Gandham.

Rajeev
Email:[email protected]
 Beta-Oxidation may be defined as the
oxidation of fatty acids on the β-carbon atom.
 This results in the sequential removal of a two
carbon fragment, acetyl CoA.
 Three stages
 Activation of fatty acids - in the cytosol
 Transport of fatty acids into mitochondria
 Beta-Oxidation proper in the mitochondrial
matrix
 Fatty acids are oxidized by most of the
tissues in the body.
 Brain, erythrocytes & adrenal medulla cannot
utilize fatty acids for energy requirement.
 Fatty acid activation taking place in cytoplasm.
 Fatty acids are activated to acyl CoA by
thiokinases or acyl CoA synthetases.
 The reaction occurs in two steps & requires
ATP, coenzyme A and Mg2+
 Fatty acid reacts with ATP to form
acyladenylate which then combines with
coenzyme A to produce acyl CoA.
 Two high energy phosphates are utilized,
since ATP is converted to pyrophosphate (PPi).
 The enzyme inorganic pyrophosphatase
hydrolyses PPi to phosphate.
 The immediate elimination of PPi makes this
reaction totally irreversible.
 Three different enzymes, one each for short
chain, medium chain & long chain fatty acids.
 Small chain fatty acids may also be activated
by thiophorase enzyme, using succinyl CoA.
 R-CH2-CH2-COO-
Fatty Acid
ATP
Thiokinase
PPi Pyrophosphatase
2Pi
O
R-CH2-CH2-C-AMP
Acyladenylate
CoASH
AMP
O
R-CH2-CH2-C-CoA
Acyl CoA
 The inner mitochondrial membrane is
impermeable to fatty acids.
 A specialized carnitine carrier system (carnitine
shuttle) operates to transport activated fatty
acids from cytosol to the mitochondria.
 Carnitine is β-hydroxy γ-trimethyl
aminobutyrate, synthesized by lysine &
methionine in liver & kidney.
o It occur in four stages.
1. Acyl group of acyl CoA is transferred to
carnitine catalyzed by carnitine
acyltransferase I (CAT-I) (present on the outer
surface of inner mitochondrial membrane).
2. The acyl-carnitine is transported across the
membrane to mitochondrial matrix by a
specific carrier protein (Translocase).
3. Carnitine acyltransferase ll (CAT-II) (found on
the inner surface of inner mitochondrial
membrane) converts acyl-carnitine to acyl
CoA.
4. The carnitine released returns to cytosol for
reuse by translocase.
 Inner
Mitochondrial Mitochondrial Matrix
Cytosol membrane

Acyl CoA Acyl CoA

Carnitine Carnitine

CAT-I Carrier
CAT-II
Protein

Acyl Acyl
CoASH
Carnitine Carnitine CoASH
 Each cycle of β –oxidation, liberating a two
carbon unit-acetyl CoA, occurs in a sequence
of four reactions
1. Oxidation
2. Hydration
3. Oxidation
4. Cleavage
 Acyl CoA undergoes dehydrogenation by an
FAD-dependent flavoenzyme, acyl CoA
dehydrogenase.
 A double bond is formed between α & β carbons
(i.e., 2 & 3 carbons)
2. Hydration:
 Enoyl CoA hydratase brings about the hydration
of the double bond to form β -hydroxyacyl CoA.
3. Oxidation
 β-Hydroxyacyl CoA dehydrogenase
catalyses the second oxidation & generates NADH.
 The product formed is β-ketoacyl CoA.
4. Cleavage
 The final reaction in β -oxidation is the liberation of
a 2 carbon fragment, acetyl CoA from acyl CoA.
 This occurs by a thiolytic cleavage catalysed by β-
ketoacyl CoA thiolase (or thiolase).
 The new acyl CoA, containing two carbons
less than the original, reenters the β-
oxidation cycle.
 The process continues till the fatty acid is
completely oxidized.
β-Oxidation of fatty acids

R – CH2 – CH2 – CH2 – C – O-

Fatty acid

ATP
CoASH
Mg+2 Thiokinase
ADP + PPi
O

R – CH2 – CH2 – CH2 – C –SCoA

Acyl CoA
Cytosol

Carnitine Transport system

Mitochondria
 O

R – CH2 – CH2 – CH2 – C – SCoA

Acyl CoA
SIDS
FAD
Acyl CoA
2ATP ----- ETC FADH2 Dehydrogenase
OH O

R – CH2 – CH2 CH2 – C – SCoA

Trans-enoyl CoA

H2O Enoyl CoA

Hydratase
OH O

R – CH2 – CH – CH2 – C – SCoA

β - Hydroxyacyl CoA
 OH O

R – CH2 – CH – CH2 – C – SCoA

Acyl CoA β - Hydroxyacyl CoA

NAD+
β-Hydroxy Acyl CoA
Dehydrogenase
3ATP ----- ETC NADH + H+
O O

R – CH2 – C – CH2 – C – SCoA TCA

β - Ketoacyl CoA Cycle

CoASH
Thiolase
O O

R – CH2 – C – SCoA CH3 – C – SCoA

Acyl CoA Acetyl CoA
 Palmitoyl CoA + 7 CoASH + 7 FAD +
7 NAD+ + 7 H2O 8 Acetyl CoA + 7
FADH2 +7 NADH + 7H+
 Palmitoyl CoA undergoes 7 cycles of β -
oxidation to yield 8 acetyl CoA.
 Acetyl CoA can enter citric acid cycle & get
completely oxidized to CO2 & H2O.
 Mechanism ATP yield

I. β- 0xidation 7 cycles
7 FADH2 [Oxidized by Electron Transport Chain (ETC) each 14
FADH2 gives 2 ATP ]

7 NADH (Oxidized by ETC, each NADH 21

Liberate 3ATP)

II. From 8 Acetyl CoA

Oxidized by citric acid cycle, each acetyl CoA 96
provides 12 ATP

Total energy from one molecule of palmitoyl CoA 131

Energy utilized for activation -2

(Formation of palmitoyl Co A)
Net yield of oxidation of one molecule of palmitate =129
 The availability of free fatty acid (FFA)
regulates the net utilisation through β-
oxidation.
 The level of FFA is controlled by
glucagon:insulin ratio.
 Glucagon increases FFA level & insulin has
the opposite effect.
 CAT-I is the regulator of entry of fatty acid
into mitochondria.
 Malonyl CoA inhibits CAT-I activity.
 Thus during de novo synthesis of fatty acid,
the beta oxidation is inhibited.
 Unexpected death of healthy infants, usually
overnight
 Due to deficiency of medium chain acyl CoA
dehydrogenase.
 Glucose is the principal source of energy, soon
after eating or feeding babies.
 After a few hours, the glucose level & its
utilization decrease & the rate of fatty acid
oxidation must simultaneously increase to
meet the energy needs.
 The sudden death in infants is due to a
blockade in β -oxidation caused by a
deficiency in medium chain acyl CoA
dehydrogenase (MCAD)
 Characterized by severe hypoglycemia,
vomiting, convulsions, coma & death.
 lt is caused by eating unriped ackee fruit-
contains an unusual toxic amino acid,
hypoglycin A.
 This inhibits the enzyme acyl CoA
dehydrogenase & β -oxidation of fatty acids is
blocked, leading to various complications
 Abnormalities in transport of fatty acids into
mitochondria & defects in oxidation leads to
deficient energy production by oxidation of long
chain fatty acids.
 Features:
 Hypoglycemia, hyperammonemia, weakness &
liver diseases.
 Acyl carnitine accumulates when the transferases
or translocase is deficient.
 Dietary supplementation of carnitine improve the
condition.
 Oxidation of odd chain fatty acids is similar
to that of even chain fatty acids.
 At the end 3 carbon unit, propionyl CoA is
produced.
 Propionyl CoA is converted into succinyl CoA.
 Succinyl CoA is an intermediate in TCA cycle
 Propionyl CoA is gluconeogenic.
 Propionyl CoA is carboxylated to D-methyl
malonyl CoA by a biotin dependent
carboxylase.
 Biotin & ATP is utilized in this step.
 Methylmelonyl CoA Recemase:
 Recemase acts upon D-methyl malonyl CoA to
give L-methyl malonyl CoA.
 This reaction is essential for the entry of this
compound into metabolic reactions of body.
 Methylmalonyl CoA Mutase:
 Mutase catalyzes the conversion of L-methyl
malonyl CoA (a branched chain compound) to
succinyl CoA (a straight chain compound).
 Mutase is an vitamin B12 dependent enzyme.
 Succinyl CoA enters the TCA cycle, & converted
into oxaloacetate, it is used for
gluconeogenesis.
 Propionyl CoA is also derived from
metabolism of valine & isoleucine.
 CH3 CH3
I CO2 Propionyl CoA I
CH2 carboxylase H - C- COO-
I I
CO-S-CoA Biotin CO-S-CoA
Propionyl CoA ATP ADP + Pi D-methyl malonyl CoA

Methylmalonyl
CoA recemase
COO-
I
TCA
CH2
I Methylmalonyl CH3
CH2 CoA mutase I
-OOC – C - H
I
CO-S-CoA Vitamin B12 I
Succinyl CoA CO-S-CoA
L - methyl malonyl CoA
 Propionyl CoA carboxylase deficiency:
 Characterized by propionic acidemia,
ketoacidosis & developmental abnormalities.
 Methyl malonic aciduria:
 Two types of methyl malonic acidemias
 Due to deficiency of vitamin B12
 Due to defect in the enzyme methyl malonyl
CoA mutase or recemase.
 Accumulation of methyl malonic acid in body.
 Methyl malonic acid is excreted into urine.
 Symptoms:
 Severe metabolic acidosis, damages the
central nervous system & growth retardation.
 Fatal in early years of life.
 Treatment:
 Some patients respond to treatment with
pharmacological doses of B12.
 Oxidation of fatty acids on α-carbon atom is
known as α-oxidation.
 In this, removal of one carbon unit from the
carboxyl end.
 Energy is not produced.
 No need of fatty acid activation & coenzyme A
 Hydroxylation occurs at α-carbon atom.
 It is then oxidized to α-keto acid.
 This, keto acid undergoes decarboxylation,
yielding a molecule of CO2 & FA with one
carbon atom less.
 Occurs in endoplasmic reticulum.
 Some FA undergo α - oxidation in
peroxisomes.
 α- oxidation is mainly used for fatty acids
that have a methyl group at the beta-carbon,
which blocks beta- oxidation.
 Major dietary methylated fatty acid is
phytanic acid.
 It is derived from phytol present in
chlorophyll, milk & animal fats.
 Due to deficiency of the enzyme α-
hydroxylase (phytanic acid oxidase)
 α – oxidation does not occur.
 Phytanic acid does not converted into
compound that can be degraded by beta –
oxidation.
 Phytanic acid accumulates in tissues.
 Severe neurological symptoms,
polyneuropathy, retinitis pigmentosa, nerve
deafness & cerebellar ataxia.
 Restricted dietary intake of phytanic acid
(including milk-is a good source of phytanic
acid)
 Minor pathway, takes place in microsomes.
 Catalyzed by hydroxylase enzymes involving
NADPH & cytochrome P-450.
 Methyl (CH3) group is hydroxylated to CH2OH &
subsequently oxidized with the help of NAD+ to
COOH group to produce dicarboxylic acids.
 When β-oxidation is defective & dicarboxylic acids
are excreted in urine causing dicarboxylic aciduria.
 It is a rare disorder.
 It is characterized by absence of
peroxisomes in almost all the tissues.
 Long chain fatty acids are not oxidized.
 Long chain fatty acids are accumulated in
tissues-mainly brain, liver & kidney.
 It also known as cerebrohepatorenal
syndrome.
 Textbook of Biochemistry-U Satyanarayana

 Textbook of Biochemistry-DM Vasudevan