1. Significance of Fatty Acid Metabolism
8. Fatty Acid Activation and Transport into the
Mitochondria
Overview
Fatty acyl CoA reacts with carnitine
2. Acetyl CoA- the Center of Lipid Metabolism
Summary
Overview
9. Mitochondrial beta-oxidation
Structure of Acetyl CoA
Dehydrogenation
3. General Features of Fatty Acid Structure
Hydration
2 essential features
2nd dehydrogenation
Carbon-carbon double bonds
Thyiolytic cleavage
Saturated fatty acids
Monounsaturated fatty acids
Complete beta-oxidation of palmitoyl CoA
Note: this Shocked movie file (480K) requires the
Shockwave plug-in to be viewed.
Polyunsaturated fatty acids
Beta-oxidation of double bond at odd-numbered
Carbons denoted by Greek letters
4. Nomenclature of Fatty Acids
Four common systems
5. De novo Synthesis of Fatty Acids
carbon
Acyl CoA dehydrogenase
2,4-dienoyl CoA reductase
Substrate for enoyl isomerase
Reaction sums
Handling the 3-carbon propionyl CoA
Enzymes and isolated reactions
Carboxylation by biotin dependent CoA
Biotin
D-isomer is converted to L-isomer
1st reaction
L-isomer is converted to succinyl CoA
2nd reaction
Summary
3rd reaction
10. Synthesis and Utilization of Ketone Bodies
4th reaction
Overview
5th reaction
1st step
6th reaction
2nd step
Transfer of butyryl group
3rd step
Dimer
Acetoacetate can be reduced
6. Modification of Dietary and Endogenous Fatty Acids
Overall reaction
Acetone
Acetoacetate activated by transfer of CoA from
succinyl CoA
Reversal of beta-oxidatio
Acetoacetyl CoA cleaved by thiolase
7. Mobilization and Transport of Adipose Fatty Acid
Triacylglycerol
11. Overall Regulation of Fatty Acid Metabolism
1. Significance of Fatty Acid Metabolism
Acetyl CoA Metabolism -- Overview
Fatty Acid Metabolism -- Schematic Overview
Major metabolic sources of acetyl CoA and some of the
processes in which it serves as a substrate.
Fatty acids are taken up by cells, where thy may serve as
precursors in the synthesis of other compounds, as fuels for
energy production, and as substrates for ketone body
synthesis. Ketones bodies may then be exported to other
tissues, where they can be used for energy production.
Energy
Fats are an important source of dietary calories.
Typically 30-40% of calories in the American diet are from
fat. Fat is the major form of energy storage. In a typical
individual the fuel reserves are distributed as follows:
fat: 100,000 kcal.
protein: 25,000 kcal.
carbohydrate: 650 kcal.
Intermediates in synthesis.
Fatty acids are intermediates in the synthesis of other
important compounds. Examples include:
phospholipids (in membranes).
eicosanoids, including prostaglandins and leucotrienes, which
play a role in physiological regulation.
Diseases
Some diseases involve disturbances in fatty acid metabolism.
These include:
diabetes mellitus
various disorders of fatty acid oxidation.
Sudden Infant Death Syndrome and Reye Syndrome might be
related to medium chain acyl CoA dehydrogenase deficiency.
Precursors of Acetyl CoA
Acetyl CoA is at the center of lipid metabolism. It is produced
from:
fatty acids
glucose (through pyruvate)
amino acids
ketone bodies.
Products of Acetyl CoA metabolism
It is the precursor of fatty acids, which in turn give rise to:
triglycerides (triacylglycerols)
phospholipids
eicosanoids (e.g., prostaglandins)
ketone bodies
It is the precursor of cholesterol, which can be converted to:
steroid hormones
bile acids
It produces energy, generated by the complete oxidation of
acetyl CoA to carbon dioxide and water through the
tricarboxylic acid cycle and oxidative phosphorylation.
The structure of Acetyl CoA consists of two parts.
1. Acetyl group
2. Coenzyme A
beta-mercaptoethylamine
pantothenic acid (not synthesized in man -- an essential
nutrient)
phosphate
3', 5'-adenosine diphosphate
Acetyl CoA Structure. The thioester bond linking the acetyl
group to CoA is a "high energy" bond.
Function
CoA is a commonly used carrier for activated acyl groups
(acetyl, fatty acyl and others). The thioester bond which links
the acyl group to CoA has a large negative standard free
energy of hydrolysis (-7.5 kcal/mole).
One system of fatty acid classification is based on the number
of double bonds.
0 double bonds: saturated fatty acids
1 double bond: monounsaturated fatty acids
2 or more double bonds: polyunsaturated fatty acids
III General Features of Fatty Acid Structure
The elements of fatty acid structure are quite simple. The
many fatty acids which occur naturally arise primarily through
variation of chain length and degree of saturation.
Stearic Acid Structure
Stearic acid is a typical long chain saturated fatty acid.
There are two essential features:
1. A long hydrocarbon chain. The chain length ranges from 4
to 30 carbons; 12-24 is most common). The chain is typically
linear, and usually contains an even number of carbons.
2. A carboxylic acid group
Oleic Acid Structure
Carbon-Carbon Double Bonds
Carbon-carbon double bonds are almost always cis. If there is
more than one, they occur at three-carbon intervals, e.g., C=C-C-C=C-.
The Divinylmethane Pattern in Fatty Acids
Oleic acid is a typical monounsaturated fatty acid.
Linoleic Acid Structure
Polyunsaturated fatty acids have their doubly bonded carbons
spaced by one methyl carbon, as shown. This is the
divinylmethane pattern (as if methane had two vinyl groups
attached). The double bond in naturally occurring fatty acids
is in the cis-configuration. The pattern may be repeated to
yield fatty acids with many double bonds. This is called the
divinylmethane pattern because it is as if a methane carbon (in
the center) is attached to two vinyl groups (carrying the
double bonds).
Linoleic acid is a typical polyunsaturated fatty acid.
IV Nomenclature of Fatty Acids
Sum of the reactions:
8 acetyl CoA + 7 ATP + 14 (NADPH + H+) -> palmitate
(16:0) + 8 CoA + 7 (ADP + Pi) + 14 NADP+ + 6 H2O
Sources of acetyl CoA for fatty acid synthesis: mostly from
glycolytic breakdown of glucose. First glucose is converted to
pyruvate by glycolysis, then pyruvate is converted to acetyl
CoA by the pyruvate dehydrogenase complex. (See diagram)
There are four common systems; three of them attempt to
denote the chain length and the number and positions of any
double bonds.
Trivial Names: Trivial names contain no clues to the
structures; one must memorize the name and associate it with
a separately memorized structure.
IUPAC: IUPAC names follow the nomenclature conventions
of the International Union of Pure and Applied Chemistry.
These names describe the structures in detail (if one knows the
conventions), but tend to be unwieldy.
Two Abbreviation Systems: After the common names, these
are the most frequently used to denote complicated structures.
Carboxyl-reference names indicate the number of carbons,
the number of double bonds, and the positions of the double
bonds, counting from the carboxyl carbon (which is numbered
1).
Omega-reference names indicate the number of number of
double bonds and the position of the double bond closest to
the omega carbon, counting from the omega carbon (which is
numbered 1 for this purpose).
Glucose Yields Acetyl CoA -- Schematic
Glucose is first degraded to pyruvate by aerobic glycolysis (in
the cytoplasm). Pyruvate dehydrogenase (in the mitochondria)
then oxidatively decarboxylates pyruvate, forming acetyl CoA
and other products. Acetyl CoA can then serve as a substrate
for citrate synthesis. Citrate, in turn, can be oxidized by the
tricarboxylic acid cycle in the mitochondria, or it can be
transported out of the mitochondria and split in the cytoplasm
to generate cytoplasmic acetyl CoA for fatty acid synthesis.
Enzymes and Isolated Reactions of Fatty Acid Synthesis
Acetyl CoA carboxylase catalyzes the reaction:
V. De Novo Synthesis of Fatty Acids
Fatty acid synthesis is the process of combining eight twocarbon fragments (acetyl groups from acetyl CoA) to form a
16-carbon saturated fatty acid, palmitate.
Acetyl CoA carboxylase has three important features. It
contains the prosthetic group, biotin. Biotin transfers CO2
from bicarbonate to the acetyl group. Biotin is not synthesized
in humans, and is an essential nutrient.
Palmitate can then be modified to give rise to the other fatty
acids. These modifications may include 1) chain elongation
to give longer fatty acids, such as the 18-carbon stearate. 3)
desaturation, giving unsaturated fatty acids.
Tissue locations of greatest importance:
liver, adipose (fat), central nervous system, lactating
mammary gland.
The carboxylation reaction is driven to completion by
hydrolysis of ATP. The enzyme catalyzes the rate-limiting
reaction for fatty acid synthesis, and is under tight short-term
control.
It is down-regulated by:
palmitoyl CoA (endproduct regulation)
phosphorylation of the enzyme (via a glucagon-cAMP
cascade).
It is up-regulated by:
citrate (allosteric)
dephosphorylation of the enzyme (influenced by the
insulin/glucagon ratio).
will be lost as bicarbonate ion. This -SH group is part of a
phosphopantethenic acid prosthetic group of the ACP.
3. In the third reaction the acetyl group is transferred to the
malonyl group with the release of carbon dioxide:
To summarize, it is controlled both allosterically (citrate,
palmitoyl
CoA)
and
by
covalent
modification
(phosphorylation/dephosphorylation).
Fatty acid synthase is a multifunctional enzyme with seven
activities.
Seven Activities of Fatty Acid Synthesis
Condensation of an Acyl Group with a Malonyl Group
The first iteration of the sequence catalyzed by this enzyme
can be represented as follows.
The acetyl group displaces the carboxyl of the malonyl group,
forming a beta-ketoacyl group. This reaction is catalyzed by
beta-ketoacyl Acyl Carrier Peptide synthase. The carboxyl
released in the form of bicarbonate regenerates the
bicarbonate used earlier in the acetyl CoA carboxylase
reaction.
1.
In the first reaction acetyl CoA is added to a cysteine -SH
group of the condensing enzyme (CE) domain:
4. In the fourth reaction the keto group is reduced to a
hydroxyl group by the beta-ketoacyl reductase activity:
An acetyl group is transferred from acetyl CoA to the -SH
group of the condensing enzyme domain of fatty acyl
synthase, forming acetyl-CE. The reaction is catalyzed by the
acyltransferase activity offatty acyl synthase. Mechanistically
this is a two step process, in which the group is first
transferred to the ACP (acyl carrier peptide), and then to the
cysteine -SH group.
Reduction of Beta-ketoacyl Acyl Carrier Peptide by NADPH
5. In the fifth reaction the -hydroxybutyryl-ACP is
dehydrated to form a trans- monounsaturated fatty acyl group
by the -hydroxyacyl dehydratase activity:
2. In the second reaction malonyl CoA is added to the ACP
sulfhydryl group:
Dehydration of Beta-hydroxyacyl Acyl Carrier Peptide
Transfer of a Malonyl Group to the Acyl Carrier Peptide
During fatty acid synthesis the incoming two carbon fragment
is introduced as the three-carbon malonyl group. It is added to
the -SH group of the acyl carier peptide domain of fatty acid
synthase. In a subsequent reaction the carbon shown in green
6. In the sixth reaction the double bond is reduced by
NADPH, yielding a saturated fatty acyl group two carbons
longer than the initial one (an acetyl group was converted to a
butyryl group in this case):
Reduction of 2-enoyl Acyl Carrier Peptide. A 2-enoyl acyl
group on the acyl carrier peptide is reduced by NADPH in a
reaction catalyzed by enoyl acyl carrier peptide reductase.
The butyryl group is then transferred from the ACP sulfhydryl
group to the CE sulfhydryl:
Source of Acetyl Groups and Reducing Equivalents for Fatty
Acid Synthesis
Acetyl groups are produced in the mitochondria by
pyruvate dehydrogenase, and are transported to the cytoplasm.
Citrate synthase converts acetyl CoA and
oxaloacetate to citrate. Citrate exits the mitochondria on the
citrate-malate antiport. In the cytoplasm citrate is cleaved by
the citrate cleavage enzyme to regenerate oxaloacetate and
acetyl CoA. Oxaloacetate in the cytoplasm is reduced to
malate by NADH from glycolysis; this supplies the malate for
the citrate-malate antiport.
NADPH is produced mostly by the hexose monophosphate
pathway. The malic enzyme might also contribute to NADPH
production.
VI. Modification of Dietary and Endogenous Fatty Acids
Preparing for the Second Round of Beta-oxidation
The initial two acetyl groups have been converted to a fourcarbon saturated fatty acyl group (a butyryl group in this
diagram). This saturated fatty acyl group is now transferred to
the condensing enzyme domain of fatty acyl synthase. The
acyl carrier peptide domain is now free to accept another
malonyl group, initiatiating the next round of the elongation
process.
This is catalyzed by the same transferase activity as was
used previously for the original acetyl group. The butyryl
group is now ready to condense with a new malonyl group
(third reaction above) to repeat the process.
The palmitate produced by fatty acid synthase is typically
modified to give rise to the other fatty acids.
Fatty acids from dietary sources, too, are often modified.
These modifications may include:
chain elongation to give longer fatty acids
desaturation, giving unsaturated fatty acids.
Elongation can occur in all tissues; the process differs in the
endoplasmic reticulum vs. the mitochondria.
In endoplasmic reticulum the reactions resemble those of de
novo fatty acid synthesis.
7. When the fatty acyl group becomes 16 carbons long, a
thioesterase activity hydrolyses it, forming free palmitate:
palmitoyl-ACP + H2O -> palmitate + ACP-SH
Fatty acyl synthetase has three important features.
1. It is essential, but not rate-limiting, for fatty acid synthesis.
It is not subject to short term control.
2. ACP and the catalytic activities are on a single contiguous
protein (257 kDa).
3. In animals the synthase is active only as a dimer. The
malonyl/acetyl transferase, condensing enzyme and
dehydratase activities from the first subunit and all the other
activities from the second subunit form one functional unit. A
second functional unit forms from the remainder of the two
subunits.
In contrast, bacterial activities are all on separate enzymes.
Interestingly, the enoyl reductase of Mycobacterium
tuberculosis is the target of isoniazid and other major
antituberculosis drugs.
Notice that malonyl CoA is the source of the added carbons,
as in de novo fatty acid synthesis. The activities are closely
associated with the endoplasmic reticulum membranes. The
activities are separable; they are not part of a multifunctional
enzyme. No ACP is involved; CoA esters are used directly.
Mitochondrial Fatty Acid Elongation, a Minor Pathway
In the mitochondria fatty acid elongation occurs by a
reversal of beta-oxidation. Notice that here acetyl CoA is the
source of the added carbons.
Desaturation of fatty acids
Desaturation of fatty acids can also occur in all tissues.
The Overall Reaction.
RCH2CH2...CH2COSCoA + NADPH + H+ + O2 -->
RCH=CH...CH2COSCoA + NADP+ + 2H2O
A cis double bond is formed. The reaction requires an electron
transport system involving:
1.cytochrome b5
2.desaturase
3.NADPH-cytochrome b5 reductase
This complex system avoids generating H2O2 in the
vicinity of the sensitive double bonds. The system is
associated with the membranes of the endoplasmic reticulum.
Specificity: In humans there are four distinct desaturases, each
with a different specificity: 9, 6, 5, 4 (that is, they act at the 9-,
6-, 5- or 4-carbons.)
A minimum chain length of 16-18 carbons is
required. The specificity of distance from the carboxyl
carbon, along with the need for a 16-18 carbon chain means
that n-6 andn-3 fatty acids are not synthesized in humans.
Because some of these fatty acids are metabolically essential,
they must be supplied in the diet.
Desaturation and 2-carbon elongation often alternate,
e.g., conversion of dietary linoleic acid (18:2 9,12) to
arachidonic acid (20:4 5,8,11,14), which is important because
it is a precursor of eicosanoids.
18:2 9,12 --> 18:3 6,9,12 --> 20:3 8,11,14 --> 20:4 5,8,11,14 -> eicosanoids
The final products of triacylglycerol hydrolysis are
glycerol and unesterified fatty acids. HSL is activated by
epinephrine, norepinephrine, ACTH and glucagon, acting via
phosphorylation of the enzyme. It is inhibited by insulin.
Unesterified fatty acids are bound to serum albumin
for transport to other tissues, where they are used. Major
target tissues are muscle and liver. At the target cells
unesterified fatty acids are taken up passively. Within the
target cells they are bound to fatty acid binding protein. Next
they must be activated.
VIII Fatty Acid Activation and Transport into the
Mitochondria
Fatty acids inside the cell, like glucose, must be
activated before proceeding through metabolism. Activation
consists of conversion of the unesterified fatty acid to its CoA
derivative. Fatty acids are activated by fatty acyl CoA
synthetase. The reaction:
R-COOH + CoASH + ATP <--> R-CO-SCoA + AMP + PPi
The subsequent hydrolysis of PPi draws the reaction in the
forward direction, maintaining a low cytosolic free fatty acid
concentration:
PPi + H2O --> 2 Pi
The reaction occurs in the endoplasmic reticulum and the
outer mitochondrial membrane. The fatty acyl group is
transported into the mitochondrial matrix for where it
undergoes beta-oxidation.
In the intermembrane space of the mitochondria fatty acyl
CoA reacts with carnitine in a reaction catalyzed by carnitine
acyltransferase I (CAT-I), yielding CoA and fatty acyl
carnitine. CAT-I is associated with the inner leaflet of the
outer mitochondrial membrane.
VII. Mobilization and Transport of Adipose Fatty Acid
Fatty acids, as triacylglycerol (triglyceride), are
stored in white adipose tissue. Brown adipose tissue is a
thermogenic tissue, and is not important in energy storage.
Fatty acids are stored primarily in adipocytes as
triacylglycerol. Triacylglycerol must be hydrolyzed to release
the fatty acids.
Adipocytes are found mostly in the abdominal cavity
and subcutaneous tissue. Adipocytes are metabolically very
active; their stored triacylglycerol is constantly hydrolyzed
and resynthesized.
Unesterified fatty acid release from the adipocytes is
initiated by the action of hormone sensitive lipase (HSL).
In liver the CAT-I reaction is rate-limiting; the
enzyme is allosterically inhibited by malonyl CoA. Malonyl
CoA concentration would be high during fatty acid synthesis.
The inhibition of CAT-I prevents simultaneous synthesis and
degradation of fatty acids.
Fatty acyl carnitine is transported across the inner
mitochondrial membrane in exchange for carnitine by an
antiport translocase. In the mitochondrial matrix fatty acyl
carnitine reacts with CoA in a reaction catalyzed by carnitine
acyltransferase II (CAT-II), yielding fatty acyl CoA and
carnitine. The fatty acyl CoA is now ready to undergo betaoxidation.
The scheme summarizes the entire proces:
IX Mtochondrial -oxidation of long-chain fatty acids
Beta-oxidation is the process by which long
chain fatty acyl CoA is degraded. The products of betaoxidation are acetyl CoA, FADH2, NADH and H+ .
The FADH2, NADH and H+ yield ATP when
oxidized by the mitochondrial electron transport system.
Acetyl CoA can also yield energy through oxidation.
Overall reaction
The overall reaction, using palmitoyl CoA (16:0) as a model
substrate:
Involvement of the beta-carbon in this and subsequent steps
gives the pathway its name.
There are three fatty acyl CoA dehydrogenases. Each is
specific for a different acyl chain length, so different enzymes
are involved in different stages of beta-oxidation.
Long chain fatty acyl CoA dehydrogenase (LCAD) acts on
chains greater than C12.
Medium chain fatty acyl CoA dehydrogenase (MCAD) acts
on chains of C6 to C12.
Short chain fatty acyl CoA dehydrogenase (SCAD) acts on
chains of C4 to C6.
MCAD deficiency is thought to be one of the most
common inborn errors of metabolism.
Hydration of the double bond is catalyzed by enoyl CoA
hydratase. The product is an L-3-hydroxyacyl CoA.
7 FAD + 7 NAD+ + 7 CoASH + 7 H2O +
H(CH2CH2)7CH2CO-SCoA --> 8 CH3CO-SCoA + 7
FADH2 + 7 NADH + 7 H+
Fate of the acetyl CoA: Oxidation by the citric acid cycle to
CO2 and H2O. In liver only, acetyl CoA may be used for
ketone body synthesis.
Fate of the FADH2 and NADH + H+: FADH2 and NADH +
H+ are oxidized by the mitochondrial electron transport
system, yielding ATP.
A second dehydrogenation, of the alcohol, occurs in a NADlinked Reaction catalyzed by beta-hydroxyacyl CoA
dehydrogenase. The product is a ketone.
There are four individual reactions of beta-oxidation, each
catalyzed by a separate enzyme.
1) Dehydrogenation between the alpha and beta carbons (C2
and C3) in a FAD-linked reaction.
2) Hydration of the double bond by enoyl CoA hydratase.
3) A second dehydrogenation in a NAD-linked reaction.
4) Thiolytic cleavage of the thioester by beta-ketoacyl CoA
thiolase.
Dehydrogenation occurs between the alpha and beta carbons
(C2 and C3) in a FAD-linked reaction catalyzed by acyl CoA
dehydrogenase. The product contains a trans- double bond.
Thiolytic cleavage of the thioester is catalyzed by betaketoacyl CoA thiolase.
The Thiolase Reaction: Thiolase (3-ketoacyl CoA thiolase)
cleaves a long chain fatty acyl CoA, forming acetyl CoA and a
long chain fatty acyl CoA that is two carbons shorter.
Regulation: This reaction is inhibited by high concentrations
of acetyl CoA.
Reaction products: The products are acetyl CoA and a long
chain fatty acyl CoA that is two carbons shorter than the
original fatty acyl CoA.
SECOND:
2,4-dienoyl CoA reductase reduces the compound,
leaving one trans- double bond, but in the wrong position.
NADPH + H+ is required.
Beta-oxidation is regulated as a whole primarily by
fatty acid availability; once fatty acids are in the mitochondria
they are oxidized as long as there is adequate NAD+ and CoA.
(Video sequence available)
Additional Enzymes are Needed for Complete Oxidation of
Unsaturated and Odd-Carbon Fatty Acids.
- The action of enoyl CoA isomerase may be required.
If there is a double bond at an odd-numbered carbon (e.g.,
18:19), the action of enoyl CoA isomerase is required to move
the naturally occurring cis- bond and convert it to the transbond used in beta-oxidation.
Beta-oxidation now proceeds normally.
Handling the three-carbon propionyl CoA.
Fatty acids with an odd number of carbons in their chains
require a means of handling the three-carbon propionyl CoA
that is the final fragment produced by beta-oxidation of such a
chain.
The first step is carboxylation by the biotin-dependent
propionylCoA coarboxylase in an ATP-requiring reaction.
Generating a trans- double bond instead of a cis.
If there is also a double bond at an even-numbered carbon
(e.g., the second double bond in 18:2 9,12), the problem is to
generate a trans-double bond instead of a cis-. This occurs in
an indirect manner. Both activities occur in the mitochondrial
matrix.
FIRST: The cycles of beta-oxidation prior to the one
involving the original 12 double bond act as previously
described to get past the 9 double bond.
Beta-oxidation then continues as usual through the acyl CoA
dehydrogenase step of the next cycle, generating a transdouble bond at the 2 position.
The D- isomer is then converted to the L- isomer by
methylmalonyl CoA racemase.
Ketone body synthesis from acetyl CoA occurs in
hepatic mitochondria. The rate of the process increases in
starvation.
In the final step, the L- isomer is converted to succinyl CoA
by methylmalonyl CoA mutase.
The first step: The first step is formation of acetoacetyl CoA
in a reversal of the thiolase step of beta-oxidation.
Succinyl CoA can then be metabolized in the tricarboxylic
acid cycle.
A summary of the entire process is shown in the following
scheme:
X. Synthesis and utilization of ketone bodies
Ketone body synthesis from acetyl CoA
The second step:. In the second step, a third molecule of
acetyl CoA condenses with the acetoacetyl CoA, forming 3hydroxy-3-methylglutaryl CoA (HMG CoA) in a reaction
catalyzed by HMG CoA synthase. Since so much acetyl CoA
is used in this process, its rate is very sensitive to acetyl CoA
concentration. When [acetyl CoA] is high, ketone body
synthesis is rapid.
The third step: In the third step HMG CoA is cleaved to yield
acetoacetate (a ketone body) in a reaction catalyzed by HMG
CoA lyase (HMG CoA cleavage enzyme). One molecule of
acetyl CoA is also produced.
Acetoacetate can be reduced. Subsequently acetoacetate can
be reduced to -hydroxybutyrate by -hydroxybutyrate
dehydrogenase in a NADH-requiring reaction. The extent of
this reaction depends on the state of the NAD pool of the cell;
when it is highly reduced, most or all of the ketones can be in
the form of -hydroxybutyrate.
Acetone: Some acetoacetate spontaneously decarboxylates to
yield acetone. The odor of acetone can be smelled on the
breath of individuals with severe ketosis.
Ketone body production is regulated primarily by availability
of acetyl CoA. If mobilization of fatty acids from adipose
tissue is high, hepatic beta-oxidation will occur at a high rate,
and so will synthesis of ketone bodies.