8- fatty acids biosynthesis

(lipogenesis)
 Introduction
• Organic acids containing a long hydrocarbon chain and a
terminal carboxyl group .
• They exist free in the body as well as fatty acyl esters in
more complex molecules such as triglycerides or
phospholipids .
• Fatty acids can be oxidized in all tissues, particularly
liver and muscle to provide energy.
• They also structural component of membrane lipids such
as phospholipids and glycolipids.
• Esterified fatty acids, are stored in adipose cell.
• Fatty acids are also precursors of Ecosanoids.
Structure and classification
 Sources of fatty acids :
• Diet

• Adipolysis (lipolysis)

• De novo synthesis (from precursors) –

carbohydrates ,protein, and other molecules obtained
from diet in excess of body's need can be converted to
fatty acids, which are strored as triglycerides.
 Fatty acid biosynthesis

• Cellular location : cytoplasm

• Site : liver , kidney , brain , lung , mammary gland and adipose tissue.

• Substrate : acetyl –co A

• End product : free palmetate (16-C plasmatic acid ), which can be

elongated /shortened with / without destruction to synthesize differ
types of FA as per body need .
• Cofactors requirement include : NADPH2, ATP,Mn2+ , biotin-
Vit.7 And acetyl Co A (as source of CO2)
Two things are require for de novo fatty acids synthesis:
1- a source of reducing equivalent , specifically NADPH.
2- sources of carbon , specifically acetyl-co A.
( de novo synthesis = (from the beginning) refers to synthesis of a complex molecules
from simple molecules ,as opposed to recycling after degradation )

Sources of NADPH
NADPH is a donor of reducing equivalent (equal).
The oxidative reactions of the pentose phosphate pathway are the main
source of the hydrogen require in the reductive synthesis of fatty acids .
NADPH and CO2 are generated in this reaction , both of them are
utilized for fatty acid synthesis. also NADPH formed during conversion
of malate to pyruvate by malic enzyme ,and others.
 2- Sources Acetyl-coA and its fate

•Acetyl-co A , the precursor for fatty acid synthesis is produced

from pyruvate, ketogenic amino acids ,fatty acid oxidation and by
alcohol metabolism.
•Its substrate for TCA cycle and precursor for fatty acids, ketene
bodies.
 Steps of fatty acid biosynthesis
1-Transportation of acetyl –Co A
• The first step in de novo fatty acid synthesis is the transfer
of acetate units from mitochondrial acetyl CoA to the
cytosol.
• Fatty acids synthesis requires considerable amounts of
acetyl –Co A,
• Nearly all acetyl -Co A used in fatty acids synthesis is
found in mitochondria.
• Mitochondrial acetyl CoA is produced by the oxidation of
pyruvate , and by the catabolism of fatty acids , ketone
bodies, and certain amino acids .
• Acetyl- Co A has to move out from the mitochondria to
cytosol .
• Acetate out of mitochondria as citrate ,by citrate shuttled
the mitochondrial inner membrane is impermeable to
acetyl - Co A.
• Intra- mitochondrial Acetyl- Co A first reacts with
oxaloacetate to form citrate (TCA cycle), citrate passes
into cytosol across citrate transporter . In the cytosol,
citrate is cleaved by citrate lyase regenerating Acetyl -Co
A.
• [Note: This process of translocation of citrate from the
mitochondrion to the cytosol, where it is cleaved by ATP-citrate
lyase to produce cytosolic acetyl CoA and OAA, occurs when
the mitochondrial citrate concentration is high. This is observed
when isocitrate dehydrogenase is inhibited by the presence of
large amounts of ATP, causing citrate and isocitrate to
accumulate. Therefore, cytosolic citrate may be viewed as a
high-energy signal.]
• Because a large amount of ATP is needed for fatty acid
synthesis, the increase in both ATP and citrate enhances this
pathway.
 Fate of oxaloacetate
• The other product of citrate cleavage , oxaloacetate can
be –
- Channeled towards glucose production
- Converted to malate by malate dehydrogenase
- Converted to pyruvate by malic enzyme , producing
more NADPH , that can be used for fatty acids synthesis
• Pyruvate and malate pass through special transporters
presents in the inner mitochondrial membrane.
Notes : NADH+H also come from Hexose monophosphate shunt (PPP)
 Extramitochondrial (cytoplasmic) synthesis of fatty
acids (De novo synthesis)
• Three stages of fatty acid synthesis:

A- production of acetyl -Co A & NADPH

B- conversion of acetyl -Co A to malonyl -Co A

C- reaction of fatty acid synthase complex

 Enzymes and cofactors
• Two main enzymes :
1. Acetyl –CoA carboxylase
2. Fatty acid synthase
Both the enzymes are multienzyme complexes (composed of two or
more enzymes that function in a biosynthetic pathway)
• Coenzymes and cofactors
1. Biotin (B7)
2. NADPH
3. Mn++
4. Mg++
 Details of enzymes
• Acetyl – CoA carboxylase : is the initial & controlling step
in fatty acid synthesis
• Multienzyme complex containing
 Biotin
 Biotin carboxylase
 Biotin carboxyl carrier protein
 Transcarboxylase
 A regulatory allosteric site
Notes : allosteric enzymes: are enzymes that change their
conformational ensemble upon binding of an effector.
Allosteric regulation: is a regulation of an enzyme by binding
an effector molecule at a site other than enzyme active site .
 Details of enzymes
• fatty acid synthase complex: polypeptides containing seven
enzymes activities
• in mammals, the fatty acid synthase complex is a dimer containing all
seven enzyme activities of fatty acid synthase on one polypeptide
chain .
• Advantage of multienzyme complex :
- Intermediates of the reaction can easily interact with the active sites of
the enzyme
- One gene codes all enzymes
- The efficiency of the process enhanced
 Steps of fatty acid synthesis
Step -B : Carboxylation of Acetyl CoA
The input to fatty acid synthesis is acetyl –CoA ,which is carboxylated
to Malonyl - CoA ,Enzyme: acetyl CoA carboxylase , Prosthetic
group - biotin , ATP dependent .

The CO2 group in carboxybiotin is transferred to acetyl CoA to form

malonyl CoA.
Acetyl CoA carboxylase is the regulatory enzyme.
HCO3+ATP+acetyl-CoA ADP +Pi + malonyl -
CoA
Prosthetic group : a non-protein group forming part of or combined with a protein.
Fatty acid synthase prosthetic groups:
1- the thiol (-SH) of the side chain of a cysteine residue of keto acyl
synthase enzyme (KS) (also called condensation enzyme) .
2- the thiol (-SH) of phosphopantetheine , it’s a component of acyl
carrier protein .
Step C : The Reactions of Fatty Acid Synthesis
 Assembly of a long chain fatty acid
• Once malonyl- CoA is synthesized , long carbon fatty acid chain
may be assembled in a repeating 3 step sequence.
• The four separate stages after loading of precursors via thioester
derivatives
(1) Condensation of the precursors
(2) Reduction
(3) Dehydration
(4) Reduction
• With each passage through the cycle the fatty acyl chain is
extended by two carbon.
• Three steps (2,3and4)are repeated till a fatty acid with 16 carbon
atoms is synthesized .
• When chain reaches 16 carbons , the product palmitate (16:0)
leaves the cycle
It is liberated from the enzyme complex by the activity of seventh
enzyme in the complex Thoesterase (deacylase) .
 The overall equation for palmitic
acid biosynthesis starting from
acetyl-S-CoA:

8 Acetyl—S—CoA + 14NADPH + 14H+ + 7ATP

+ H2O palmitic acid + 8CoA + 14NADP+ +
7ADP + 7P.
It is not a reversible