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STK3043
Acetyl Coenzyme A: A Key
Biological Intermediate

Acetyl Co A
What is Acetyl Coenzyme A ?
Comparison of Organic and Acetyl
Coenzyme A Reactions
Malonyl Coenzyme A; a Partnership with
Acetyl Coenzyme A
How is Acetyl Coenzyme A used in
Biosynthesis ?
Biosynthesis of Acetyl Coenzyme A

What is Acetyl Coenzyme A ?
Acetyl coenzyme A is a thioester derivative of
acetic acid 1 (Figure 1)
...
Thioesters are simply the sulphur
analogues of esters and compound 3 is a
thioester analogue of compound 2
...


Acetyl Coenzyme A
Acetyl coenzyme A provides a two-carbon
fragment (labelled 1 and 2 in structure 4) in
biosynthesis
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Acetyl
coenzyme A 4 is usually referred to as a
biological equivalent of acetate because it can
provide a two-carbon acetyl fragment in
biosynthetic reactions

Comparison of Organic and
Acetyl Coenzyme A Reactions
Before we consider how acetyl coenzyme A 4 is
used in biosynthesis it is useful to consider some
related organic reactions
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In this reaction, the nucleophile
attacks at the carbonyl group of compound 5
giving the reaction intermediate 6 which
subsequently expels the good leaving group
(chloride) giving the product, methyl acetate 2
...
In principle,
carboxylic acids such as acetic acid 1
could undergo nucleophilic acyl
substitution but this type of reaction is
generally poor because, as we have
already mentioned, hydroxide is a poor
leaving group
...
Thus, one
way to go from acetic acid 1 to a product 2
is to activate the carboxylic acid group by
converting it into the acid chloride 5
...
In the
same way that acetic acid 1 can be activated
towards nucleophilic substitution by converting it
into its acid chloride 5, acetic acid 1 can also be
activated in biological systems as acetyl
coenzyme A 4; the coenzyme A substituent is a
good leaving group
...
The methyl protons of
esters such as 2 are relatively acidic and can be
removed by the action of a suitable base (Figure
4)
...
In a similar
way, acetyl coenzyme A 4 can be deprotonated
in biological systems by a suitably basic group of
an enzyme
...
Malonyl
coenzyme A 7 is a thioester derivative of the
dicarboxylic acid, malonic acid 8
...


Malonyl Coenzyme A; a Partnership with
Acetyl Coenzyme A

Biotin is attached through its carboxyl
group to an associated enzyme, biotin
carboxyl carrier protein (BCCP) during the
carboxylation reaction of acetyl coenzyme
A 4
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The initial reaction
involves the carboxylation of the biotinBCCP complex with bicarbonate giving
molecule 9 as shown in Figure 7
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We have already seen in Figure 3 of the
Section 2 that acetyl coenzyme A 4 can be
deprotonated giving a carbanion
derivative
...
In
Figure 8, the carbanion derivative of acetyl
coenzyme A 4 is the nucleophile and it
attacks at the carbonyl group of the biotinBCCP complex 9 as shown
...


Malonyl Coenzyme A; a Partnership with
Acetyl Coenzyme A
The mechanism shown in Figure 8 is in fact a
simplified representation as to what actually
happens
...
You will appreciate that this reaction is
controlled by an enzyme, so the base, acetyl
coenzyme A 4 and the carboxylated biotin can
all be brought together by the enzyme so that a
synchronous reaction can occur
...
This is represented diagrammatically in
Figure 10
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In this
reaction the -SCoA groups of molecules 4 and 7 are both
substituted by the thiol groups (-SH) of the enzyme
complex giving the complex 10
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How is Acetyl Coenzyme A
used in Biosynthesis ?
Once the compounds 4 and 7 have been
anchored to the fatty acid synthetase, a
carbon-carbon bond formation reaction
then occurs as shown in Figure 11
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Since malonyl coenzyme A 7 came
originally from acetyl coenzyme A 4, we
have, in effect, condensed two molecules
of acetyl coenzyme A 4 to give a fourcarbon atom unit 11
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In reality, a synchronous reaction occurs; as
carbon dioxide is lost carbon-carbon bond
formation takes place as shown in Figure 12
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We shall
see later how fatty acids and polyketides are
biosynthesized from intermediate 11
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Glucose is then broken down in several
steps to acetyl coenzyme A
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