Chapter 21

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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.
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