ATP -> glucose-6P + ADP, Glucose-1P + UTP -> UDP-glucose.
• Enzymes: Glycogenin initiates, glycogen synthase extends the chain.

Fate of Pyruvate under Anaerobic Conditions

• Anaerobic Pathways: Conversion to lactate, recycling of NAD+.
• Lactate Production: Essential for glycolysis under anaerobic conditions.

Cori Cycle

• Definition: Converts lactate from muscles to glucose in liver during recovery.

Gluconeogenesis

• Definition: Pyruvate to glucose, energy-consuming.
• Location: Mainly liver, during fasting.
• Process: Pyruvate converted to oxaloacetate, then to PEP.

Malate-Aspartate Shuttle

• Function: Transports oxaloacetate as malate for gluconeogenesis.

Pentose Phosphate Pathway (PPP)

• Function: Generates NADPH and ribose-5P.
• Phases:
  • Oxidative: Produces NADPH and CO2.
  • Non-Oxidative: Recycles ribose-5P to glucose-6P.

Enzyme Regulation

• Isozymes: Different proteins with same enzymatic activity (e.g., hexokinase).
• PFK1: Regulated by ATP, ADP, AMP, and citrate.

Glucagon's Role

• Function: Regulates glucose utilization and storage pathways.

Fructose 2,6-Bisphosphate

• Production: Catalyzed by PFK2, influences glycolysis and gluconeogenesis.

Pyruvate Kinase Isozymes

• Liver vs Muscle: Regulate glycolysis in different tissues.

Pyruvate in Regulation

• Central Role: Links glycolysis, gluconeogenesis, and TCA cycle.

Redox Potential

• Balance: Maintained by NADH/NAD+ levels and shuttles.

Responses to Epinephrine and Glucagon

• Liver vs Muscle: Different responses to these hormones.

TAG Pathway to Cells

• Process: Solubilized by bile salts, transported as chylomicrons, broken into FFA and glycerol.

Carnitine Shuttle and Beta-Oxidation

• Carnitine Shuttle: Transports FFAs into mitochondria.
• Beta-Oxidation: Breaks down FFAs into acetyl-CoA.

Ketone Bodies

• Definition: Produced in liver during starvation or diabetes.

Peroxisomes

• Role: Site of beta-oxidation in plants.

Cross-Regulation of Pathways

• Balancing: Insulin and glucagon regulate glucose and FA metabolism.

Pyruvate Transport and Warburg Effect

• Transport: Through mitochondrial membranes, relates to cancer cell metabolism.

Pyruvate Dehydrogenase Complex

• Structure: Multi-enzyme complex in mitochondria, converts pyruvate to acetyl-CoA.

TCA Cycle

• Metabolites: Various biological molecules synthesized from cycle intermediates.

Oxidative Phosphorylation

• Importance: Major ATP generator using electron carriers.

Electron Carriers

• Types: NADH, NADPH, FADH2, ubiquinone, cytochromes.

ATP Synthase and Respiration

• Function: Uses proton gradient to synthesize ATP.

Regulation of OxPhos

• Coupling: ATP synthase and electron transport are interdependent.

Mitochondrial Disorders

• Symptoms: Affect high ATP-demand tissues, such as blindness and stroke.

Inborn Errors of Metabolism

• Definition: Genetic disorders in metabolic pathways.
• Phenylalanine Catabolism: Leads to disorders like phenylketonuria (PKU).

Mitochondrial Donation

• IVF Technique: Combines mtDNA from healthy donor with maternal DNA.

Mitonuclear Communications

• Signaling: Bidirectional adaptation via anterograde and retrograde signaling.

Diabetes

• Types: Differences between Type 1 and Type 2, insulin resistance, and glucose homeostasis.

Diabetic Ketoacidosis

• Definition: Life-threatening due to blood pH changes.

Metabolic Techniques

• Metabolomics: Analytical challenges, steps, and applications in research.