L bio10 Fatty acid biosynthesis.pptx

AL AZHAR UNIVERSITY
Faculty of Medicine for Girls
Year 2-Semester 4
Academic year: 2022 / 2023
Nutrition and Metabolism Module
Course code: IMP 07- 20425
Credit hours: 3 hrs.
Duration :3 weeks
Biochemistry Department
Lecture
Fatty acid biosynthesis
Prof. Hasnaa Sayed

OBJECTIVES
• On completion of this lecture ,the student will be able to:
• 1-Define De novo synthesis of saturated fatty acid ( palmitic acid).
• 2-Explain enzymes of the De novo synthesis of fatty acid .
• 3-Mention the major sources of NADPH+H for cytoplasmic fatty acid synthesis .
• 4-Point out steps of synthesis of saturated fatty acid ( palmitic acid).
• 5-Illstrate how acetyl CoA is transported from mitochondria to the cytoplasm .
• 6-Explain the biochemical importance of acetyl CoA carboxylase .
• 7-Outline the equation of synthesis of palmitic acid from acetyl CoA &malonyl CoA
• 8-Explain regulation of fatty acid synthesis .
• 9-Outline the fate of palmitic acid .
• 10-Differentiate between microsomal and mitochondrial elongation of fatty acids .
• 11-Explain the Synthesis of unsaturated fatty acids.

Fat Fatty acid synthesis
The major fatty acid synthesized in the body is the palmitic acid (16 C).
Stearic acid (18 carbon) is formed by elongation of palmitic acid.
Synthesis of fatty acids include two pathways:
(1) De novo synthesis by extramitochondrial or cytoplasmic system (the major
system).
(2) Two elongation pathways:
(a)Microsomal pathway for elongation (major pathway) of fatty acids in
smooth endoplasmic reticulum.
.
(b)Mitochondrial pathway (minor pathway) for elongation of the FA.

De novo synthesis of palmitic fatty acid
(cytoplasmic pathway):
 DE novo synthesis of fatty acids is the formation
of palmitic acid from acetyl Co A subunits
produced from a number of different pathways
within the cell most commonly from carbohydrate
metabolism (oxidation of glucose).
 Carbohydrates and protein obtained from the diet
in excess of the body's needs for these
compounds can be converted to fatty acids,
which are stored as triacylglycerols .

Site: In many tissues including liver, brain, lung, Kidney, intestine ,
lactating mammary glands and adipose tissue.
Intracellular location: cytoplasm.
Condition: Well fed state.
Product: Palmitic acid (16 carbon).
Requirements:
A-Enzymes of fatty acid synthesis are:
1. Acetyl CoA carboxylase (ACC): used to form malonyl CoA from acetyl CoA.
2. Fatty acid synthase enzyme:
 It is a multienzyme complex. It is formed of two identical polypeptide chains (a dimmer)
each subunit is called monomer. Each monomer contains:
a. 7 enzymes.
b. Acyl carrier protein (ACP)
c. Two SH groups one on each terminus: one from pantothenic acid of ACP and the other
from cysteine of Ketoacyl synthase enzyme.
. The 2 monomers are arranged antiparallel( head to tail) so the –SH group of ACP of one
monomer is very close to the –SH group provided by 3 -ketoacyl synthase of the other
monomer
•.Fatty acid synthase can synthesize two fatty acids at the same time.

B. Two substrates:
.Cytoplasmic Acetyl CoA. It is the source of carbon atoms in fatty acid (The
building unit). Acetyl CoA is synthesized in the mitochondria from:
1-Oxidative decarboxylation of pyruvate (major source)
2- Catabolism of certain amino acids ( Leucine, Isoleucine, Lysine and
Tryptophane)
. Malonyl CoA from acetyl CoA by acetyl CoA carboxylase
C- Coenzymes and cofactor:
.NADPH as a reducing equivalent needed for the reductive reactions in the
pathway of fatty acid synthesis.
.Biotin needed by Acetyl CoA carboxylase enzyme .
.Mn++: Cofactor for ACC enzyme.
D- ATP as a source of energy.
E. HCO3- as a source CO2.

Major sources of NADPH+H for cytoplasmic fatty acid
synthesis :
1. Hexose monophosphate pathway is the major supplier of
NADPH for fatty acid synthesis.
2. Conversion of malate to pyruvate+ CO2 by malic enzyme
(NADP+ dependent malate dehydrogenase) in adipose
tissue:

3.Conversion of isocitrate to -ketoglutarate + CO2 by cytoplasmic
isocitrate dehydrogenase

Steps of synthesis of saturated fatty acid ( palmitic acid):
De novo synthesis of saturated fatty acid mainly palmitic acid
occurs in 3 steps:
I. Transport of acetyl CoA from mitochondria to cytoplasm by citrate
shuttle.
II.Carboxylation of acetyl CoA to Malonyl CoA by ACC enzyme.
 III. Synthesis of palmitic acid by fatty acid synthase enzyme

1.Transport of acetyl CoA from mitochondria to cytoplasm:
 All enzymes of fatty acid synthesis are present in cytoplasm but
mitochondrial membrane is impermeable to Acetyl CoA .
 Acetyl CoA is unable to traverse inner mitochondrial membrane
so it requires a special mechanism to be transported across inner
mitochondrial membrane. This mechanism is called citrate
shuttle.
Citrate shuttle:
1. Citrate is formed by condensation of Acetyl-CoA with
Oxaloacetate within mitochondria by citrate synthase citrate.
2. Citrate is translocated into the extra-mitochondrial compartment
via the tricarboxylic acid transporter.
3. In cytoplasm citrate undergoes cleavage, into acetyl CoA and
oxaloacetate by citrate lyase, in the presence of CoA and ATP.

II. Carboxylation of acetyl CoA to Malonyl CoA by ACC
enzyme.

2020-2021
Lecture (bio 4) Fatty acid biosynthesis

1-Step [1 ] is catalyzed by acyl transacylase enzyme
2--Step [3 ] is catalyzed by malonyl transacylase enzyme.
3--Step [4 ] is catalyzed by 3-ketoacyl synthase enzyme.
4-Step [5 ] is catalyzed by 3-ketoacyl reductase enzyme.
5-Step [6 ] is catalyzed by hydratase enzyme.
6-Step [7 ] is catalyzed by Enoyl reductase enzyme.
7- The sequence of reactions (from 3 : 7 )is repeated 6 more times to produce
fatty acids 6,8,10 ,12 ,14 and finally 16 carbons ( palmitic acid ).
8-Free palmitate is formed by thioesterase enzyme .

III.Synthesis of palmitic acid by fatty acid synthase
complex are:

.
Regulation of fatty acid synthesis:
 Acetyl CoA carboxylase is the key enzyme & the step is the
committed step. The enzyme is regulated by:
I. Short term regulation by:
1. Allosteric regulation:
 Allosteric activation of ACC: by citrate in well fed state.
. Allosteric inhibition of ACC: by long-chain fatty acyl CoA (the end
product of the pathway or feedback inhibition) .
-Along-chain fatty acyl CoA also causes an inhibition of pyruvate
dehydrogenase complex thus regulating the availability of Acetyl-CoA
for fatty acid synthesis.

2. Covalent modification: Regulation by phosphorylation and
dephosphorylation:
 In well fed state insulin is released  dephosphorylation
and activation of ACC .
 In fasting state, epinephrine and glucagon are released 
phosphorylation and inactivation of ACC.

3. Substrate availability: Increase CHO feeding  insulin
secretion leading to:
 i.  of glucose oxidation   Pyruvate acetyl CoA and
oxaloacetate .
 ii.HMP  NADPH+H.
 iii.ATP.

II. Hormonal regulation (Long term regulation) by:
1. Insulin hormone induce synthesis of ACC and fatty acid synthase
enzymes so high carbohydrate diets  excess insulin  increase in ACC
synthesis.
2. Anti-insulin hormones, glucagon and epinephrine during fasting  inhibit
ACC thus inhibit lipogenesis
3. Lipogenesis is also regulated by:
Prolactin hormone during lactation  increase synthesis of Fatty acid
synthase complex.
4. The Fatty Acid Synthase Complex & Acetyl-CoA Carboxylase Are Adaptive
Enzymes
These enzymes adapt to the body's physiologic needs via changes in gene
expression which lead to increases in total amount present in the fed state and
decreases during intake of a high-fat diet and in conditions such as starvation,
and diabetes mellitus.

Elongation of palmitic fatty acid:
Palmitic acid (the primary end product of fatty acid synthase activity) can
be further elongated by the addition of two-carbon units to carboxylate end to
form longer chain fatty acids by system of separate enzymes.
There are two systems for elongation:
1. Microsomal: It is the most active system (major pathway) :
Intracellular location: the smooth endoplasmic reticulum .
Elongation is done by addition of two carbon units from malonyl CoA and
NADPH is utilized.
Importance of microsomal elongation
The brain has the ability to produce the very-long-chain fatty acids (over 22
carbons) that are required for synthesis of brain lipids.
2. Mitochondrial: It is rare, acetyl CoA is the two-carbon donor and NADH
supplies the electrons. It is actually reverse of β oxidation of fatty acids .

Synthesis of unsaturated fatty acids
 Unsaturated fatty acids are either one double bond (monounsaturated) or
more than one double bond (polyunsaturated).
 Desaturation of saturated fatty acids means introduction of double bond
through the saturated chain by desaturase systems in the endoplasmic
reticulum.
 The human body can synthesize monounsaturated fatty acids because the
body has their desaturases.
 The two most common monounsaturated fatty acids are palmitoleic and
oleic fatty acids.
 They can be formed by desaturase system which is formed of:
 1. Δ9 desaturase enzyme in the endoplasmic reticulum.
 2. NADH.
 3. Cytochrome b5.
 The double bond is typically inserted between carbons 9 and 10 of stearic
acid to produce oleic (18:1(9) and between carbons 9 and 10 of palmitic
acid to produce palmitoleic (16:1(9) .

II. Synthesis of polyunsaturated fatty acids
 Human body has 9, 6, 5 and 4 desaturases.
 The body lack the ability to introduce double bonds after carbon 10
to the ω end of the chain. Therefore, the polyunsaturated linoleic
(18:2 (9,12)) and α linolenic (18:3(9,12,15)) fatty acids can’t be
synthesized in the body considered as essential fatty acids.
 Arachidonic acid is the only polyunsaturated fatty acid which can be
synthesized in the body from linoleic acid. It is formed by
desaturation, elongation and desaturation again of linoleic acid.

Formative Assessment
MCQ
•
1 – The end product of cytosol fatty acid synthase in humans is:
A) Oleic acid B) Linoleic acid
C) Palmitic acid D) Arachidonic acid
•

References
1. Lippincott's illustrated review (7thEdition), Lippincott,
2017,Philadelphia.
2. Harper’s illustrated biochemistry,31th Edition, by McGraw
Hill Education. 2018, New York.
3. Medical biochemistry for second year medical students,
Volume II by members of biochemistry department under
supervision of Professor Hoda Elkholy, biochemistry
department, Faculty of medicine for Girls, Al-Azhar
University , 2020, Cairo.

L bio10 Fatty acid biosynthesis.pptx

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