Lecture - II

1. Most of the fatty acids in triacylglycerols and

phospholipids of animals and plants are unsaturated.

2. An unsaturated fatty acid is one in which there is at least

one double bond.

3. Two types:

a. Monounsaturated fatty acid (MUFA) – with 1 double bond

b. Polyunsaturated fatty acid (PUFA) – with > 1 double
bond

4. Almost all have cis unsaturation.

 Oleic Acid-Monounsaturated
Fatty Acid

(MUFA - cis-Δ9-Octadecenoic acid)

 1.This occurs after the 3rd round of β-oxidation.

2.The resulting cis- β, γ- double bond-containing enoyl-

CoA is not a substrate for enoyl-CoA hydratase.

3.The auxiliary enzyme – enoyl-CoA isomerase solves

this problem during the β-oxidation of MUFAs.
a . C o n v e r t s c i s - Δ 3- o r t r a n s - Δ 3- d o u b l e b o n d
(double bond between C-3 and C-4) to the more
s t a b l e , e s t e r - c o n j u g a t e d t r a n s - Δ 2- f o r m ( d o u b l e
bond between C-2 and C-3).

b . T h i s t r a n s - Δ 2- e n o y l - C o A c a n n o w b e h y d r a t e d t o
the corresponding L-3-hydroxy-acyl-CoA by the
action of the enzyme enoyl-CoA hydratase as
usual.
1. Arises in the 5th round of β-oxidation.

2. Presence of a double bond at an even-

numbered C-atom (between C-4 and C-5)
results in the formation of 2,4-dienoyl-CoA,
which is a poor substrate for enoyl-CoA
hydratase enzyme.

3. Problem solved by the combined action of

2 auxiliary enzymes – enoyl-CoA isomerase
and 2, 4-dienoyl-CoA reductase during β-
oxidation of PUFAs.
a. NADPH-dependant 2, 4-dienoyl-CoA reductase
reduces the cis-Δ4 double bond.

b. The combined action of enoyl-CoA isomerase and

2, 4-dienoyl-CoA reductase enzymes mediates
the conversion of a trans-Δ2, cis-Δ4 –dienoyl-CoA
intermediate into the trans-Δ2 enoyl-CoA
substrate necessary for β-oxidation.
Number of ATP molecules yielded is
somewhat LOWER than for the
corresponding saturated fatty acid.

Reason: Unsaturated fatty acids have

fewer hydrogen atoms, and thus fewer
electrons to be transferred via the
respiratory chain to molecular oxygen.
1. Rare

2. Found in the lipids of many plants and some marine

organisms

3. Small quantities of the 3-C propionate are added as a mold-

inhibitor in the cereals of bread, which can thus enter the
human diet

4. Cattle and other ruminants form large amounts of 3-C

propionate during the fermentation of carbohydrates in their
rumen

5. 3-C propionate is also produced by the oxidation of

branched-chain amino-acids like isoleucine, valine and
methionine
1. Long-chain, odd-numbered fatty acids are
oxidized by the same pathway of β-oxidation.

2. However, the substrate for the last pass

through the β-oxidation pathway is a 5-C fatty-acyl
CoA.

3. This 5-C acyl-CoA is subsequently cleaved into

the 3-C propionyl-CoA and 2-C acetyl-CoA.
 The Methylmalonate pathway
a. The propionyl-CoA is not a suitable substrate
for TCA-cycle oxidation.

b. So, it has to be converted to succinyl-CoA for

entry into the citric acid cycle in a pathway called
methylmalonate pathway.
It helps the thioester (-COSCoA) moiety to migrate
from C-2 to C-3 in exchange for a hydrogen atom.
This results in the unusual isomerisation of L-
methylmalonyl-CoA to succinyl-CoA via an
intramolecular rearrangement.

Intramolecular rearrangement
C-C-C C-C-C

C C
1. Propionic acidemia
Propionyl CoA carboxylase is non-
functional; so, propionyl CoA is converted
into propionic acid, which builds up in the
bloodstream and causes a build-up of
dangerous acids and toxins, which can
cause damage to the brain, heart, and liver,
cause seizures, and delays to normal
development like walking and talking.
2. Pernicious anaemia
Occurs in individuals with a deficiency of
v i t a m i n B 12; t y p e o f m e g a l o b l a s t i c a n e m i a s ;
caused by loss of gastric parietal cells,
which are responsible, in part, for the
secretion of intrinsic factor, a protein
essential for subsequent absorption of
vitamin B 12 in the ileum; there are
decreased numbers of red blood cells, low
hemoglobin levels, and progressive
neurological deterioration.
3. Methylmalonic acidemia

Vitamin B 12 is needed for the

conversion of methylmalonyl-CoA to
Succinyl-CoA by methylmalonyl-CoA
mutase. Mutations leading to defects
i n v i t a m i n B 12 m e t a b o l i s m o r i n i t s
transport frequently result in the
development of methylmalonic
acidemia.
a. The succinyl-CoA formed from
propionyl-CoA cannot undergo net
degradation by the citric acid cycle
enzymes alone.

b. So, there is a conversion of succinyl-

CoA to pyruvate via succinate, fumarate
and malate

c. This pyruvate then enters TCA cycle

through acetyl-CoA.
1.The propionyl-CoA may also form
acetyl-CoA by the β-hydroxy-propionate
pathway.

2. Ubiquitous in plants, which have no

vitamin B 12 functional co-enzymes to
convert propionyl-CoA to succinyl-CoA.

3.The acetyl-CoA so formed is further

oxidized through the TCA cycle.
Acetoacetate Acetone

B-hydroxybutyrate
1. In the liver and kidney mitochondria.

2. Entry of acetyl-CoA, generated out

of fatty-acid oxidation, in the TCA-
cycle depends on the availability of
oxaloacetate generated out of
carbohydrate degradation
to form the condensation product
citrate.

3. But, if fat breakdown predominates,

then acetyl-CoA undergoes a different
fate.
1. If the carbohydrate is not available or improperly utilised, then
there is hardly any formation of oxaloacetate.

So, an excess of acetyl-CoA remains uncondensed.

2. In fasting, starvation and diabetes mellitus, all the oxaloacetate is

utilised in the formation of glucose by gluconeogenesis, and hence
becomes unavailable for condensation with acetyl-CoA to form the
usual citrate and enter the TCA cycle.

Under these conditions, acetyl-CoA remaining in excess is

diverted to form ketone bodies by the process of ketogenesis.
a. Because individuals with untreated
diabetes mellitus or ketosis produce
large quantities of acetoacetate, their
blood contains significant amounts of
acetone, which is toxic.

b. Acetone is volatile, and imparts a

characteristic sweet odor to their
breath, which is sometimes useful in
diagnosing diabetes.
1. After ketogenesis, ketone bodies
diffuse from the liver and kidneys into the
blood, from where they are transported to
the extra-hepatic peripheral tissues, like
skeletal muscles, cardiac muscles, renal
cortex and adipose tissues, for use as
alternative fuels.

2. In the extra-hepatic tissues,

acetoacetate and D-3-hydroxy-butyrate
are converted to acetyl-CoA, which enters
the TCA cycle and get oxidized to liberate
metabolic energy.
D-ßhydroxybutyrate

Acetoacetate

Acetoacetyl-CoA
a. The concentration of ketone-bodies in
b l o o d i s m a i n t a i n e d a r o u n d 1 m g d l -1.

b. However, during severe starvation,

fasting and untreated diabetes mellitus,
ketone bodies are overproduced.
1a. Accumulation of ketone bodies – acetone, acetoacetate
and D-3-hydroxy-butyrate is termed ‘ketosis’.

b. Ketosis includes two abnormal situations –

‘ketonemia’ = higher than normal quantities of ketone

bodies present in the blood of untreated diabetics, and

‘ketonuria’ = higher than normal quantities of ketone bodies

present in the urine of untreated diabetics.

c. Ketonuria follows ketonemia. (K e t o a c i d o s i s )

 Condition Urinary excretion Blood concentration
(mg 24h-1) (mg 100ml-1)

Normal < than or equal to <3

125

Extreme ketosis 5000 90

(untreated
diabetics)
a. Lowering of blood pH due to rise in the blood-
levels of the keto-acids - acetoacetate and D-3-
hydroxy-butyrate is termed ‘acidosis’.

b. Both acetoacetate and D-3-hydroxy-butyrate are

strong acids. Therefore, increase in their
concentrations in blood would cause acidosis. The –
COOH group has a pKa around 4. Therefore, the
ketone bodies in blood dissociate and release
protons, which lower the blood pH.

c. Extreme acidosis can lead to coma, and in some

cases death, if not treated.
An abnormal medical condition that
involves both ketosis and acidosis
is collectively termed
‘ketoacidosis’.
 Treatment of overproduction of
ketone bodies

1.Rapid treatment of diabetic ketoacidosis

is required to correct the metabolic
abnormalities, and the associated water
and electrolyte imbalance.

2.Administration of insulin is necessary to

stimulate glucose-uptake by tissues and
inhibition of ketogenesis.
 Prevention of overproduction of
ketone bodies

In individuals on very low-calorie diets,

using the fats stored in adipose tissue as
their major energy source, levels of ketone
bodies in the blood and urine must be
monitored to avoid the dangers of
ketoacidosis.