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Frederick A. Bettelheim
William H. Brown
Mary K. Campbell
Shawn O. Farrell
www.cengage.com/chemistry/bettelheim
Chapter 29
Biosynthetic Pathways
William H. Brown • Beloit College
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:
(Glucose)n + Pi
Glycogen
phosphorylase
(Glucos e)n-1 + Glucose 1-phosphate
Glycogen
(one unit smaller)
29-2
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:
(Glucose)n-1 + UDP-glucose
(Glucos e)n + UDP
Glycogen
(one unit larger)
Most synthetic pathways are different from the
degradation pathways. Most also differ in location and in
energy requirements.
29-3
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.
6 H2 O + 6 H2 O + energy
(from
su n ligh t)
chloroph yll
C6 H1 2 O6 + 6 H2 O
Glu cose
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Synthesis of Glucose
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.
29-5
Synthesis of Glucose
Figure 29.1 Gluconeogenesis.
29-6
Synthesis of Glucose
Figure 29.1 Gluconeogenesis (continued)
29-7
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 .
H
CH2 OH
O
H
H
OH
HO
H
O
H
O O
O-P-O-P-OCH2
O O
OH
H
HN
O
O
H
HO
Uridine d iphosph ate glu cose
(UD P-glucose)
N
H
H
OH
29-8
Other Carbohydrates
• glycogenesis: The synthesis of glycogen from glucose.
Glu cose 1-ph osp hate + UTP
(Glucose)n + UD P-glucose
UD P-glucose + pyrophosp hate
(Glucos e)n+1 + UD P
Glu cose 1-ph osp hate + UTP + (Glucose)n
(Glucos e)n+1 + UD P + pyrophosp hate
• The biosynthesis of other di-, oligo-, and
polysaccharides also uses this common activation step
to form an appropriate UDP derivative.
29-9
The Cori Cycle
Figure 29.2
Lactate from
glycolysis in
muscle is
transported to
the liver, where
gluconeogensis
converts it back
to glucose.
29-10
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 boxidation.
• 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-SH.
29-11
Fatty Acid Biosynthesis
Figure 29.3 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).
29-12
Fatty Acid Biosynthesis
Step 1: Priming of the system by acetyl-CoA.
O
CH3 C-SCoA + HS-ACP
A cetyl-CoA
O
CH3 C-S-ACP + HS-CoA
Acetyl-ACP
O
CH3 C-S-ACP + HS-synth ase
Acetyl-ACP
O
CH3 C-S-Synthas e + HS-ACP
Acetyl-synthase
O
CH3 C-SCoA + HS-synth ase
A cetyl-CoA
O
CH3 C-S-synthas e + HS-CoA
Acetyl-synthase
29-13
Fatty Acid Biosynthesis
• Step 2: ACP-malonyltransferase reaction:
O
CH2 C-SCoA + HS-ACP
O
CH2 C-S-ACP + HS-CoA
COOMalonyl-CoA
COOMalonyl-ACP
• Step 3: Condensation reaction:
O
O
CH3 C-S-synth ase + CH2 C-A CP
COOAcetyl-synthase
Malonyl-ACP
O
O
CH3 C-CH2 - C-S- A CP + CO 2 + HS-synth ase
Acetoacetyl-ACP
29-14
Fatty Acid Biosynthesis
• Step 4: The first reduction:
O
O
CH3 C-CH2 - C-S- A CP + N AD PH + H+
Acetoacetyl-ACP
OH
H
H3 C
C
O
CH2 -C- S- ACP + N AD P+
• Step 5: Dehydration:D-b-Hydroxybutyryl-ACP
H
H3 C
OH
C
O
CH2 -C- S- ACP
D-b-Hydroxybutyryl-ACP
O
C-S-A CP
H
C C
H3 C
H
Crotonyl-ACP
+ H2 O
29-15
Fatty Acid Biosynthesis
• Step 6: the second reduction:
O
H
C-S-A CP
C
H3 C
C
H
Crotonyl-ACP
+ N AD PH + H+
O
CH3 -CH 2 - CH2 -C- S- ACP + N AD P+
Butyryl-ACP
29-16
Fatty Acid Biosynthesis
• The cycle now repeats on butyryl-ACP.
O
O
CH 3 CH 2 CH2 C-S- ACP + CH 2 C-S-A CP
Butyryl-ACP
CO 2 Malonyl-ACP
3.
4.
5.
6.
condens ation
reduction
dehydration
reduction
O
CH3 CH2 CH 2 CH 2 CH2 C- S- ACP
Hexanoyl-ACP
• Chains up to C16 (palmitic acid) are obtained by this
sequence of reactions.
29-17
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.
R-CH2 -CH2 -( CH2 ) nCOOH + O2 + NADPH + H+
enzyme
R
(CH2 ) n COOH
+ 2 H2 O + NADP+
C C
H
H
29-18
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
+ NADH + H+
C=O
2CH2 -OPO3
D ihydroxyaceton e
ph osp hate
CH2 -OH
+ NAD+
HO CH
2CH2 -OPO3
Glycerol
1-p hosphate
29-19
Membrane Lipids
• Glycerol 1-phosphate combines with two acyl CoA
molecules, which may be the same or different:
CH2 -OH
O
+ 2 RC-S-CoA
HO CH
CH2 -OPO3 2 Glycerol
Acyl CoA
1-phosp hate
O
CH2 -OCR
O
+ 2 CoA-SH
RCO CH
CH2 -OPO3 2 A phosp hatidate
• 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.
29-20
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 molecules of
acetyl CoA to form the six-carbon compound 3hydroxy-3-methylglutaryl CoA (HMG-CoA).
• The enzyme HMG-CoA reductase then catalyzes the
reduction of the thioester group to a primary alcohol.
O
3 CH3 CSCoA
Acetyl CoA
O
-
O
OH O
SCoA
3-Hyd roxy-3methylglutaryl-CoA
HMG-CoA
reductase
O
-
OH
O
OH
Mevalonate
29-21
Cholesterol
• 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) and steroids.
O
-
OH
O
OH
Mevalonate
OP2 O6 3 Isopentenyl
pyrophos phate
Is oprene
29-22
Cholesterol
• 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.
OP2 O6 3 Geranyl pyrophos phate
OP2 O6 3 Farnesyl pyrophos phate
29-23
Cholesterol
• 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).
Cholesterol
HO
• Isopentenyl pyrophosphate is a key building block:
Steroid hormon es
Ch oles terol
3-
OP2 O6
Is op entenyl
pyrop hosph ate
Bile acids
Terp enes
29-24
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:
O
O
+
O- C- CH2 - CH 2 - C-COO - + N H4
N AD PH + H+
a-Ketoglutarate
N AD P+
O
-
N H3 +
O- C- CH2 - CH 2 - CH- COO Glutamate
29-25
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.
COOCOOC= O + CH- NH3 +
CH3
CH2
CH2
COOPyruvate
Glutamate
COOCH- NH3 + +
CH3
Alanine
COOC= O
CH2
CH2
COOa-Ketoglutarate
29-26
Amino Acids
a-Ketoglutarate
Glutamate
Glutamine
Proline
Arginine
3-Phosphoglycerate
Serine
Cys teine
Glycine
Oxaloacetate
As partate
As paragine
Methionine
Threonine
Isoleucine
Lysine
Pyruvate
Valine
Alanine
Leucine
Phosphoenolpyruvate +
Erythros e 4-phos phate
Phenylalanine
Tyrosine
Tryptophan
Ribose 5-phosphate
Histidine
29-27
Chapter 29 Biosynthetic Pathways
End
Chapter 29
29-28