Beta oxidation and fattyacid synthesis B.Pharmacy 2nd Semester 2022 (2021-2022) Previous Year's Question Papers/Notes Download - HK Technical PGIMS

Lipid Metabolism
Introduction:
Oils and fats are major energy reserves of living beings. They are also known as triacylglycerols.
They are hydrolyzed in cytoplasm by lipases to give glycerol and fatty acids. The glycerol formed enters
the glycolytic pathway by being converted to dihydroxyacetone phosphate. Each fattyacid is converted
into the corresponding acyl coenzyme-A and transported into the mitochondrial matrix where it is
degraded. Fatty acids are oxidized mainly by beta-oxidation.
Beta-oxidation pathway for saturated fatty acids with even number of carbon atoms:
Beta-Oxidation is defined as the oxidation of fatty acids on the beta-carbon atom. In betaoxidation, fatty acids are degraded by the sequential of two carbon fragment, acetyl CoA. Knoop
discovered beta-oxidation of fatty acids. Mitochondria is the site of beta-oxidation. Several enzymes
known collectively as fattyacid oxidase enzyme system are found in the mitochondrial matrix, adjacent
to the respiratory chain. These enzymes catalyses beta-oxidation of long chain fatty acids to acetyl CoA.
Fattyacids are oxidized by most of the tissues in the body. However, brain, erythrocytes and adrenal
medulla cannot utilize fatty acids for energy.
The beta-oxidation pathway involves three stages1. Activation of fatty acids in cytosol
2. Transport of activated fatty acids into mitochondria.
3. Beta-oxidation proper in the mitochondrial matrix.
Step: 1
The first step of beta-oxidation is the activation of fattyacid in presence of ATP dependent
Thiokinase or acyl CoA synthetase. The activation step is extramitochondrial and require coenzyme-A.
Step: 2
Activated long chain fattyacyl CoA is not permiable to mitochondrial membrane. Long chain
activated fattyacid penetrate the inner mitochondrial membrane only in combination with carnitine.
Chemical name of carnitine is beta-hydroxy gama-trymethyl ammonium glycerate.
Carnitine is considered as carrier molecule it acts as a ferryboat helps in the transportation of
long chain CoA across the mitochondrial membrane for which the enzyme carnitine acetyl
transferase is required.
(CH3)3-N+-CH2-CHOH-CH2-COOH
In this step enzyme carnitine acyl transferase-I (CAT-I) will transfer fattyacyl group to the
hydroxyl group of carnitine to form acyl carnitine this reaction occurs on the cytosolic side of
inner mitochondrial membrane.
Step: 3
Fattyacyl CoA undergoes sequence of 4 reactions, namely dehydrogenation, hydration,
oxidation and thiolytic cleavage.
As a result of these reactions, it loses two carbon fragments in the form of acetyl CoA. The
residual acyl CoA, which is now shorten by two carbon atoms, which again undergoes same
sequence of reactions till the entire long chain fatty acyl CoA broken down to acetyl CoA.
A) Dehydrogenation: Fattyacyl CoA is dehydrogenated to transenoyl CoA with the FAD
accepting the hydrogen atoms. In this step FADH2 gets oxidized in ETC to give 1.5 ATP
molecules. The enzyme involved in this reaction is FAD linked dehydrogenase.
B) Hydration: It is catalysed by enoyl CoA hydratase this step forms beta-hydroxy fattyacyl
CoA.
C) Oxidation: Beta-hydroxy fattyacyl CoA is again oxidized to form Beta -keto fattyacyl CoA by
NAD+ dependent dehydrogenase. NADH produced in this step enters into ETC to generate
2.5 ATP’s.
D) Thiolytic Cleavage : Beta-keto fattyacyl CoA now undergoes thiolytic cleavage by second CoA
molecule, forming acetyl CoA and acyl CoA which is shortened by 2 carbon atoms, this
reaction is catalysed by an enzyme called thiolase. This shortened acyl CoA molecule again
enters the beta-oxidation as in step1.
Energetics of Beta-Oxidation:
Regulation:
1. Availability of free fattyacid regulates the net utilization through beta-oxidation.
2. Glucagon enhances the free fattyacid synthesis and insulin inhibits the synthesis of free
fattyacid.
3. CAT-I regulates the entry of fattyacid into mitochondria. Malonyl CoA is the inhibitor of CAT-I
thus, during the de nevo fattyacid synthesis beta-oxidation gets inhibited.
Defects in beta-oxidation:
Abnormality in the transfer of fattyacids and beta-oxidation leads to hyperammonemia,
hypoglycemia, hypoketomia, muscle weakness and liver disease. This may leads to deficient energy
production by the oxidation of long chain fattyacds.
Acyl carnitine accumulates when the transferase or CAT-I is deficient. As a result of this fattyacids
cannot be transported to mitochondrial matrix.
Denovo synthesis of fattyacids: (Palmitic acid)
Fatty acids are mainly synthesized mainly by denovo synthetic pathway operating in the cytoplasm.
So it is referred to as extra mitochondrial or cytoplasmic fattyacid synthase system.
The major fattyacid synthesized in denovo system is palmitic acid, the 16C saturated fattyacid. The
process occurs in liver, adipose tissue, kidney, brain and mammary glands.
Steps involved in fattyacid synthesis:
Step1: Carboxylation of acetyl CoA
In this step acetyl CoA undergoes carboxylation o form malonyl CoA in the presence of an enzyme
acetyl CoA carboxylase, rate limiting enzyme. Biotin a member of beta-complex membrane is also
essential for this reaction.
Step2: Addition of 3C and 2C units:
A) Acetyl transacylase catalyses the transfer of acetyl group (2 carbons) to the cysteinyl SH group
of condensing enzyme (CE) of the other monomer of the fatty acid synthase complex.
B) One molecule of acetyl CoA (2C) and one molecule of malonyl CoA (3C) binds to the multi
enzyme complex.
C) Malonyl transacylase transfers malonyl group to the SH group of ACP (acyl carrier protein) of
one monomer of the enzyme.
Step3: Condensation
Acetyl (2C) and malonyl (3C) units are condensed to from beta-Kato acyl ACP or aceto acetyl ACP (4C).
During this process one carbon is lost as carbon dioxide. The enzyme involved is condensing enzyme (CE)
or ketoacyl synthase.
Step4: Reduction
The acetoacetyl ACP is reduced to beta-hydroxy fatty acyl ACP by NADPH dependent beta-keto acyl
reductase.
Step5: Dehydration
Beta-hydroxy fatty acyl ACP is then dehydrated to enoyl ACP which is otherwise known as alpha beta
unsaturated acyl ACP by dehydratase.
Step6: second reduction
Enoyl ACP again reduced to butyryl ACP by enoyl reductase. In this step second molecule of NADPH is
utilized to form butyryl ACP.
Cycling of Reactions:
Butyryl ACP undergoes repeated sequence of reactions namely condensation, reduction, dehydration
and reduction. Cycle’s are repeated 7 times till the 16th carbon palmitic acid is formed.
Step7: Release of Palmitic acid:
The thio-esterase or de-acyclase activity (TE) releases palimitate from multi enzyme complex.
In liver and adipose tissues, the end product is palmitic acid. But in lactating mammary glands the end
products are capric acid (10C) and lauric acid (12C).
The net reaction of denovo synthesis of fatty acid is summarized as :
1 Acetyl CoA + 7 Malonyl CoA+ 14 NADPH + 14 H + 1 Palmitate + 7 CO2+14 NADP+8 COA+6H2O