Acyl-CoA

Part III => METABOLISM and ENERGY
§3.4 Noncarbohydrate Metabolism
§3.4a Fatty Acid Degradation
§3.4b Ketone Bodies
§3.4c Amino Acid Breakdown
Section 3.4a:
Fatty Acid Degradation
Synopsis 3.4a
- Triglycerides (or fats) in the diet or adipose tissue are broken down into fatty
acids by a group of enzymes referred to as “lipases”
- Degradation of such fatty acids releases free energy—how?
- In the cytosol, fatty acids to be degraded are linked to coenzyme A (CoA) and
then transported into the mitochondrion via a carnitine shuttle for oxidation
- In the mitochondrion, each round of so-called “β-oxidation” of fatty acids
produces FADH2, NADH, and acetyl-CoA
- Acetyl-CoA is subsequently oxidized via the Krebs cycle and the energy
released is stored in the form of GTP, FADH2 and NADH—see §3.5
- FADH2 and NADH ultimately donate their electrons to produce ATP via the
electron transport chain (ETC)—see §3.6
Coenzyme A—a common metabolic cofactor
Coenzyme A (CoA) is involved in numerous metabolic pathways, including:
(1) Biosynthesis of fatty acids
(2) Oxidation of fatty acids
(3) Oxidation of pyruvate
Triglyceride Breakdown
-O
Lipase
-O
+
-O
Fatty Acids
- Triglycerides (or triacylglycerols) are fatty acid esters (usually with different fatty acid R groups) of
glycerol—see §1.4!
- Triglycerides are largely stored in the adipose tissue where they function as “high-energy”
reservoirs—due to being more reduced (carry more electrons, or more hydrogens!) than their
carbohydrate and protein counterparts, they yield significantly more energy per unit mass upon
oxidative catabolism (see §3.6)
- In order to release such energy to be used as “free energy”, triglycerides must first be deesterified or hydrolyzed into free fatty acids via the action of lipases
- Once released from their parent triglycerides within the cytosol, fatty acid (FA) degradation to
generate acetyl-CoA (for subsequent oxidation via the Krebs cycle) requires TWO umbrella stages
(additional stages are needed for the oxidation of unsaturated fatty acids—a subject that is
beyond the scope of this lecture):
(A) FA Derivatization
(B) FA Oxidation
(A) FA Derivatization: Overview
Fatty Acid
- In order to be oxidized to provide free
energy, fatty acids are first “primed” with
coenzyme A (CoA) to generate the acyl-CoA
derivative within the cytosol
1 Acyl-CoA synthetase
Acyl-CoA (cytosolic)
- Recall that acyl is a functional group with
the general formula R-C=O, where R is an
alkyl sidechain (or in this case, the polar tail
of fatty acids)
2 Carnitine acyltransferase I
Acyl-carnitine
- Given the rather charged character of CoA
moiety (vide infra), acyl-CoA produced in
the cytosol cannot cross the inner
mitochondrial membrane (IMM) to reach
the mitochondrial matrix (the site of Krebs
cycle)
- Accordingly, acyl-CoA is subjected to
reversible conversion to acyl-carnitine in
order to exploit the carnitine shuttle system
located within the IMM to translocate it to
the mitochondrial matrix
3 Carnitine-acylcarnitine translocase
(Mitochondrial Transit)
Acyl-carnitine
4 Carnitine acyltransferase II
Acyl-CoA (mitochondrial matrix)
FA Derivatization: (1) Acyl-CoA Synthetase
- In order to be oxidized to provide free energy, fatty acids are first “primed” with CoA in
an ATP-dependent reaction to generate the acyl-CoA derivative within the cytosol
- The reaction is catalyzed by a family of enzymes called “acyl-CoA synthetases” or
“thiokinases”
- First step mediated via nucleophilic attack of O atom of fatty acid carboxylate anion on
the -phosphate of ATP to generate the acyladenylate mixed anhydride intermediate
and PPi—which undergoes exergonic hydrolysis to Pi to drive the reaction to completion
- Second-step involves nucleophilic attack by the thiol (-SH) group of CoA on the carbonyl
C atom of acyladenylate mixed anhydride intermediate to generate acyl-COA and AMP
- The overall result is that the free energy of fatty acid is conserved via the generation of a
“high-energy” thioester bond of acyl-CoA within the cytosol—but how does acyl-CoA get
into the mitochondrial matrix (the site of Krebs cycle)?
FA Derivatization: (2) Carnitine Acyltransferase I
Carnitine
Acyl-CoA
Carnitine
acyltransferase I
Acyl-carnitine
CoA
- Given the rather charged character of CoA moiety, acyl-CoA produced in the cytosol cannot cross
the inner mitochondrial membrane (IMM) to reach the mitochondrial matrix (the site of Krebs
cycle)
- Accordingly, acyl-CoA is first converted to acyl-carnitine by carnitine acyltransferase I—an
enzyme located at the outer (intermembraneous space) surface of IMM—in order to exploit the
carnitine shuttle system for its delivery into the mitochondrial matrix
- Carnitine, a quaternary amine, has no known physiological function other than its role in the
shuttling of fatty acids from the intermembraneous space to mitochondrial matrix
- Note that the free energy of thioester bond in acyl-CoA is conserved in the ester (or O-acyl)
bond in acyl-carnitine
FA Derivatization: (3) Carnitine-Acylcarnitine Translocase
Cytosol
Mitochondrial
Matrix
(intermembraneous
space)
Carnitineacylcarnitine
translocase
Acyl-carnitine
Acyl-carnitine
Acyl-carnitine is shuttled across the inner mitochondrial membrane
(IMM)—from the cytosol (or the intermembraneous space) to the
mitochondrial matrix—by the carnitine-acylcarnitine translocase
FA Derivatization: (4) Carnitine Acyltransferase II
Acyl-carnitine
CoA
Carnitine
acyltransferase II
Carnitine
Acyl-CoA
- Inside the mitochondrial matrix, carnitine acyltransferase II catalyzes the
reverse transfer of acyl group of acyl-carnitine back to CoA to generate acylCoA and free carnitine
- Acyl-CoA is then not only “chemically” but also “spatially” primed to be
converted to acetyl-CoA for subsequent entry into the Krebs cycle
FA Derivatization: Outline
RCOOH
1
SCoA
5
2
Carnitine
acyltransferase I
Carnitineacylcarnitine
translocase
Carnitine
acyltransferase II
4
3
Acyl-CoA is transported from the cytosol (or the intermembraneous space) to the
mitochondrial matrix by the carnitine shuttle system as follows:
(1) Fatty acid is “primed” with CoA in the cytosol
(2) Acyl group of cytosolic acyl-CoA is transferred to carnitine  acyl-carnitine
(3) Acyl-carnitine is shuttled across the IMM into the mitochondrial matrix by carnitineacylcarnitine translocase
(4) Acyl group of matrix acyl-carnitine is transferred to mitochondrial matrix CoA  acyl-CoA,
thereby freeing up free carnitine pool
(5) Free carnitine within the matrix is shuttled back to the cytosol to repeat the cycle
(B) FA Oxidation: Overview
- Within the mitochondrial matrix, oxidation of acylCoA into acetyl-CoA (a Krebs cycle substrate) occurs
via four distinct steps—each requiring the
involvement of a specific mitochondrial enzyme
- This process is referred to as “ -oxidation”—due to
the fact that the acyl group of acyl-CoA is oxidized at
its -carbon atom in a repetitive fashion so as to
degrade fatty acids with the removal of a two-carbon
unit in the form of acetyl-CoA during each round
FA Nomenclature
(cf x:m symbolism introduced in §1.4)
Acyl-CoA
1 Acyl-CoA dehydrogenase
trans- 2-Enoyl-CoA
2 Enoyl-CoA hydratase
L- -Hydroxyacyl-CoA
9
3
- The position of C=C double bond is indicated by the
notation n, where n denotes the numeric position of
the first C atom within C=C from the carbonyl end
- Thus, 9 is indicative of a C=C double bond beginning
@ C9 within the fatty acid tail
- On the other hand, cis- 9 is indicative of a C=C double
bond at the same position but with cis-configuration
- What does trans-
2
suggest?!
-Hydroxyacyl-CoA
dehydrogenase
-Ketoacyl-CoA
4
-Ketoacyl-CoA thiolase
Acetyl-CoA
FA Oxidation: (1) Acyl-CoA Dehydrogenase
Dehydrogenation
- Dehydrogenation of saturated C -C single
bond within acyl-CoA results in the
formation of enoyl-CoA harboring a C =C
double bond
- Since such dehydrogenation begins at C
atom numbered 2, the product is prefixed
with trans- 2 to indicate the position of the
C =C double bond
- Reaction catalyzed by acyl-CoA
dehydrogenase using FAD as an oxidizing
agent or electron acceptor—thus the energy
released due to the oxidation of acyl group
is conserved in the form of FADH2
- FADH2 will be subsequently reoxidized back
to FAD via the mitochondrial electron
transport chain (ETC)
FA Oxidation: (2) Enoyl-CoA Hydratase
Hydration
- Hydration of unsaturated C =C
double bond within trans- 2-enoylCoA (prochiral) results in the
formation of L- -hydroxyacyl-CoA
- Reaction catalyzed by enoyl-CoA
hydratase in a stereospecific manner
producing exclusively the L-isomer
- The addition of an –OH group at the
C position “primes” L- -hydroxyacylCoA for subsequent oxidation to a
keto group—that can then serve as a
nucleophilic center for the release of
first acetyl-CoA
L- -Hydroxyacyl-CoA
FA Oxidation: (3) -Hydroxyacyl-CoA Dehydrogenase
Oxidation
- Oxidation of –OH to a keto group at the C
position within L- -hydroxyacyl-CoA results
in the formation of corresponding ketoacyl-CoA
- Reaction catalyzed by -hydroxyacyl-CoA
dehydrogenase using NAD+ as an oxidizing
agent or electron acceptor—the energy of
electron transfer is conserved in NADH
- NADH will be subsequently reoxidized back
to NAD+ via the mitochondrial electron
transport chain (ETC)
L- -Hydroxyacyl-CoA
-hydroxyacyl-CoA
dehydrogenase
FA Oxidation: (4) -Ketoacyl-CoA Thiolase
Thiolysis
- Thiolysis (or breaking bonds with –SH group—cf hydrolysis and phosphorolysis) initiated by
nucleophilic attack of the thiol group (-SH) of CoA on the keto group within -ketoacyl-CoA
results in the cleavage of C -C bond, thereby releasing the first acetyl-CoA (to enter the
Krebs cycle) and an outgoing acyl-CoA
- Reaction catalyzed by -ketoacyl-CoA thiolase
- The outgoing acyl-CoA is two C atoms shorter than the parent acyl-CoA that entered the first
round of -oxidation—this acyl-CoA will undergo subsequent rounds of -oxidation (Steps 14) to generate additional acetyl-CoA molecules—how many?!
- Complete -oxidation of a 2n:0 fatty acid requires n-1 steps—ie it will generate n acetyl-CoA,
n-1 NADH, and n-1 FADH2! That would be bucketloads of energy—but exactly how much?!
FA Oxidation: Bucketloads of ATP
Palmitic Acid (16:0)
Palmitoyl-CoA
6
7 FADH2
ETC
10.5 ATP
7 NADH
ETC
17.5 ATP
-Oxidation
- Palmitic acid is a saturated fatty acid harboring
16 carbon atoms (16:0)
- It is the most commonly occurring fatty acid in
living organisms
- So how much energy does -oxidation of a single
chain of palmitic acid (16 C atoms) generate?
8 Acetyl-CoA
- Complete degradation of palmitic acid would
require 7 rounds of -oxidation producing 7
FADH2, 7 NADH and 8 acetyl-CoA—the final
round produces 2 acetyl-CoA!
- Further oxidation of each acetyl-CoA via the
Krebs cycle produces 3 NADH, 1 FADH2 and 1
GTP (enzymatically converted to ATP) per
molecule (and there are 8 acetyl-CoA!)—see 3.5
- Oxidation of each NADH and FADH2 via the ETC
respectively produces 2.5 and 1.5 molecules of
ATP—see 3.6
Krebs
cycle
Fat Is hypercaloric!
24 NADH
ETC
60 ATP
8 FADH2
ETC
12 ATP
8 GTP
8 ATP
Total Energy = 108 ATP
Exercise 3.4a
- Describe the activation of fatty acids. What is the energy cost for
the process?
- How do cytosolic acyl groups enter the mitochondrion for
degradation?
- Summarize the chemical reactions that occur in each round of βoxidation. Explain why the process is called β-oxidation?
- How is ATP recovered from the products of β-oxidation?
Section 3.4b:
Ketone Bodies
Synopsis 3.4b
- While acetyl-CoA produced via fatty acid oxidation is by and large
funneled into the Krebs cycle in most tissues, it can also be converted to the
so-called ketone bodies in a process referred to as “ketogenesis”
- Ketone bodies include small water-soluble molecules such as
acetoacetate, acetone and -hydroxybutyrate
- Ketogenesis primarily occurs within the mitochondrial matrix of liver cells under conditions
of starvation or in the case of non-carbohydrate diet during glucose shortage—why produce
ketone bodies?!!
- Being small and water-soluble, ketone bodies serve as important metabolic fuels for tissues
such as the:
(1) Heart (virtually no glycogen reserves)—since heart primarily relies on fatty acids
for energy production, ketone bodies serve as an alternative source of fuel that
can be readily “burned” via the Krebs cycle to generate energy
(2) Brain (low glycogen reserves that likely mediate neuronal activity rather than
glucose metabolism)—since fatty acids and acetyl-CoA cannot enter the brain due
to the presence of the so-called blood-brain-barrier (BBB), the ability of ketone
bodies to passively diffuse through the BBB renders them perfect candidates as
an alternative source of fuel (when glucose is in short supply) and as precursors
for fatty acid biosynthesis
BBB  an highly selective filter/barrier separating the
circulating blood in the brain from the extracellular fluid
Ketone Bodies: Ketogenesis
SCoA
Acetyl-CoA
Ketone bodies include:
- Acetoacetate
- -hydroxybutyrate
- Acetone
(1) How is acetyl-CoA converted to
ketone bodies such as acetoacetate
(2) How is acetoacetate subsequently
utilized as a source of fuel via the
Krebs cycle?
Acetoacetate
Conversion of acetone back to acetyl-CoA
-hydroxybutyrate is easily converted
occurs via lactate and pyruvate in the liver
back to acetyl-CoA via acetoacetate
Acetoacetate
decarboxylase
(or spontaneously)
NADH
CO2
NAD+
-hydroxybutyrate
dehydrogenase
H
3
Acetone
-Hydroxybutyrate
Ketone Bodies: (1) Acetyl-CoA  Acetoacetate
1
Glutaric Acid (5C)
The conversion of acetyl-CoA to ketone
bodies such as acetoacetate in the liver
occurs via three major enzymatic steps:
(1) Thiolase condenses two molecules of
acetyl-CoA into acetoacetyl-CoA
2
(2) Hydroxymethylglutaryl-CoA synthase
adds another molecule of acetyl-CoA to
acetoacetyl-CoA to generate -hydroxy-methylglutaryl-CoA
3
(3) Hydroxymethylglutaryl-CoA lyase breaks
down -hydroxy- -methylglutaryl-CoA
into acetyl-CoA and acetoacetate—the
ketone body
Ketone Bodies: (2) Acetoacetate  Acetyl-CoA
Ketone bodies such as acetoacetate and
-hydroxybutyrate (produced by the liver)
travel in the bloodstream to reach tissues
such as the heart and brain, where they
are converted back to acetyl-CoA via the
following enzymatic steps:
1
(1) -hydroxybutyrate dehydrogenase
mediates the oxidation of hydroxybutyrate into acetoacetate
(2) Ketoacyl-CoA transferase condenses
acetoacetate with succinyl-CoA to
generate acetoacetyl-CoA
2
(3) Thiolase breaks down acetoacetyl-CoA
into two acetyl-CoA molecules using
free CoA as a nucleophile
The newly generated acetyl-CoA can now
serve either as a Krebs cycle substrate for
energy production (or as a precursor for
fatty acid biosynthesis!)
3
Exercise 3.4b
- What are ketone bodies?
- Which organs utilize ketone bodies as an alternative source of fuel?
- How are ketone bodies synthesized and degraded?
Section 3.4c:
Amino Acid Breakdown
Synopsis 3.4c
- After their release from dietary/cellular proteins, free amino acids can be broken down
into the following metabolites for energy production (or in biosynthetic pathways):
- α-Ketoglutarate
- Succinyl-CoA
- Fumarate
- Oxaloacetate
- Pyruvate
- Acetoacetate
- Acetyl-CoA
- Of these seven metabolites, four are Krebs cycle intermediates:
- -ketoglutarate
- Succinyl-CoA
- Fumarate
- Oxaloacetate
- Pyruvate and acetoacetate (a ketone body) can be easily converted to acetyl-CoA–the
spark that starts the Krebs cycle “ignition” by virtue of its ability to donate a two-carbon
unit in the form of an acetyl group
- In a nutshell, the breakdown products of amino acids essentially serve as a “fuel” for
the Krebs cycle—but be aware that acetyl-CoA can also be converted into fatty acids!
Protein Digestion
Chymotrypsin
—Ala—Ser—Phe—Pro—Lys—Gly—Ala—Arg—Trp—Thr—Asp—Tyr—Gly—Lys—Cys—
Trypsin
- Dietary proteins are degraded into free amino acids by the collaborative action of three major digestive
proteases: pepsin, trypsin, and chymotrypsin
- Trypsin preferentially cleaves peptide bonds on the C-terminus of Lys and Arg (see §2.2)
- Chymotrypsin preferentially cleaves peptide linkages on the C-terminus of large hydrophobic residues
such as Trp, Phe, and Tyr (see §2.2)
- With preference for hydrophobic and aromatic residues, pepsin displays a high degree of promiscuity (or
broad specificity) in its ability to cleave peptide bonds
- The released amino acids enter the bloodstream from the digestive tract to be absorbed by other tissues
- Once inside the cells, excess dietary amino acids are broken down into metabolic intermediates, many of
which enter the Krebs cycle for energy production
- During starvation, the degradation of cellular proteins serves as an alternative source of such free amino
acids that are ultimately broken down into metabolic intermediates for energy production
Products of Amino Acid Breakdown
In the context of their catabolic breakdown,
amino acids can be divided (albeit with a
substantial overlap!) into two major groups:
(1) Glucogenic amino acids—these are amino
acids that can be directly broken down into
glucose precursors such as pyruvate, ketoglutarate, succinyl-CoA, fumarate, or
oxaloacetate—used in the synthesis of
glucose (gluconeogenesis)
(2) Ketogenic amino acids—these are
amino acids that can be directly broken
down into ketogenic precursors such as
acetyl-CoA or acetoacetate—used in the
synthesis of ketone bodies (ketogenesis)
Helpful Hints:
(a) Of the 20 standard amino acids, only Leu
and Lys are NOT glucogenic—ie they are
exclusively ketogenic!
(b) Of the other 18 amino acids, only five
amino acids are both glucogenic and
ketogenic—Trp, Ile, Phe, Thr and Tyr (use
WIFTY as a mnemonic!)
Ala/Cys/Gly/Ser/Thr Breakdown  Pyruvate
Ala/Cys/Gly/Ser/Thr are broken down into
pyruvate by one or more enzymes:
5a
(1) Alanine aminotransferase catalyzes the
exchange of amino group of alanine with
keto of -ketoglutarate yielding pyruvate in a
process referred to as “transamination”
5b
(2) Serine-threonine dehydratase catalyzes
dehydration of serine to pyruvate
(3) Cysteine aminotransferase catalyzes
transamination of cysteine using ketoglutarate as keto donor to thiolpyruvate
(3a), which can then be converted to
pyruvate by sulfur transferase (3b)
4
(4) Serine hydroxymethyltransferase catalyzes
conversion of glycine to serine, which can
then be dehydrated to pyruvate per Step 2
(5) Threonine dehydrogenase catalyzes
oxidation of threonine to -amino- ketobutyrate (5a), which can then be
converted by -amino- -ketobutyrate lyase
to acetyl-CoA and glycine (5b), and utimately
to pyruvate via Steps 4 and 2
-Ketoglutarate
Glutamate
3a
Thiolpyruvate
3b
H2S
1
2
Asn/Asp Breakdown  Oxaloacetate
1
Aminotransferases
2
Asparaginase
Asn/Asp are broken down into oxaloacetate via the action of specific enzymes:
(1) Aminotransferases catalyze transamination of aspartate or the exchange of amino
group of aspartate with keto of -ketoglutarate yielding oxaloacetate
(2) Asparaginase catalyzes hydration of asparagine to aspartate, which is then
converted to oxaloacetate as per Step 1
Arg/Glu/Gln/His/Pro Breakdown  -Ketoglutarate
Arg/Gln/His/Pro are all broken down into Glu, which is then oxidized to -ketoglutarate
via the action of specific enzymes:
(1) Arginase catalyzes hydration of arginine to ornithine (1a), which is then
transaminated by ornithine- -aminotransferase to glutamate and glutamate-5semialdehyde (1b), and the latter oxidized to glutamate by the action of glutamate5-semialdehyde dehydrogenase (1c)
(2) Proline oxidase converts proline to
pyrroline-5-carboxylate (2a), which
then spontaneously linearizes into
glutamate-5-semialdehyde (2b), and
finally oxidized to glutamate as per Step 1c
3b
2a
1a
(3) Histidine ammonia lyase deaminates histidine
1b
into urocanate (3a), which is then hydrated by
urocanate hydratase to 4-imidazolone-5propionate (3b)—the latter is cleaved by imidazolone
Propionase to N-formiminoglutamate (3c), which is
subsequently degraded to glutamate by glutamate
formiminotransferase (3d)
3c
2b
3d
1c
4
(4) Glutaminase catalyzes hydration of glutamine
to glutamate
(5) Glutamate dehydrogenase catalyzes oxidation
of glutamate (free as well as that generated via
Steps 1-4) to -ketoglutarate
3a
5
Met/Thr Breakdown  Succinyl-CoA
Met/Thr are both broken down into propionylCoA, which is then converted to succinyl-CoA
via a series of enzymatic reactions:
(1) Serine-threonine dehydratase deaminates
threonine to -ketobutyrate (1a), which is
then oxidized by -keto acid
dehydrogenase to propionyl-CoA (1b)
(2) Methionine adenosyltransferase catalyzes
the reaction of methionine with ATP to
generate S-adenosylmethionine (2a),
which is then demethylated by a
methyltransferase to Sadenosylhomocysteine (2b)—the latter is
hydrolyzed by adenosylhomocysteinase to
homocysteine (2c), which is then
combined with serine by cystathionine synthase to cystathionine (2d), which is
subsequently broken down by cystathione
-lyase into cysteine and -ketobutyrate
(2e), and latter oxidized to propionyl-CoA
as per Step 1b
(3) Propionyl-CoA is ultimately converted to
succinyl-CoA via three enzymatic steps
2a
2b
2c
2d
1a
2e
1b
3
Val Breakdown  Succinyl-CoA
Valine
1
Val is broken down into succinyl-CoA via a series of
complex enzyamtic reactions:
(1) Branched-chain aminotransferase transaminates
valine to -ketoisovalerate using -ketoglutarate as
an amino group donor
-Ketoisovalerate
2
Isobutyryl-CoA
3
(2) Branched-chain -Keto acid dehydrogenase catalyzes
oxidative decarboxylation of -ketoisovalerate to
isobutyryl-CoA using NAD+ as an electron acceptor
4
(3) Acyl-CoA dehydrogenase oxidizes isobutyryl-CoA to
methylacrylyl-CoA using FAD as an electron acceptor
(4) Methylacrylyl-CoA is then degraded to propionyl-CoA
via a series of four enzymatic reactions
(5) Propionyl-CoA is finally converted to succinyl-CoA via
three distinct enzymatic steps
R1 = —CH3
R2 = —CH3
5
Ile Breakdown  Succinyl-CoA
Ile breakdown into succinyl-CoA also follows a series of
complex enzymatic reactions (with the first three steps
being essentially the same as those noted for the
breakdown of Val):
Isoleucine
1
R1 = —CH3
R2 = —CH2—CH3
-Keto- -methylvalerate
2
(1) Branched-chain aminotransferase transaminates
isoleucine to -keto- -methylvalerate using ketoglutarate as an amino group donor
3
(2) Branched-chain -Keto acid dehydrogenase catalyzes
oxidative decarboxylation of -keto- -methylvalerate
to -methylbutyryl-CoA using NAD+ as an electron
acceptor
4
-Methylbutyryl-CoA
(3) Acyl-CoA dehydrogenase oxidizes -methylbutyryl-CoA
to tiglyl-CoA using FAD as an electron acceptor
(4) Tiglyl-CoA is then degraded to propionyl-CoA via a
series of three enzymatic reactions
(5) Propionyl-CoA is finally converted to succinyl-CoA via
three distinct enzymatic steps
5
Leu Breakdown  Acetyl-CoA / Acetoacetate
Leucine
Leu breakdown into acetyl-CoA and acetoacetate
proceeds via a series of complex enzymatic reactions
(with the first three steps being essentially the same as
those noted for the breakdown of Val and Ile):
(1) Branched-chain aminotransferase transaminates
leucine to -ketoisocaproic acid using -ketoglutarate
as an amino group donor
1
-Ketoisocaproic acid
2
Isovaleryl-CoA
3
(2) Branched-chain -Keto acid dehydrogenase catalyzes
oxidative decarboxylation of -ketoisocaproic acid to
isovaleryl-CoA using NAD+ as an electron acceptor
4
(3) Acyl-CoA dehydrogenase oxidizes isovaleryl-CoA to methylcrotonyl-CoA using FAD as an electron acceptor
(4) -methylcrotonyl-CoA is then degraded to acetl-CoA
and acetoacetate via a series of three enzymatic
reactions
R1 = —H
R2 = —CH—(CH3)2
Lys Breakdown  Acetoacetate
Lys breakdown into acetoacetate occurs via 11
distinct steps, with each being catalyzed by an
enzyme as follows:
(1) Saccharopine dehydrogenase (reduction)
(2) Saccharopine dehydrogenase (oxidation)
(3) Amino adipate semialdehyde dehydrogenase
(4) Aminoadipate aminotransferase
(5)
-Keto acid dehydrogenase
(6) Glutaryl-CoA dehydrogenase
(7) Decarboxylase
(8) Enoyl-CoA hydratase
(9)
-Hydroxyacyl-CoA dehydrogenase
(10) Hydroxymethylglutaryl-CoA synthase
(11) Hydroxymethylglutaryl lyase
Trp Breakdown  Acetoacetate
- Trp breakdown into acetoacetate occurs via a total of 16 steps, each requiring a specific enzyme
- First four reactions convert tryptophan into 3-hydroxyanthranilate
- 3-Hydroxyanthranilate is then degraded to -ketoadipate via five reactions
-
-Ketoadipate is broken down into acetoacetate via seven reactions as noted for Lys breakdown
Phe/Tyr Breakdown  Fumarate / Acetoacetate
- Breakdown of Phe involves its hydroxylation into Tyr (Step 1)
- Tyr then undergoes transamination to p-hydroxyphenylpyruvate (Step 2)
- P-Hydroxyphenylpyruvate is then broken down into fumarate and acetoacetate
via three distinct reactions (Steps 3-5)
Exercise 3.4c
- Describe the two general metabolic fates of the carbon skeletons
of amino acids
- List the seven metabolites that represent the end products of
amino acid catabolism. Which are glucogenic? Which are
ketogenic?
- Which amino acids can be broken down into the Krebs cycle
intermediates?
- Which amino acids can be broken down into pyruvate?
- Which amino acids can be broken down into acetyl-CoA and/or
acetoacetate?