Integration of Metabolism

Cellular Locations for Metabolism Citric Acid Cycle, Oxidative Phosphorelation, Fatty Acid Oxidation - Mitochondria Glycolysis - Cytosol Fatty Acid Synthesis – Cytosol Nucleic Acid synthesis - Nucleus Protein Synthesis – Ribosomes & RER

TCA Cycle Urea Acetoacetyl CoA Serine Glycogen Triacylglycerols Cholesterol Fatty acids Alanine Purine monophosphate Uric acids Glutamine Pyrimidine monophosphate Glycine Other amino acids Other amino acids Other amino acids Malonyl CoA G-6-P G-3-P Pyruvate Acetyl CoA Oxaloacetate  -ketoglutarate Ribose-5-P PRPP PEP Aspartate Glutamate  -Oxidation Urea Cycle Integration of Fuel Metabolism

Glycolysis PFK is the most important control site in glycolysis: In liver, when glucose is low, glucagon activates phosphatase to convert F-2, 6-BP to F-6-P. PFK is Inhibited, which slows down glycolysis. In muscle, when glucose is low, epinephrine activates a kinase to convert F-6-P to F-2,6-BP. PFK is Activated, which accelerates glycolysis. Cytosol

Glucose-CO 2 -Lipids Pyruvate d.h. complex is a key irreversible step in animals: No conversion of lipids to carbohydrates

Citric Acid Cycle Pyruvate d.h.complex Citrate synthase Isocitrate d.h.  -ketoglutarate d.h. mitochondria

Pentose Phosphate Pathway G-6-P d.h. Cytosol

Gluconeogenesis Most in cytosol: Liver and Kidney (mit.) (inside ER) F-1,6-bisphosphatase is the key control site

Integration of Fuel Metabolism TCA Cycle Urea Acetoacetyl CoA Serine Glycogen Triacylglycerols Cholesterol Fatty acids Alanine Purine monophosphate Uric acids Glutamine Pyrimidine monophosphate Glycine Other amino acids Other amino acids Other amino acids Malonyl CoA G-6-P G-3-P Pyruvate Acetyl CoA Oxaloacetate  -ketoglutarate Ribose-5-P PRPP PEP Aspartate Glutamate  -Oxidation Urea Cycle

Key Junctions: G-6-P, Pyruvate, and Acetyl CoA

Glycolysis Pentose phosphate pathway Fatty acids synthesis TCA cycle, Oxidative phosphorylation  -oxidation of Fatty acids Ketone body formation Gluconeogenesis Urea synthesis Communications between different compartments are achieved by a number of carriers to carry metabolic intermediates across membranes. Compartmentalization of the Major Pathway of Metabolism

 -Ketoglutarate Glutamate Glutamine Proline Arginine Oxaloacetate Aspartate Asparagine Methionine Threonine Lysine Isoleucine Pyruvate Alanine ValineLeucine Phosphoenolpyruvate Phenylalanine Tyrosine Tryptophan Tyrosine 3-Phosphoglycerate Serine GlycineCysteine Ribose 5-phosphate Histidine

Catabolism: The Breakdown of Macro- nutrients for Energy Stages 1-4

Lipolysis

Stage 2: Beta Oxidation

Lipogenesis

Gluconeogenesis Noncarbohydrate molecules transformed into glucose by various anabolic pathways Amino acids, lactate, glycerol Occurs primarily in liver & kidneys Provides glucose to cells during starvation Stimulated by glucagon & cortisol

Gluconeogenesis

Gluconeogenesis from Amino Acids Glucogenic amino acids All except leucine & lysine Removal of amino group via transamination & deamination along with conversion of carbon skeleton to oxaloacetate necessary Requires coenzymes (B vitamins)

Ketogenesis Ketones Organic compounds used as energy source during starvation, fasting, low-carb diets, or uncontrolled diabetes Ketogenesis Metabolic pathways used to produce ketones

Ketones β-oxidation leads to substantial amounts of acetyl CoA production Ketone body formation is an “overflow” pathway for acetyl CoA use If OAA is not present, then acetyl CoA does not go through TCA cycle and will be converted to ketones Low rates of glycolysis lead to reduced OAA production

Ketogenesis

Ketone body formation Ketone bodies Acetoacetate β-hydroxybutyrate Acetone Acetyl CoA + acetyl CoA = acetoacetyl CoA Acetoacetyl CoA – CoA = acetoacetate Acetoacetate can be converted to acetone and β - hydroxybutyrate

Why is ketogenesis important? Muscles, brain & kidneys have enzymes that allow them to use ketones for ATP production Serve as a major source of energy during times of glucose insufficiency Spare use of amino acids

What happens when ketone production exceeds ketone use? Ketosis High levels of ketones in blood When? Early lactation in dairy cows Late pregnancy in sheep with multiple pregnancies Diabetics Ketoacidosis Severe ketosis Lowered blood pH, nausea, coma, death

Ketosis Cure is infusion of glucose

An Introduction to Cellular Metabolism

Metabolic Turnover and Cellular ATP Production

Nutrient Use in Cellular Metabolism

Lipid Synthesis

Lipid Transport and Utilization

A Summary of the Pathways of Catabolism and Anabolism

The Absorptive State

The Postabsorptive State