Post on 19-Dec-2015
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General, Organic, and General, Organic, and Biochemistry, 7eBiochemistry, 7e
Bettelheim,Bettelheim,
Brown, and MarchBrown, and March
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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