© 2003 Thomson Learning, Inc. All rights reserved General, Organic, and Biochemistry, 7e Bettelheim, Brown, and March

© 2003 Thomson Learning, Inc. All rights reserved Chapter 28 Biosynthetic Pathways Biosynthetic Pathways

© 2003 Thomson Learning, Inc. All rights reserved 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 flexibility: 1.flexibility: if a normal biosynthetic pathway is blocked, the organism can often use the reverse of the degradation pathway overcoming Le Chatelier’s principle: 2.overcoming Le Chatelier’s principle: we can illustrate by this reaction

© 2003 Thomson Learning, Inc. All rights reserved 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 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

© 2003 Thomson Learning, Inc. All rights reserved Carbohydrate Biosynthesis We discuss the biosynthesis of carbohydrates under three headings: conversion of CO 2 glucose in plants synthesis of glucose in animals and humans conversion of glucose to other carbohydrates Conversion of CO 2 to carbohydrates in plants photosynthesis takes place in plants, green algae, and cyanobacteria

© 2003 Thomson Learning, Inc. All rights reserved Synthesis of Glucose Gluconeogenesis: 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 there are three irreversible steps in glycolysis ---phosphoenolpyruvate to pyruvate + ATP ---fructose 6-phosphate to fructose 1,6-bisphosphate ---glucose to glucose 6-phosphate these three steps are reversed in gluconeogenesis, but by different reactions and using different enzymes

© 2003 Thomson Learning, Inc. All rights reserved Synthesis of Glucose

© 2003 Thomson Learning, Inc. All rights reserved 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) + P i

© 2003 Thomson Learning, Inc. All rights reserved Other Carbohydrates glycogenesis: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

© 2003 Thomson Learning, Inc. All rights reserved 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  - oxidation fatty acids are synthesized two carbon atoms at a time the source of these two carbons is the acetyl group of acetyl CoA acyl carrier protein, ACP-SH The key to fatty acid synthesis is a multienzyme complex called acyl carrier protein, ACP-SH

© 2003 Thomson Learning, Inc. All rights reserved Fatty Acid Biosynthesis 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)

© 2003 Thomson Learning, Inc. All rights reserved Fatty Acid Biosynthesis Step 1: priming of the system by acetyl-CoA

© 2003 Thomson Learning, Inc. All rights reserved Fatty Acid Biosynthesis Step 2: ACP-malonyltransferase reaction Step 3: condensation reaction

© 2003 Thomson Learning, Inc. All rights reserved Fatty Acid Biosynthesis Step 4: the first reduction Step 5: dehydration

© 2003 Thomson Learning, Inc. All rights reserved Fatty Acid Biosynthesis Step 6: the second reduction

© 2003 Thomson Learning, Inc. All rights reserved Fatty Acid Biosynthesis The cycle now repeats on butyryl-ACP chains up to C 16 (palmitic acid) are obtained by this sequence of reactions

© 2003 Thomson Learning, Inc. All rights reserved Fatty Acid Biosynthesis higher fatty acids, for example C 18 (stearic acid), are obtained by addition of one or more additional C 2 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 2’ of one of the ribose units

© 2003 Thomson Learning, Inc. All rights reserved 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)

© 2003 Thomson Learning, Inc. All rights reserved Membrane Lipids glycerol 1-phosphate combines with two acyl CoA molecules, which may be the same or different to complete the synthesis of a phospholipid, an activated serine, choline, or ethanolamine is added to the phosphatidate by a phosphoric ester bond sphingolipids and glycolipids are assembled in similar fashion from the appropriate building blocks

© 2003 Thomson Learning, Inc. All rights reserved Cholesterol All carbon atoms of cholesterol as well as of the steroids synthesized from it are derived from the two-carbon acetyl group of acetyl CoA synthesis starts with reaction of three 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

© 2003 Thomson Learning, Inc. All rights reserved Cholesterol in a series of steps requiring ATP, mevalonate undergoes phosporylation and decarboxylation to give the C 5 compound, isopentenyl pyrophosphate this compound has the carbon skeleton of isoprene, and is a key building block for all terpenes (Section 12.5)

© 2003 Thomson Learning, Inc. All rights reserved Cholesterol isopentenyl pyrophosphate (C 5 ) is the building block for the synthesis of geranyl pyrophosphate (C 10 ) and farnesyl pyrophosphate (C 15 ) in these structural formulas, the bonds joining isoprene units are shown in red

© 2003 Thomson Learning, Inc. All rights reserved Cholesterol two farnesyl pyrophosphate (C 15 ) units are joined to form squalene (C 30 ) and, in a series of at least 25 steps, squalene is converted to cholesterol (C 30 ) isopentenyl pyrophosphate is a key building block

© 2003 Thomson Learning, Inc. All rights reserved Amino Acids Most nonessential amino acids are synthesized from intermediates of either glycolysis or the citric acid cycle glutamate is synthesized by amination and reduction of  -ketoglutarate, a citric acid cycle intermediate

© 2003 Thomson Learning, Inc. All rights reserved Amino Acids glutamate in turn serves as an intermediate is the synthesis of several amino acids by the transfer of its amino group by transamination

© 2003 Thomson Learning, Inc. All rights reserved Amino Acids

© 2003 Thomson Learning, Inc. All rights reserved End Chapter 28 Biosynthetic Pathways