28 28-1 © 2003 Thomson Learning, Inc. All rights reserved General, Organic, and Biochemistry, 7e Bettelheim, Brown, and March

2828

28-1© 2003 Thomson Learning, Inc.All rights reserved

General, Organic, and General, Organic, and Biochemistry, 7eBiochemistry, 7e

Bettelheim,Bettelheim,

Brown, and MarchBrown, and March

2828


Chapter 28Chapter 28

Biosynthetic Biosynthetic PathwaysPathways

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IntroductionIntroduction• 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:flexibility: if a normal biosynthetic pathway is blocked, the organism can often use the reverse of the degradation pathway

2.overcoming Le Chatelier’s principle:overcoming Le Chatelier’s principle: • we can illustrate by this reaction

(Glucose)n +Pi

Glycogen

phosphorylase(Glucose)n-1

Glycogen(one unit smaller)

+Glucose 1-phosphate

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IntroductionIntroduction• 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

(Glucose)n-1 +UDP-glucose (Glucose)nGlycogen

(one unit larger)

+ UDP

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Carbohydrate BiosynthesisCarbohydrate Biosynthesis• We discuss the biosynthesis of carbohydrates

under three headings:• conversion of CO2 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

cyanobacteria6H2O 6H2O C6H12O6 6H2O+ +energy chlorophyll +

(from sun light)

Glucose

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Synthesis of GlucoseSynthesis 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

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Synthesis of GlucoseSynthesis of Glucose

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Other CarbohydratesOther 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

OH

HO

H

O-P-O-P-OCH2

H

OHH

OH

CH2OH

H

O-

O

O-

O

HHHO OH

H HO

HN

N

O

O

Uridine diphosphate glucose (UDP-glucose)

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Other CarbohydratesOther 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

UTP

UTP

UDP

UDP

pyrophosphate

pyrophosphate

Glucose 1-phosphate + UDP-glucose +

(Glucose)n +UDP-glucose (Glucose)n+1 +

Glucose 1-phosphate + + (Glucose)n

(Glucose)n+1 + +

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Fatty Acid BiosynthesisFatty 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

• The key to fatty acid synthesis is a multienzyme complex called acyl carrier protein, ACP-SHacyl carrier protein, ACP-SH

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Fatty Acid BiosynthesisFatty 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)

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Fatty Acid BiosynthesisFatty Acid Biosynthesis• Step 1: priming of the system by acetyl-CoA

CH3C-SCoAO

+ HS-ACP

+ HS-synthase

+ HS-synthase

CH3C-S-ACPO

CH3C-SCoAO

CH3C-S-ACPO

CH3C-S-synthaseO

CH3C-S-SynthaseO

+ HS-CoA

+

+ HS-ACP

HS-CoA

Acetyl-CoA Acetyl-ACP

Acetyl-ACP Acetyl-synthase

Acetyl-synthaseAcetyl-CoA

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Fatty Acid BiosynthesisFatty Acid Biosynthesis• Step 2: ACP-malonyltransferase reaction

• Step 3: condensation reaction

CH2C-SCoA

COO-

O+ HS-ACP CH2C-S-ACP

COO-

O+ HS-CoA

Malonyl-CoA Malonyl-ACP

CH3C-S-SynthaseO

+ CH2C-ACPCOO-

O

CH3C-CH2-C-S-ACPO O

+ CO2 + HS-synthase

Acetyl-synthaseMalonyl-ACP

Acetoacetyl-ACP

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Fatty Acid BiosynthesisFatty Acid Biosynthesis• Step 4: the first reduction

• Step 5: dehydration

CH3C-CH2-C-S-ACP

O

Acetoacetyl-ACP

+ NADPH + H+

D--Hydroxybutyryl-ACP

C

OH

CH2-C-S-ACPHH3C

O+ NADP+

O

D--Hydroxybutyryl-ACP

OH

C CC-S-ACP

H3C H

+ H2O

Crotonyl-ACP

C

OH

CH2-C-S-ACPHH3C

O

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Fatty Acid BiosynthesisFatty Acid Biosynthesis• Step 6: the second reduction

CH3-CH2-CH2-C-S-ACP

O

Butyryl-ACP

+ NADPH + H+

OH

C C

C-S-ACP

H3C HCrotonyl-ACP

+ NADP+

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Fatty Acid BiosynthesisFatty Acid Biosynthesis• The cycle now repeats on butyryl-ACP

• chains up to C16 (palmitic acid) are obtained by this sequence of reactions

+ CH2C-S-ACPCO2

-

Malonyl-ACP

CH3CH2CH2C-S-ACPO

CH3CH2CH2CH2CH2C-S-ACP

Butyryl-ACP

Hexanoyl-ACP

3. condensation4. reduction

6. reduction5. dehydration

O

O

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Fatty Acid BiosynthesisFatty 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 2’ of one of the ribose units

R-CH2-CH2-(CH2)nCOOH + O2 + NADPH + H+

RC C

(CH2)nCOOH

H H+ 2H2O + NADP+

enzyme

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Membrane LipidsMembrane 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-OHC=OCH2-OPO3

2-NADH + H+

CH2-OHCHCH2-OPO3

2-HO NAD+

Dihydroxyacetonephosphate

Glycerol1-phosphate

+ +

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Membrane LipidsMembrane 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

CH2-OHCHCH2-OPO3

2-HO 2RC-S-CoA

O CH2-OCR

CH

CH2-OPO32-

RCOO

O

2CoA-SH+ +

Acyl CoA A phosphatidateGlycerol1-phosphate

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CholesterolCholesterol• 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

3CH3CSCoAO

-O SCoA

OO OH

Acetyl CoA 3-Hydroxy-3-methylglutaryl-CoA

-O OH

O OH

Mevalonate

HMG-CoAreductase

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CholesterolCholesterol• in a series of steps requiring ATP, mevalonate

undergoes phosporylation and decarboxylation to give the C5 compound, isopentenyl pyrophosphate

• this compound has the carbon skeleton of isoprene, and is a key building block for all terpenes (Section 12.5)

-O OH

O OH

MevalonateOP2O6

3-

Isopentenylpyrophosphate

Isoprene

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CholesterolCholesterol• isopentenyl pyrophosphate (C5) is the building block

for the synthesis of geranyl pyrophosphate (C10) and farnesyl pyrophosphate (C15)

• in these structural formulas, the bonds joining isoprene units are shown in red

OP2O63-

OP2O63-

Geranyl pyrophosphate Farnesyl pyrophosphate

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CholesterolCholesterol• two farnesyl pyrophosphate (C15) units are joined to

form squalene (C30) and, in a series of at least 25 steps, squalene is converted to cholesterol (C30)

• isopentenyl pyrophosphate is a key building block

OP2O63-

Isopentenylpyrophosphate

Terpenes

CholesterolSteroid hormones

Bile acids

HOCholesterol

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Amino AcidsAmino 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

-O-C-CH2-CH2-C-COO-

-Ketoglutarate

+ NH4+

-O-C-CH2-CH2-CH-COO-

NH3+

Glutamate

NADPH + H+

NADP+

O

O O

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Amino AcidsAmino Acids• glutamate in turn serves as an intermediate is the

synthesis of several amino acids by the transfer of its amino group by transamination COO-

C=OCH3

COO-

CH-NH3+

CH2

CH2

COO-

COO-

CH-NH3+

CH3

COO-

C=OCH2

CH2

COO-

-KetoglutaratePyruvate

+

AlanineGlutamate

+

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Amino AcidsAmino Acids-Ketoglutarate

GlutamateGlutamineProlineArginine

Oxaloacetate

AspartateAsparagineMethionineThreonine

LysineIsoleucine

3-Phosphoglycerate

SerineCysteineGlycine

Pyruvate

ValineAlanineLeucine

Phosphoenolpyruvate + Erythrose 4-phosphate

PhenylalanineTyrosineTryptophan

Ribose 5-phosphateHistidine

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End End Chapter 28Chapter 28

Biosynthetic PathwaysBiosynthetic Pathways

Documents

28 28-1 © 2003 Thomson Learning, Inc. All rights reserved General, Organic, and Biochemistry, 7e Bettelheim, Brown, and March