Download The digestion of triacylglycerols produces a mixture of the anions of

Organic chemistry and Biological chemistry for Health Sciences
59-191
Lecture 25
Biosynthesis of fatty acid:
Whenever acetyl CoA molecules are made within mitochondria but are not needed for
catabolism, they are exported to the cytosol for anabolism, synthesis of other species.
The cell has to invest ATP to make fatty acids from smaller molecules and the first
investment occurs in the first step. Bicarbonate ion reacts with acetyl CoA to form
malonoyl CoA. The malonoyl CH2 unit is between two carbonyl groups and so is
activated for fatty acid synthesis.
A huge complex of seven enzymes called fatty acid synthase synthesizes the fatty acid.
A long molecular unit, the acyl carrier protein (ACP), is in the center of this complex. It
serves as swinging arm carrier. It’s like the boom of a construction crane. Thus the arm
first picks up the malonoyl unit and bring it over to the first enzyme. After the first
reaction the boom carries the product over to the second enzyme. At each succeeding
stop a reaction is catalyzed that contributes to chain lengthening.
The transfer of the malonoyl unit of malonoyl CoA to the swinging arm of ACP occurs in
the enzyme 1. A similar reaction also occurs over enzyme 6 where another molecule of
acetyl CoA ties to a different unit of the synthase, E. The product is acetyl E. Then
enzyme 1 transfers the acetyl group of acetyl E to the malonoyl group of malonoyl ACP.
Carbon dioxide, the initial activator of the aceyl unit, is ejected. The E unit is also
vacated. Acetoacetyl ACP forms, it’s now over enzyme 2. The chain has grown by two
carbons.
The keto group of acetoacetyl ACP is next reduced by enzyme 3 to a 20 alcohol and
passed to enzyme 4. The alcohol group is dehydrated by enzyme 4 to introduce a double
bond, putting the unit over enzyme 5 to give butyryl ACP. The overall effect of these
steps is to reduce the keto group to CH2. NADPH is used as the reducing agent.
The butyral group is now transferred to the vacant E unit that initially held an acetyl
group. Butyral E instead of acetyl E is now over enzyme 6. This completes one cycle of
fatty acid synthesis. Four-carbon butyral unit has been synthesized from two-carbon
acetyl unit.
The steps now repeat. A new malonyl unit is joined to the ACP. The newly made butyryl
group is transferred to the malonyl unit as CO2 is again ejected. This elongates the chain
to six carbons, positions it on the swinging arm, and gets it ready for the multistep
reduction of the keto group to CH2. The chain will be that of the six carbon acyl group,
the hexanoyl group.
In the next repetition of this series, the six carbon acyl group will be elongated to an eight
carbon group and the process will repeat until the chain is 16 carbon long. Overall the net
equation for the synthesis of the palmitate ion from acety CoA is as follows:
(See the attached sheets!)
14 NADPH is required to make one palmitate ion.
Biosynthesis of cholesterol:
Cholesterol is synthesized from acetyl units by a multistep process. The body uses
cholesterol to make various bile salts, sex hormones and cell membranes. About 80% to
95% of all cholesterol synthesis in mammals take place in cells of the liver and the
intestines.
When acetyl CoA builds up in the liver, the following equilibrium shifts to the right.(see
attached reaction!)
When cholesterol synthesis is switched on, acetoacetyl CoA combines with another
acetyl CoA to form HMG CoA. Both a reduction and hydrolysis occurs in the next step,
which is a complex change catalyzed by HMG-CoA reductase. Mevalonate is next
carried through a long series of reactions until cholesterol is made.
HMG-CoA reductase is the key enzyme in the synthesis pathway. The control of HMGCoA reductase is the major factor in the overall control of the biosynthesis of cholesterol.
Cholesterol inhibits the synthesis and activity of that enzyme. In the presence of
cholesterol, the enzyme is not totally deactivated. There is just less of it free to do
catalytic work. Thus if the diet is relatively rich in cholesterol, the body tends to make
less. If the diet is very low in cholesterol, the body makes more.
KETOACIDOSIS:
Gluconeogenesis consumes oxaloacetate, the acceptor of acetyl units in the citric acid
cycle. Thus when oxaloacetate is diverted from the citric acid cycle, acety coenzymeA is
less able to unload its acetyl group into the cycle. Yet acetyl coenzyme A continues to be
made by the fatty acid oxidation, so acetyl CoA levels build up.
As the supply of acetyl CoA increases in the liver, the following equilibrium reaction that
makes acetoacetyl CoA shifts to the right (see the attached sheet!). As the level of
acetoacetyl CoA increases more HMG-SCoA is synthesized. As the level of HMG-SCoA
increases, a liver enzyme splits it to acetoacetate ion and coenzyme A.
So, in effect, excessive amounts of acetyl CoA generate acetoacetate and hydrogen ion.
The formation of hydrogen ion makes the situation dangerous. Increased synthesis of
glucose by gluconeogenesis is the cause. Conditions of starvation or untreated diabetes
mellitus can be instigators of accelerated gluconeogenesis.
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The buffer must neutralize the acid produced by the formation of acetoacetate.
Increasingly rapid production of acetoacetate and hydrogen ion overwhelms the capacity
of blood buffer. A condition called metabolic acidosis results. It is called metabolic
acidosis because the cause lies in the disorder of metabolism. Because the chief species
responsible for the acidosis has keto group, the condition is often called ketoacidosis.
The acetoacetate ion, acetone and -hydroxybutyrate ion are called ketone bodies.
Acetone and -hydroxybutyrate ion are produced from acetoacetate ion. Acetone arises
from acetoacetate by the loss of carboxyl group. -hydroxybutyrate is produced when
the keto group of acetoacetate is reduced by NADH.
The ketone bodies enter circulation. Acetone is volatile, so most of it leaves the body via
the lungs. Individual with severe ketoacidosis have “acetone breath” the noticable odor of
acetone on the breath.
The ketone bodies are not abnormal constituents of blood. Acetoacetate and hydroxybutyrate can be used in skeletal muscles to make ATP. Heart muscle uses these
two for energy in preference to glucose. Even the brain can use these ions for energy
when blood sugar level drops in starvation or prolonged fasting. Ketone bodies create a
problem only when they are made at a rate faster than the blood buffer can handle the
associated acid.
Normally the levels of acetoacetate and -hydroxybutyrate in the blood are 2 mol/dL
and 4mol/dL respectively. In prolonged untreated diabetes these values can increase as
much as 200 fold. The condition of excessive level of ketone bodies in the blood is called
ketonemia.
As ketonemia becomes more and more advanced, the ketone bodies begin to appear in
the urine, a condition called ketonuria. When there is a combination of ketonemia,
ketonuria and acetone breath, the overall state is called ketosis. The individual will be
described as ketoic. As unchecked ketosis becomes more severe, the associated
ketoacidosis worsens and the pH of the blood continues its fatal descent.
To leave ketone body anions in the urine, the kidneys have to leave positive ions with
them to keep everything electrically neutral. One Na+ ion has to leave with each
acetoacetate ion, for example. This loss of Na+ is often referred to as the loss of the base,
although Na+ ion is not itself a base. But the loss of one Na+ ion stems from the
appearance of one acetoacetate ion plus one H+ ion that the blood had to neutralize using
HCO3-. Thus each Na+ ion that leaves the body corresponds to the loss of one HCO3- ion,
the true base, consumed in neutralizing one H+. So the loss of Na+ is an indicator of the
loss of base.
Na+ ion has to accompany a bicarbonate ion when it goes from the kidneys into the
blood. The kidneys normally manufacture HCO3- ion in order to replenish the blood
buffer system. The greater the number of Na+ ions that have to be left in urine in order to
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clear ketone bodies from the blood, the less is the amount of true base, HCO3-, that can be
put into the blood.
The solute excreted in the urine cannot be allowed to make the urine too concentrated.
Osmotic balance will be upset if that happens. So loss of ion in urine is accompanied by
excretion of water to prevent the osmotic imbalance. To satisfy this need, the individual
has a powerful thirst. Other wastes, such as urea, are also being produced at higher than
normal rates, because amino acids are being sacrificed in gluconeogenesis. These wastes
add to the demand for water to make urine.
If during a state of ketosis, insufficient water is drunk, water is simply taken from
extracellular fluids. The blood volume tends to drop, and the blood becomes more
concentrated. It also thickens and becomes more viscous, which makes the delivery of
blood more difficult.
Because the brain has the highest priority for blood flow, some of this flow is diverted
from the kidneys to try to ensure that the brain gets what it needs. This only worsens the
situation in the kidneys, and they have an increasingly difficult time clearing waste. As
the water shortage worsens, some water is borrowed from the intracellular supply. This,
in addition to a combination of other developments leads to coma and, eventually death.
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