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

TCACycle

Urea

Acetoacetyl CoA

Serine

Glycogen

Triacylglycerols

Cholesterol

Fatty acids

Alanine

Purine monophosphate

Uric acids

Glutamine

Pyrimidinemonophosphate

Glycine

Otheraminoacids

Otheraminoacids

Otheraminoacids

Malonyl CoA

G-6-P

G-3-P

Pyruvate

Acetyl CoA

Oxaloacetate

-ketoglutarate

Ribose-5-PPRPP

PEP

Aspartate

Glutamate

-Oxidation

UreaCycle

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-CO2-Lipids

Pyruvate d.h. complex is akey 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 PathwayG-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

TCACycle

Urea

Acetoacetyl CoA

Serine

Glycogen

Triacylglycerols

Cholesterol

Fatty acids

Alanine

Purine monophosphate

Uric acids

Glutamine

Pyrimidinemonophosphate

Glycine

Otheraminoacids

Otheraminoacids

Otheraminoacids

Malonyl CoA

G-6-P

G-3-P

Pyruvate

Acetyl CoA

Oxaloacetate

-ketoglutarate

Ribose-5-PPRPP

PEP

Aspartate

Glutamate

-Oxidation

UreaCycle

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

GlycolysisPentose phosphate pathwayFatty acids synthesis

TCA cycle, Oxidative phosphorylation-oxidation of Fatty acidsKetone body formation

GluconeogenesisUrea synthesis

Communications betweendifferent compartmentsare 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

IsoleucinePyruvate

Alanine Valine Leucine

Phosphoenolpyruvate

Phenylalanine Tyrosine Tryptophan

Tyrosine

3-Phosphoglycerate

Serine

Glycine Cysteine

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

Lipid Transport and Utilization

A Summary of the Pathways of Catabolism and Anabolism

The Absorptive State

The Postabsorptive State