Chapter 21 Biosynthetic Pathways Introduction In most living organisms, the pathways by which a compound is synthesized are usually different from the pathways by which it is degraded; two reasons are 1. Flexibility: If a normal biosynthetic pathway is blocked, the organism can often use the reverse of the degradation pathway for synthesis. 2. Overcoming Le Châtelier’s principle: ◦ We can illustrate by this reaction: Introduction • Phosphorylase catalyzes both the forward and reverse reactions. • A large excess of phosphate would drive the reaction to the right; that is, drive the hydrolysis of glycogen. • To provide an alternative pathway for the synthesis of glycogen, even in the presence of excess phosphate: Most synthetic pathways are different from the degradation pathways. Most also differ in location and in energy requirements. Carbohydrate Biosynthesis We discuss the biosynthesis of carbohydrates under three headings: • Conversion of CO2 to glucose in plants. • Synthesis of glucose in animals and humans. • Conversion of glucose to other carbohydrates. Conversion of CO2 to carbohydrates in plants • Photosynthesis takes place in plants, green algae, and cyanobacteria. Conversion of Atmospheric CO2 to Glucose in Plants Conversion of CO2 to carbohydrates in plants • Photosynthesis takes place in plants, green algae, and cyanobacteria. Synthesis of Glucose in Animals Gluconeogenesis: The synthesis of glucose from noncarbohydrate sources. • These sources are most commonly pyruvate, citric acid cycle intermediates, and glucogenic amino acids. • Gluconeogenesis is not the exact reversal of glycolysis; that is, pyruvate to glucose does not occur by reversing the steps of glucose to pyruvate. Synthesis of Glucose • There are three irreversible steps in glycolysis: ---Phosphoenolpyruvate to pyruvate + ATP. ---Fructose 6-phosphate to fructose 1,6bisphosphate. ---Glucose to glucose 6-phosphate. • These three steps are reversed in gluconeogenesis, but by different reactions and using different enzymes. Other Carbohydrates Glucose is converted to other hexoses and to di-, oligo-, and polysaccharides. • The common step in all of these syntheses is activation of glucose by uridine triphosphate (UTP) to form uridine diphosphate glucose (UDP-glucose) + Pi . Other Carbohydrates • glycogenesis: The synthesis of glycogen from glucose. • The biosynthesis of other di-, oligo-, and polysaccharides also uses this common activation step to form an appropriate UDP derivative. The Cori Cycle Figure 21.2 The Cori cycle. Lactate from glycolysis in muscle is transported to the liver, where gluconeogensis converts it back to glucose. Fatty Acid Biosynthesis While degradation of fatty acids takes place in mitochondria, the majority of fatty acid synthesis takes place in the cytosol. These two pathways have in common that they both involve acetyl CoA. • Acetyl CoA is the end product of each spiral of b-oxidation. • Fatty acids are synthesized two carbon atoms at a time • The source of these two carbons is the acetyl group of acetyl CoA. Fatty Acid Biosynthesis The key to fatty acid synthesis is a multienzyme complex called acyl carrier protein, ACP-SH. ◦ Acts as a merry-go-round transport system ◦ Carries the growing fatty acid chain over a number of enzymes ◦ With each complete turn, a C2 fragment is added to the growing fatty acid chain ◦ The source of C2 fragment is malonly-ACP, a C3 compound bonded to ACP. It becomes C2 with the loss of CO2 Fatty Acid Biosynthesis At the beginning of this cycle, the ACP picks up an acetyl group from acetyl coA and delivers it to the first enzyme, fatty acid synthase or synthase Fatty Acid Biosythesis The C2 fragment is condensed with a C3 fragment attached to the ACP and gives off CO2 C4 is formed which is then reduced twice and dehyrate ◦ Marked the end of the cycle In the next cycle, the fragment is transferred to synthase and another malony-ACP (C3 fragment) ◦ CO2 is released and a C6 fragment is obtained The merry-go-round continues to turn and long chain fatty acid can be obtained from this process Fatty Acid Biosynthesis ◦ Higher fatty acids, for example C18 (stearic acid), are obtained by addition of one or more additional C2 fragments by a different enzyme system. ◦ Unsaturated fatty acids are synthesized from saturated fatty acids by enzyme-catalyzed oxidation at the appropriate point on the hydrocarbon chain. ◦ The structure of NADP+ is the same as NAD+ except that there is an additional phosphate group on carbon 3’ of one of the ribose units. Fatty Acid Biosynthesis Figure 21.3 The biosynthesis of fatty acids. • ACP has a side chain that carries the growing fatty acid • ACP rotates counterclockwise, and its side chain sweeps over the multienzyme system (empty spheres). Membrane Lipids The two building blocks for the synthesis of membrane lipids are: • Activated fatty acids in the form of their acyl CoA derivatives. • Glycerol 1-phosphate, which is obtained by reduction of dihydroxyacetone phosphate (from glycolysis): CH2 -OH C=O + NADH + H+ 2CH2 -OPO3 Dihydroxyacetone phosphate CH2 -OH HO CH + NAD+ 2CH2 -OPO3 Glycerol 1-phosphate Membrane Lipids • Glycerol 1-phosphate combines with two acyl CoA molecules, which may be the same or different: CH2 -OH O + 2RC-S-CoA HO CH CH2 -OPO3 2Glycerol Acyl CoA 1-phosphate O CH2 -OCR O + 2CoA-SH RCO CH CH2 -OPO3 2A phosphatidate • To complete the synthesis of a phospholipid, an activated serine, choline, or ethanolamine is added to the phosphatidate by formation of a phosphoric ester. • Sphingolipids and glycolipids are assembled in similar fashion from the appropriate building blocks. Cholesterol All carbon atoms of cholesterol and of all steroids synthesized from it are derived from the two-carbon acetyl group of acetyl CoA. • Synthesis starts with reaction of three molecules of acetyl CoA to form the six-carbon compound 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). • The enzyme HMG-CoA reductase then catalyzes the reduction of the thioester group to a primary alcohol. Cholesterol • In a series of steps requiring ATP, mevalonate undergoes phosporylation and decarboxylation to give the C5 compound, isopentenyl pyrophosphate. • This compound is a key building block for all steroids and bile acids. Cholesterol • Isopentenyl pyrophosphate (C5) is the building block for the synthesis of geranyl pyrophosphate (C10) and farnesyl pyrophosphate (C15). Amino Acids Most nonessential amino acids are synthesized from intermediates of either glycolysis or the citric acid cycle. • Glutamate, for example, is synthesized by amination and reduction of a-ketoglutarate, a citric acid cycle intermediate: Amino Acids • Glutamate in turn serves as an intermediate in the synthesis of several amino acids by the transfer of its amino group by transamination.