Lecture #14
Fatty Acid Metabolism
Slide 1. Overview of Catabolism. We are now going to consider the left
wing of the catabolism diagram. (I always like to start on the left rather than
the right for reasons I will not expound upon here.) We are going to look at
lipid catabolism starting with triacylglycerols. The triacylglycerols provide
another source of energy for living cells. Quantitatively, triacylglycerols
constitute the most important energy store in humans. Remember that
carbohydrates stored as glycogen constitutes less than one days supply of
energy. In contrast the fats stored as triacylglycerols contain on an average
enough energy to fuel basal metabolism in humans for one or two months.
Slide 2. Lipid Metabolism Summary. The general pattern of lipid
metabolism is summarized on this slide. When energy is needed, lipid
catabolism occurs. The triacylglycerols from the diet or from lipid stores
can be broken down by lipases to fatty acids and glycerol. The fatty acids
components of triacylglycerols are converted to acetylCoA by the oxidation pathway. The acetylCoA can enter the TCA cycle or can serve as
a starting material for a number of biosynthetic pathways. The glycerol
component is integrated into glycolysis or gluconeogenesis by a short series
of reactions that feed into the glycolysis or the gluconeogenesis pathways.
On the anabolism side lipid biosynthesis occurs when there is excess energy.
The fatty acids can be synthesized from acetylCoA and glycerol can be
produced from glycolysis intermediates. The two components can be
combined in ATP-dependent reactions to form triacylglycerols.
Slide 3. Lipid digestion in the lumen of the intestine. Most dietary lipids
are ingested as the triacylglycerol compounds. The dietary lipids are
emulsified in the intestine by bile acids secreted from the gall bladder.
Pancreatic lipases hydrolyze the triacylglycerols into free fatty acids and 2monoglycerides in the lumen of the intestine.
Slide 4. The digestion and absorption of triacylglycerols. This diagram
shows the pathway of dietary triacylglycerol digestion from the lumen of the
intestine to the lymph system.
-The triacylglycerols are hydrolyzed into free fatty acids and 2monoglycerides in the lumen of the intestine.
-The 2-monoglycerides and fatty acids are transported into the enterocytes
where they are reassembled into triacylglycerols and packaged into large
chylomicron complexes.
-The chylomicrons are exported from the cell and transported in the lymph
system to adipocyte cells.
-The adipocytes store the lipid as triacylglycerols until there is a need for
energy.
Slide 5. Photomicrograph of an adipocyte cell. A photomicrograph of an
adipocyte cell reveals that the lipids are stored in large vacuoles which take
up the majority of cell volume. The vacuoles are so large that they
sometimes displace the nucleus to the periphery of the cell.
Slide 6. Scanning electron micrograph of an adipocyte cell. Another look
at an adipocyte using a scanning electron micoscope reveals the same
spherical shape with a bulging nucleus on one side of the cell.
Slide 7. Lipase Mobilization in Adipose Tissue. In adipose tissue the
hydrolysis of stored triacylglycerol molecules is initiated by hormones such
as adrenaline, glucagon, and ACTH. The triacylglycerol lipase is activated
by an enzymatic cascade that is triggered by hormone binding to the
appropriate receptor. After cleavage of the first fatty acid by the
triacylglycerol lipase the second and third fatty acids are also removed from
the diacyl- and monoacylglycerol molecules. If this reaction takes place in
adipose tissue the fatty acids are released into the blood and are carried to
other tissues in a complex that includes the blood protein albumin. Some of
the glycerol is also released into the blood and can feed into glycolysis or
glyconeogenesis in other tissues.
Slide 8. Glycerol Is Converted to Glycolysis or Gluconeogenesis
Intermediates. The glycerol that is released from adipose tissue is taken up
in other tissues where it is integrated into glycolysis or gluconeogenesis by a
two step pathway. First an ATP-dependent kinase reaction yields glycerol
3-phosphate. Then the glycerol 3-phosphate is oxidized to dihydroxyacetone
phosphate by an NAD+ dependent dehydrogenase.
Slide 9. Fatty Acid Activation. Fatty acids are carried in the blood from
adipose tissues in association with serum albumin protein. The fatty acids
are taken into the cytosol of target cells where they are activated by being
coverted to acylCoA derivatives. The conversion of a fatty acid into an
acylCoA intermediate is a thermodynamically unfavorable process because
the acylCoA is a thioester derivative. Thioesters have a very high energy of
hydrolysis which means it takes a lot of energy to make them starting from a
carboxylic acid.
To make the acylCoA derivative, the fatty acid is first activated using ATP.
The intermediates in the process are inorganic pyrophospate and a fatty acyl
adenylate. (The pyrophosphate is cleaved to two inorganic phosphates with
the release of energy, a pattern that we have previously noted, which
contributes to the overall thermodynamic favorability of the reaction.) The
acyl adenylate intermediate is a mixed acid anhydride with a high energy of
hydrolysis. When it is swapped for CoA in the next step, the reaction is
thermodynamically neutral. The formation of the acyl adenylate
intermediate thus provides a way of using ATP to facilitate the synthesis of a
high energy CoA product from a free fatty acid and CoA.
Slide 10. Fatty Acyl Transport from Cytosol into Mitochondria. Fatty
acylCoA derivatives are synthesized in the cytosol of the cell, but the
oxidation of such derivatives takes place in the matrix of the mitochondria.
An elaborate little dance must take place to get the fatty acylCoA into the
mitochondrial matrix. In the cytosol the activated CoA derivative is first
transferred to carnitine, a polar carrier molecule. The fatty acyl carnitine
derivative is then transported through the mitochondrial inner membrane
into the matrix. In the matrix the fatty acyl group is transferred from
carnitine back to CoA.
Slide 11. Fatty Acyl Transfer from CoA to Carnitine. The transfer of a
fatty acyl group from fatty acylCoA to carnitine occurs in the cytosol and is
catalyzed by an acyl transferase enzyme. The reaction is energetically
neuteral, and thus is reversible. The fatty acyl group is transferred from the
thiol group of CoA to a hydroxyl group (noted in red) on carnitine.
Slide 12. Carnitine Cycle. The overall carnitine cycle is outlined on this
slide. The activated CoA derivative is first transferred to carnitine. The fatty
acyl carnitine derivative is then transported through the mitochondrial
membrane into the matrix. In the matrix the fatty acyl group is transferred
from carnitine back to CoA. Then the carnitine is transported back into the
cytosol. The transporter that accomplishes this exchange process is an
integral membrane protein. It is antiporter that exchanges an acyl carnitine
for a free carnitine—the acyl carnitine comes into the matrix and the free
carnitine goes back out into the cytosol on the same transport protein.
Slide 13. The -Oxidation Cycle. One whole cycle of -oxidation is
illustrated on this slide. The process begins with a fatty acylCoA derivative
with n carbon atoms and it ends with a fatty acyl derivative with n minus
two carbon atoms. The two missing carbon atoms are released as acetylCoA.
These oxidation cycles are repeated—each cycle shortening the fatty
acylCoA by two carbons and releasing an acetylCoA. In the final cycle a
four carbon acylCoA (butyrylCoA) is converted to two molecules of
acetylCoA.
The -oxidation process starts with an oxidation-reduction reaction. In the
reaction, catalyzed by an acylCoA dehydrogenase, a saturated acylCoA is
converted to an unsaturated product. The new double bond, which is in the
trans configuration, is introduced between the  and  carbons (coded in
red). The cofactor in the reaction is FAD which is reduced to FADH2.
The second reaction involves the addition of water to the double bond
forming a hydroxyl group on the  carbon. The reaction is catalyzed by
enol-CoA hydratase. Note that the carbon carrying the hydroxyl group is
now a new chiral center in the L-form.
In the third step the hydroxyl group is oxidized to a ketone coupled to the
reduction of NAD+ to NADH. The enzyme that catalyzes the reaction is L3-hydroxyacyl CoA dehydrogenase.
The final step in the cycle is catalyzed by -ketothiolase. In this reaction a
CoA molecule (coded in green) attacks the  carbon of the fatty acylCoA.
The fatty acylCoA looses two carbons which are released as acetylCoA.
The thiolytic cleavage is facilitated by the presence of the carbonyl group on
the carbon of the acylCoA. That  carbon becomes the site of attachment
of the incoming CoA molecule to the shortened fatty acylCoA.
The major fate of the acetylCoA from -oxidation is entry into the TCA
cycle. Because the acetylCoA is produced in the matrix of the mitochondria
and is used by the TCA cycle in the same place that process is facilitated.
Slide 14. Compare -oxidation and TCA cycle. Here is another example
of the potential of “learning by analogy”. The -oxidation pathway and the
TCA cycle both use common reactions that occur in the same sequence.
That sequence is:
-AcylCoA dehydrogenase for -oxidation vs. succinate dehydrogenase for
the TCA cycle. Both reactions use FAD as a cofactor and convert a single
bond into a double bond.
-EnolCoA hydratase vs. fumarase. Both reactions add water to a double
bond to produce a hydroxyl group.
-3-L-hydroxy-acylCoA dehydrogenase vs. L-malate dehydrogenase. Both
reactions use NAD+ to convert a hydroxyl group to a ketone.
The point is that nature has given students of biochemistry a gift here. You
do not have to learn two completely different pathways. If you memorized
the TCA cycle, then learning -oxidation should be “duck soup”, because it
is essentially the same pathway with slightly different surrounding structures.
Slide 15. ATP Yield from Fatty Acid Oxidation. The oxidation of fatty
acids is a catabolic process which has the goal of producing energy. So the
question arises, “How much ATP can you get from the oxidation of a fatty
acid?” And as luck would have it, we are here to answer our own question.
We can divide the answer into two parts.
-One cycle of -oxidation yields 4 ATP’s--1.5 ATP’s for the FADH2 and 2.5
ATP’s for the NADH.
In a round of -oxidation there is one acetylCoA produced. The acetylCoA
enters the TCA cycle and yields 10 ATP’s--7.5 ATP’s from the 3 NADH’s,
1.5 ATP’s from the FADH2, and one ATP equivalent from GTP.
Slide 16. Total ATP Produced from Stearate. Let’s look at the complete
oxidation of a fatty acid to carbon dioxide. We arbitrarily pick stearic acid
(18 carbons, no double bonds) as the starting material.
-It costs 2 ATP equivalents to activate stearic acid to the acylCoA derivative.
(Remember that in that reaction ATP is converted to AMP and inorganic
pyrophosphate. That is the energy equivalent of 2 ATP’s going to ADP and
Pi.) Those two ATP equivalents constitute the only energy expended in the
process.
-There are 8 rounds of -oxidation, with each round producing 4 ATP’s, so
this phase yields a total of 32 ATP’s. (You might be tempted to think that
there are 9 rounds of -oxidation from a C-18 fatty acid, but remember that
the eighth round, starting with a four carbon acylCoA, produces two
acetylCoA’s.)
-There are 9 acetylCoA’s fed into the TCA cycle and each one produces 10
ATP’s for a total of 90 ATP’s.
Minus 2, plus 32, plus 90 gives you a net yield of 120 ATP’s. WOW!
Slide 17. Caloric Content of Carbohydrate vs. Fat. Now you will
probably be asking another question (And if you don’t, we will again ask it
for you.). That is, how do carbohydrates and fats compare as sources of
energy? The answer is that fats are more energy rich than carbohydrates.
When we calculate the moles of ATP produced per gram it turns out that
glucose produces 0.17 mol/g and stearate produces 0.42 mol/g. That
converts to 4 kcal/g for glucose and 9 kcal/g for stearate. In general, on a
per gram basis, fats produce more than twice the energy as carbohydrates.
This reflects the fact that fats are more highly reduced than carbohydrates,
and a more reduced compound typically yields more energy in biological
oxidation reactions.
Slide 18. Enoyl-CoA Isomerase. Up until now we have only considered
the -oxidation of saturated fatty acids. There are some minor
complications in the oxidation of unsaturated fatty acids. We will use the
oxidation of oleic acid (a 18-carbon fatty acid with one cis double bond.) as
an example. This fatty acid has its double bond between carbons 9 and 10.
The first three rounds of -oxidation proceed normally, because all the
bonds are saturated. However, on round four, cis-3-enoyl-CoA is the
substrate. The problem with cis-3-enoyl-CoA is that its cis-3 double bond
should be trans-2 in order for oxidation to continue. The enzyme, enoylCoA isomerase makes that conversion, and from there on -oxidation can
proceed normally.
Because the oleate was already unsaturated there will be one less FADH2
produced than for the equivalent saturated fatty acid. The consequence is
that the unsaturated compound will yield 1.5 less ATP’s than its saturated
analog.
Slide 19. Isomerization of a cis-4 Double Bond. Another complication
arises in the oxidation of linoleic acid, a C-18 fatty acid which has two
double bonds. The first double bond occurs between carbons 9 and 10 and is
treated to the same isomerization sequence as shown on the previous slide.
At the second double bond a cis-4-enoyl-CoA is the substrate. The
conversion of the cis-4 into the trans-2 bond takes three reactions. Two
reactions convert the cis-4 double bond to a trans-3. Then an enol-CoA
isomerase converts the trans-3 double bond to a trans-2. And with that we
will leave fatty acid oxidation.
Slide 20. Structure of propionyl CoA. Most fatty acids contain an even
number of carbon atoms and produce the two carbon compound acetyl CoA
as the only oxidation product. However there are a significant number of
fatty acids that contain an odd number of carbons. During the-oxidation
process these odd-chain fatty acids produce acetyl CoA until the last cycle.
In the last cycle the products are one molecule of acetyl CoA and one
molecule of the three carbon compound propionyl CoA. There is a special
metabolic pathway for the breakdown of propionyl CoA.
Slide 21. Propionyl CoA (C3) is converted to Succinyl CoA (C4). The
propionyl CoA is integrated into mainstream metabolism by conversion to
an intermediate of the TCA cycle, succinyl CoA. This process requires three
metabolic steps.
-In the first step propionyl CoA is carboxylate by a biotin-dependent enzyme
to yield D-methylmalonyl CoA.
-The second reaction converts the carboxylated product from D- to Lmethylmalonyl CoA.
-In the third reaction a vitamin B12 dependent enzyme catalyzes the
isomerization of L-methylmalonyl CoA to succinyl CoA.
Slide 22. The structure of coenzyme B12. This figure shows the structure
of coenzyme B12. The cofactor has a polyporphorin ring system similar to
that of the hemes, but the central metal ion in B12 is cobalt. Vitamin B12
dependent enzymes generally catalyze very exotic isomerization reactions in
which carbon atoms are moved from one place to another.
Slide 23. Ketone body formation. Ketone bodies are produced when there
is a need for energy in various tissues or when rate of the TCA cycle is
inadequate to utilize all of the acetylCoA produce by fatty acid oxidation.
Slide 24. Acetyl CoA utilization by the TCA cycle. Under most
conditions acetyl CoA is produced from glycolysis and fatty acid oxidation
at a rate which can be accommodated by the TCA cycle. Under these
circumstances most of the acetyl CoA is converted to carbon dioxide.
Slide 25. Production of ketone bodies from acetyl CoA. The acetyl CoA
is diverted from the TCA cycle to the formation of ketone bodies (short
chain fatty acids) as a normal part of metabolism, when there is a specific
need for extra energy in various tissues such as heart muscle. The
production of ketone bodies also occurs when rate of the TCA cycle is
inadequate to utilize all of the acetylCoA produced by fatty acid oxidation.
Such conditions include starvation, uncontrolled diabetes or as a result of
some low carbohydrate diets in which fatty acids are released very rapidly.
Slide 26. Conversion of acetyl CoA to ketone bodies. There are three
products of acetyl CoA metabolism which are collectively referred to as
ketone bodies. These metabolites are acetoacetate, -hydroxybutyrate and
acetone.
Slide 27. Ketone body synthesis steps 1 and 2. In the first two steps of
ketone body synthesis two units of acetyl CoA react to form acetoacetylCoA
and a third acetyl CoA unit reacts to produce HMG-CoA.
Slide 28. Ketone body synthesis steps 3 and 4. In the third step of ketone
body synthesis an acetyl CoA unit is then removed from HMG-CoA
releasing acetoacetate. The acetoacetate is converted enzymatically into hydroxybutyrate and is decarboxylated nonenzymatically to give acetone.
Slide 29. Overview of Catabolism. As we start our study of the synthesis
of fatty acids we take one last look at this chart of catabolism. We use this
figure to remind you that every pathway has to release energy, or it would
not proceed in the forward direction. We have just looked at -oxidation of
fatty acids, and we know that that catabolic pathway, which converts fatty
acids to acetylCoA, releases energy. Now, some of the energy in fatty acids
gets trapped as FADH2 and NADH, and those reduced nucleotides
eventually yield ATP. However, in addition to forming reduced nucleotides
some energy is released as heat. That is the consequence of the pathway
being thermodynamically favorable (having a negative G).
OK! So, if the -oxidation pathway is thermodynamically favorable (as it
has to be), and the pathway for fatty acid biosynthesis is also
thermodynamically favorable (as it also has to be), and the two pathways
connect the same two compounds... THEN the two pathways have to have
some differences. That is, there must be some way to introduce extra energy
into the biosynthetic pathway so that it is energy releasing, which it would
not be if it were the exact reversal of the -oxidation pathway. Keep this in
mind as we look at the biosynthesis of fatty acids.
Slide 30. Comparison of Fatty Acid Biosynthesis vs. -oxidation. This
table shows a number of differences between fatty acid biosynthesis and oxidation. Three of these differences contribute to the favorable
thermodynamics of both pathways. The differences that change the
energetics are:
- Fatty acid synthesis involves a biotin dependent carboxylation reaction, but
-oxidation does not.
- A malonic acid derivative is a participant in fatty acid biosynthesis, but not
in -oxidation.
- All of the oxidation-reduction reactions in fatty acid biosynthesis use
NADH, but one of the oxidation-reduction steps in -oxidation uses FAD+.
In addition to the energy related differences there are other contrasts
between the two systems.
- As the name implies -oxidation involves oxidation while fatty acid
synthesis involves reduction.
- The acyl carrier for -oxidation is CoA, but for fatty acid synthesis it is an
acyl carrier protein (ACP).
- The hydoxyl intermediates in the two processes have a different chirality.
Slide 31. The-Oxidation Cycle. Take another look at the -oxidation
cycle. If we were to run the -oxidation cycle backwards there would be a
sequence in which:
-AcetylCoA condenses with an acylCoA to form a -ketone.
-The -ketone is reduced to a hydroxyl group by a dehydrogenase.
-The hydroxyl group is dehydrated to form a double bond by a (de)hydratase.
-The double bond is reduced to a single bond by a dehydrogenase.
That is essentially the sequence that we will now see in fatty acid
biosynthesis.
Slide 32. Fatty Acid Biosynthesis. The sequence of reactions for the oxidation cycle running backwards is the same as the sequence for fatty acid
biosynthesis running in the forward direction. In the biosynthesis process:
-MalonylACP (the replacement for acetylCoA) condenses with an acylACP
derivative to form a -ketone.
-The -ketone is reduced to a hydroxyl group by a reductase.
-The hydroxyl group is dehydrated to form a double bond by a dehydratase.
-The double bond is reduced to a single bond by a reductase.
Slide 33. Comparison of CoA and Acyl Carrier Protein. On this slide
we compare the structure of CoA with the acyl carrier protein. The
interesting thing is that the working ends of both molecules, near the thiol
groups, are identical. At the opposite end away from the thiol group CoA
has an ADP residue, whereas the acyl carrier protein has a small protein
(molecular weight about 10,000 daltons.) The attachment to the protein
portion is through a serine hydroxyl group.
Slide 34. AcetylCoA Carboxylase. In the first step in fatty acid
biosynthesis acetylCoA is carboxylated to form malonylCoA. The reaction
is catalyzed by acetylCoA carboxylase. The acetylCoA carboxylase enzyme
contains a covalently bound coenzyme, biotin which serves as a carrier of an
activated bicarbonate molecule. The reaction takes place in two stages. In
the first stage bicarbonate becomes covalently attached to the coenzyme to
form a carboxybiotin intermediate. The attachment of bicarbonate to the
biotin coenzyme is coupled to the cleavage of ATP to ADP and Pi. In the
second stage of the reaction the activated carboxy group is transferred from
biotin to acetylCoA to form malonylCoA.
The formation of malonylCoA contributes toward making fatty acid
biosynthesis an energy releasing process. The carboxyl group that is added
to acetylCoA to form malonylCoA will be released during a subsequent step
in the biosynthetic pathway. That decarboxylation is an energy releasing
reaction, and it will help make the overall pathway thermodynamically
favorable.
Slide 35. Conversion of CoA Derivatives to ACP Derivatives. The
second step of fatty acid biosynthesis actually consists of two parallel
reactions. In one of these reactions an acetyl group is transferred from
acetylCoA to an acyl carrier protein by an acetyl transacylase enzyme. In
the other reaction a malonyl group is transferred from malonylCoA to an
acyl carrier protein by a malonyl transacylase enzyme. The products of these
reactions, acetylACP and malonylACP, will react with each other in the next
step.
Slide 36. Fatty Acid Synthesis. The complete cycle of fatty acid
biosynthesis is outlined on this slide. There are four steps in this biosynthetic
cycle, and as we saw before, these steps mimic the reversal of the oxidation cycle.
In the first reaction, catalyzed by a condensing enzyme, malonylACP reacts
with acetylACP to give a four carbon -ketoacylACP product. There are a
lot of things happening in this seemingly simple reaction. First, a two carbon
compound and a three carbon compound are condensing with each other to
form a four carbon compound. Wait! Two and three equal five, not four.
What happened to the fifth carbon atom? It turns out that in the process of
forming the condensation product, a carbon dioxide was released from the
malonylACP. That not only accounts for the fifth carbon, but also explains
where some of the energy comes from to make this reaction proceed toward
product. The release of carbon dioxide is usually thermodynamically
favorable, and this reaction is no exception to that rule. So carbon dioxide
release helps to drive this reaction toward completion. That explains why the
acetylCoA was carboxylated to malonylCoA in the first place—not to add an
extra carbon to the pathway, but to provide some additional energy, giving
the overall pathway a negative G.
There is one additional feature of the first reaction that contributes to its
favorable thermodynamics. In the process of forming the four carbon
product, an ACP molecule is released. That ACP was attached to the acetyl
group by a thioester bond which has a high energy of hydrolysis. When the
thioester bond is broken energy is released as heat. Thus, that bond cleavage
contributes towards the negative G of the overall reaction.
In the second reaction the -ketone group is reduced to an alcohol with
NADPH serving as the reductant. That reaction is catalyzed by -ketoacylACP reductase. The use of NADPH in this reaction is typical of what occurs
in anabolic oxidation-reduction reactions. Remember that NADH is
generally used to generate ATP, and NADPH is used as a reductant in
biosynthetic reactions. The hydroxyl group that is produced in this reaction
is in the D-configuration. In -oxidation cycle the equivalent hydroxyl
intermediate was of the L-configuration.
The third step involves a dehydration reaction. The elements of water are
removed creating a trans carbon-carbon double bond. The enzyme
catalyzing this reaction is 3-hydroxyacyl-ACP dehydratase.
In the final step of the cycle, enoyl-ACP reductase uses NADPH to reduce
the double bond to a single bond. The product is a four carbon butyryl-ACP.
That four carbon acyl-ACP can go on to condense with a malonylACP to
initiate a second round of biosynthesis—the product of which would be a six
carbon acyl-ACP. Each succeeding round of biosynthesis elongates the
acyl-ACP by two carbon atoms. Because fatty acid biosynthesis occurs two
carbons at a time most naturally occurring fatty acids have an even number
of carbon atoms.
Slide 37. Glyoxylate Cycle Reactions with Complete TCA Cycle. For the
most part we are focusing on mammalian biochemistry in this course, but we
will now consider a process that does not take place in mammals. It is called
the glyoxylate cycle. The glyoxylate cycle makes use of many of the
reactions of the TCA cycle, but it adds two new reactions. Those two
additional reactions are shown here in the middle of the complete TCA cycle.
Slide 38. Glyoxylate Cycle Reactions. On this slide we have removed the
TCA cycle reactions which are not involved in the glyoxylate cycle. The
first reaction that is unique to the glyoxylate cycle is catalyzed by isocitrate
lyase. That reaction cleaves isocitrate into glyoxylate and succinate. The
second unique reaction is catalyzed by malate synthase. In that reaction
glyoxylate condenses with acetylCoA to produce malate. When we combine
these two reactions with other reactions of the TCA cycle we get two four
carbon products—succinate and malate—and both of these products can go
on in the TCA cycle to produce any of the other four, or five, or six carbon
intermediates.
The genius of the glyoxylate pathway is that it provides a mechanism by
which two-carbon acetylCoA units can produce four-carbon products. The
glyoxylate cycle facilitates the net fixation of two-carbon reactants into fourcarbon products—something that cannot be accomplished by the TCA cycle
acting alone. Furthermore, one of the TCA cycle intermediates, oxaloacetate
can be used to produce phosphoenolpyruvate, and phosphoenolpyruvate can
yield glucose via gluconeogenesis. The bottom line is that bacteria can
make glucose from acetylCoA.
Mammals do not have the enzymes of the glyoxylate cycle. Without the two
glyoxylate cycle enzymes, the TCA cycle absorbs the two carbons of
acetylCoA and releases them both as carbon dioxide—there is no net
fixation of the two carbons of acetate into four carbon products. That means
there is something that can be achieved by a lowly bacterium, but not by a
mighty mammal. We and all other mammals are unable to carry out the net
synthesis of TCA cycle intermediates from acetylCoA. Furthermore, and of
extreme importance is the fact that mammals cannot accomplish the net
synthesis of glucose from acetylCoA. In fact, any compound that yields
acetate or acetylCoA as its only product cannot be used as a net source of
glucose. That can cause problems during fasting or starvation, because the
major energy storage compounds in mammals are triacylglycerols. Critical
levels of gluclose must be maintained during starvation, but the fatty acids
released from triacylglycerols cannot contribute to glucose synthesis. They
can only produce acetylCoA.