Biochemical Pathways

BIOLOGY 222 (BIOCHEMISTRY) SPRING 2000 April 25 Lecture: Integration of Metabolism A. Metabolism Basics Strategy of metabolism is to form ATP, reducing power and biosynthetic building blocks •

ATP universal currency of energy, high phosphoryl group transfer potential hydrolysis of ATP is coupled with unfavorable reactions to make them favorable o generated by oxidation of food molecules  glucose, fatty acids, common intermediate is acetyl CoA  electrons carried by NADH and FADH2 NADPH 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) o o o

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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 phosphorylation) 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 • •

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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 Ketone bodies formed if [oxaloacetate] not high enough 

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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 kidney  both organs possess glucose 6-phosphatase Pyruvate •

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

catalyzed by lipase (hormone sensitive) TAG’s continually hydrolyzed and resynthesized Glycerol exported to liver o

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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