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April 25 Lecture: Integration of Metabolism

A. Metabolism Basics
Strategy of metabolism is to form ATP, reducing power and biosynthetic building blocks

o universal currency of energy,
o high phosphoryl group transfer potential
o hydrolysis of ATP is coupled with unfavorable reactions to make them
o generated by oxidation of food molecules
 glucose, fatty acids, common intermediate is acetyl CoA
 electrons carried by NADH and FADH2
o major electron donor in reductive biosynthesis
• Biomolecules constructed from small number of building blocks
o common intermediates for pathways
• Biosynthetic and degradative pathways almost always distinct
o fatty acid synthesis (cytosol); fatty acid degradation (mito. matrix)

B. Recurring Motifs

1. Allosteric interactions

• flow of pathways determined by committed steps (first irreversible step)
• enzymes catalyzing committed steps are allosterically controlled

2. Covalent modification

• some enzyme are activated or inhibited by covalent modification (usually
• modification last longer than allosteric interaction

3. Enzyme levels

• amounts and activities of enzymes are controlled

4. Compartmentation

• different metabolic pathways are localized to different parts of cell
5. Specialization of Organs

• organs have specific roles

C. Major Pathways and Control Sites

1. Glycolysis

• Converts glucose into two molecules of pyruvate
• Generates 2 ATP and 2 NADH
• NADH oxidized by oxidative phosphorylation
• NAD+ regenerated anaerobically by lactate dehydrogenase

2. Citric Acid Cycle

• Located in mitochondrial matrix
• Complete oxidation of acetyl CoA yields
o 1 GTP, 3 NADH, 1 FADH2
• Passage of electrons to electron transport chain produces proton gradient

3. Pentose Phosphate Pathway

• Produces NADPH for biosynthetic reactions
• Produces Ribose 5-P for nucleotide synthesis
• Dehydrogenation of Glucose 6-P is committed step
o controlled by levels of NADP+

4. Gluconeogenesis

• Glucose synthesized from non-carbohydrate precursors
o lactate, glycerol, amino acids
• Major entry point is pyruvate which is carboxylated to oxaloacetate
o oxaloacetate decarboxylated to phosphoenolpyruvate
• Two hydrolytic steps bypass irreversible steps of glycolysis

5. Fatty Acid Metabolism

• Synthesized in cytosol by addition of two carbon
units donated by malonyl CoA
• Malonyl CoA formed by carboxylation of acetyl
CoA (acetyl CoA carboxylase)
o Enzyme stimulated by citrate
• Fatty acids degraded to acetyl CoA in
mitochondrial matrix by β -oxidation pathway
o Acetyl CoA enters citric acid cycle if
oxaloacetate concentration is high enough
 FADH2 and NADH transferred to ETC
o Ketone bodies formed if [oxaloacetate] not high enough

D. Key Junctions

1. Glucose 6-Phosphate is junction in catabolic and anabolic pathways
 Low level of glucose stimulates glycogenolysis and gluconeogenesis in liver and
 both organs possess glucose 6-phosphatase


• Derived from glucose 6-P, alanine, and lactate

Acetyl CoA

• Major source of acetyl CoA from oxidative decarboxylation of pyruvate and β -
oxidation of fatty acids
• Acetyl CoA also derived from ketogenic amino acids
• Fate restricted to citric acid cycle or cholesterol biosynthesis

E. Metabolic Pathways of Major Organs
1. Brain

• Glucose is virtually sole source of fuel
• lacks fuel stores (requires constant supply of glucose)
• During starvation, ketone bodies generated by liver partially replace glucose
• Fatty acids do not serve as fuel (bound to albumin in plasma)

2. Muscle

• Major fuels are glucose, fatty acids, and ketone bodies
• Large store of glycogen
o converted to glucose6-phosphate
• Lacks glucose 6-phosphatase
o retains glucose

3. Adipose Tissue

• TAG’s are largest source of energy (135,000 kcal in 70 kg human)
• Principal role is activation of fatty acids and transfer CoA derivatives to glycerol
• G3P derived from reduction of DHAP (Glycolysis)
o Requires glucose for synthesis of TAG’s
• TAG’s hydrolyzed to glycerol and FFA’s
o catalyzed by lipase (hormone sensitive)
• TAG’s continually hydrolyzed and resynthesized
• Glycerol exported to liver

4. Liver

• essential for providing fuel to brain, muscle, and other peripheral organs
• converts glucose to glycogen and breaks down glycogen to glucose
• Fatty acids derived from diet or synthesized by liver are secreted as very low
density lipoprotein (VLDL)
• During fasting converts fatty acids to ketone bodies
• Prefers keto acids derived from amino acids as fuel source