CHAPTER 21

Lipid Biosynthesis
Key topics:
Biosynthesis of fatty acids and eicosanoids
Biosynthesis of isoprenes and cholesterol
Cholesterol regulation
Biosynthesis of triacylglycerols, and membrane
lipids

Lipids Fulfill a Variety of

Biological Functions

Storage of energy
Constituents of cellular membranes
Anchors for membrane proteins
Cofactors for enzymes
Signaling molecules
Pigments
Detergents
Transporters
Antioxidants

Catabolism and Anabolic of Fatty

Acids Proceed via Different
Pathways
Catabolism of fatty acids
produced acetyl-CoA
reducing power to NADH
location: mitochondria

Anabolism of fatty acids

requires malonyl-CoA and acetyl-CoA
reducing power from NADPH
location: cytosol in animals, chloroplast in plants

Lipid Catabolism and Anabolism in

Animal and Plant Cells

Overview of Fatty Acid Synthesis

Fatty acids are built in
several passes
processing one acetate
unit at a time
Acetate from activated
malonate in the form of
malonyl-CoA
In each pass involves
reduction of a carbonyl
carbon to a methylene
carbon

Overview of Fatty Acid Synthesis

Synthesis of Malonyl-CoA (1)

The three-carbon precursor for fatty
acid synthesis is made from acetylCoA and CO2
The reaction is catalyzed by acetylCoA carboxylase (ACC)
ACC is a bifunctional enzyme
Biotin carboxylase
Transcarboxylase

ACC contains biotin, natures carrier

of CO2
Biotin shuttles between the two active
sites

Synthesis of Malonyl-CoA (2)

Bicarbonate reacts with
the terminal phosphate of
ATP to give carbamoyl
phosphate
Biotin carries out a
nucleophilic attack to
carbamoyl phosphate
The product is a good
donor of a carboxylate
group

Synthesis of Malonyl-CoA (3)

The arm swing moves
carboxybiotin to the
transcarboxylase site
Terminal methyl of acetylCoA probably
deprotonates to give a
resonance-stabilized
carbanion
The carbanion picks up
the carboxylate moiety
from biotin

Fatty Acid Synthesis

Overall goal is to attach a two-carbon acetate unit from
malonyl-CoA to a growing chain and then reduce it
Reaction involves cycles of four enzyme-catalyzed steps
Condensation of the growing chain with activated acetate
Reduction of carbonyl to hydroxyl
Dehydration of alcohol to trans-alkene
Reduction of alkene to alkane

The growing chain is initially attached to the enzyme via a

thioester linkage
During condensation, the growing chain is transferred to the
acyl carrier protein
After the second reduction step, the elongated chain is
transferred back to fatty acid synthase

Acyl Carrier Protein

Contains a covalently attached
prothetic group 4-phosphopantethiene
The acyl carrier protein delivers
acetate (in the first step) or
malonate (in all the next steps) to
the fatty acid synthase
The acyl carrier protein shuttles the
growing chain from one active site
to another during the four-step
reaction

Charging the Acyl Carrier Protein

and Fatty Acid Synthase
Two thiols participate in the fatty acid synthesis
Thiol from 4-phosphopantethine in acyl carrier protein
Thiol from cysteine in fatty acid synthase

Both thiols must be charged for the condensation

reaction to occur
In the first step, acetyl from acetyl-CoA is transferred to acyl
carrier protein
Acyl carrier protein passes this acetate to fatty acid synthase
Acyl carrier protein is then re-charged with malonyl from
malonyl-CoA

Assimilation of
Two-Carbon Units
Condensation and
First Reduction
1 Condensation of an
activated acyl group
2 the -keto group is
reduced to an alcohol

Assimilation of TwoCarbon Units

Dehydration and
Second Reduction
3 elimination of H2O
creates a double
bond, and
4 the double bond is
reduced

Enzymatic Activities in Fatty Acid

Synthase

Condensation with acetate

-ketoacyl-ACP synthase (KS)

Reduction of carbonyl to hydroxyl

-ketoacyl-ACP reductase
(KR)

Dehydration of alcohol to alkene

-hydroxyacyl-ACP
dehydratase (DH)

Reduction of alkene to alkane

enoyl-ACP reductase (ER)

Chain transfer
Malonyl/acetyl-CoA ACP
transferase

Sequence of Events in Synthesis

of Fatty Acids

Regulation of Fatty Acid Synthesis

in Vertebrates

Insulin in
Regulation of
Fatty Acid
Synthesis

C16, C18 and of Unsaturated Fatty Acids

Animals can readily introduce
one double bond to palmitate
and stearate
Vertebrates cannot introduce
additional double bonds between
C10 and methyl-terminal
We must obtain linoleate and linolenate with diet; these are
essential fatty acids
Plants, algae, and some insects
synthesize linoleate from oleate

PC-Oleate Acts as
A Substrate for
Plant Desaturases
Oleic and
Linoleic Acids
are essential
Fatty acids

Vertebrate Fatty Acyl Desaturase

Non-Heme Iron -- Mixed Function Oxidase
O2 accepts four electrons from two substrates
Two electrons come from saturated fatty acid
Two electrons come from ferrous state of Cytochrome b5

Oxidases, Monooxygenase,
Dioxygenase
Molecular oxygen can serve as an electron acceptor
Oxidases do not incorporate oxygen atoms into the
organic product
Oxygen atoms usually end up in hydrogen peroxide
Often use flavin as redox cofactors

Monooxygenases incorporate one of the oxygen atoms

into the product
The other oxygen ends up in water
Often use iron as redox cofactor
Cytochrome P450

Dioxygenases incorporate both oxygen atoms into the

organic product

Cytochrome P450 (Monooxygenase)

Eicosanoids - Signalling functions

Prostaglandins
Gastric Mucin (Cox-1)
Inflammation, Pain Fever (Cox-2)

Thromboxanes
Blood Clotting

Leukotrienes
Signal through G-protein Coupled receptors
Asthma and Bronchodilation

Synthesis of
Eicosanoids
Cyclooxygenase is a
target for many antiinflammatory drugs

The "linear" pathway from

arachidonate to leukotrienes.

COX-2specific cyclooxygenase
inhibitors

Biosynthesis of
Cholesterol
Summary
1. Acetyl CoA => Mevalonate
2. Mevalonate => Isoprenes
3. 6 isoprenes => squalene
4. Squalene to lanosterol

1. Formation of
Mevalonate
HMG-CoA
reductase is a
target for some
cardiovascular
drugs

Formation of Activated Isoprene

Pyrophosphate is a good leaving group in these
nucleophilic substitution reactions

Formation of Squalene (1)

Formation of Squalene (2)

Ring closure
converts
squalene to
the steroid
nucleus

Cholesteryl esters.
Esters more
hydrophobic
for storage
and
transport

Human Plasma Lipoproteins

Apolipoproteins of the Human

Plasma Lipoproteins

Lipoproteins and lipid transport

LCAT on
HDL
stimulated
by apoA-I.

Receptormediated
endocytosis

Sterol regulatory element-binding

proteins (SREBPs) released in
response to membrane sterol content

Regulation of
Cholesterol
Biosynthesis
Insulin high
glucose
Glucagon low
glucose

Statins inhibit HMG-CoA reductase

Steroid hormones
derived from
cholesterol

Overview of
isoprenoid
biosynthesis

Biosynthesis of
phosphatidic acid

Phosphodiester Bond Formation

Phosphatidylglycerol (PG), Phosphatidylserine

(PS) Phosphatidylethanolamine (PE)

Cardiolipin and Phosphatidyl Inositol

PS to PE to
phosphatidylcholine (PC) in
eukaryotes

Phospholipid
synthesis
pathways:
Summary

Synthesis of ether lipids

and plasmalogens

Biosynthesis of sphingolipids

Chapter 21: Summary

In this chapter, we learned that:
Malonyl-CoA is an important precursor for biosynthesis of fatty acids
Fatty acid synthesis is carried out by a large enzyme that contains
multiple catalytic activities needed for the condensation, and
subsequent reduction of acetate units
Not all organisms can synthesize polyunsaturated fatty acids; these
that can utilize mixed function oxidases as desaturase
Cholesterol biosynthesis starts with synthesis of mevalonate from
acetate; mevalonate yields two activated isoprenes; series of
isoprene condensation steps gives squalene; oxidation and ring
closure of squalene gives cholesterol