BIOCHEMISTRY. Understand how glucose is converted to fatty acid.

1. METABOLISM OF LIPIDS:
triacylglycerols, fatty acids, cholesterol and
phospholipids metabolism. Ketogenesis and
ketolysis. Regulation and pathology of lipid
metabolism. Atherosclerosis.

2. • Lipids are water-insoluble organic
biomolecules that can be extracted
from cells and tissues by nonpolar
solvents, e.g., chloroform, ether, or
benzene.

3. Classification of lipids, based on their backbone
structures:
Simple lipids:
Acylglycerols, steroids, waxes.
Complex lipids:
phospholipids
glycerophospholipids, sphingophospholipids.
glycolipids
glycosylglycerols, glycosphingolipids.

5. Triacylglycerols (Triglycerides)
• Fatty acid esters of the alcohol
glycerol are called acylglycerols
or glycerides; they are
sometimes referred to as
"neutral fats," a term that has
become archaic. When all three
hydroxyl groups of glycerol are
esterified with fatty acids, the
structure is called a
triacylglycerol:
Triacylglycerols are the most
abundant family of lipids and
the major components of depot
or storage lipids in plant and
animal cells. Triacylglycerols
that are solid at room
temperature are often referred to
as "fats" and those which are
liquid as "oils."

6. Storage and Mobilization of Fatty
Acids
• TGs are delivered to adipose tissue in the form
of chylomicrones and VLDL, hydrolyzed by
lipoprotein lipase into fatty acids and
glycerol, which are taken up by adipocytes.
• Then fatty acids are reesterified to TGs.
• TGs are stored in adipocytes.
• To supply energy demands fatty acids and
glycerol are released – mobilisation of TGs.

7. At low carbohydrate and insulin concentrations (during fasting), TG
hydrolysis is stimulated by epinephrine, norepinephrine, glucagon, and
adrenocorticotropic hormone.
TG hydro-lysis is inhibited by insulin in fed state

8. • Lipolysis - hydrolysis of
triacylglycerols by
lipases.
• A hormone-sensitive
lipase converts TGs to
free fatty acids and
monoacylglycerol
• Monoacylglycerol is
hydrolyzed to fatty acid
and glycerol or by a
hormone-sensitive lipase
or by more specific and
more active
monoacylglycerol lipase

9. Oxidation of Glycerol
• Glycerol is absorbed by the liver.
• Steps: phosphorylation, oxidation and
isomerisation.
• Glyceraldehyde 3-phosphate is an intermediate in:
• glycolytic pathway
• gluconeogenic pathways

10. Isomerase

11. ATP Generation from Glycerol Oxidation
• glycerol – glycerol 3-phosphate - 1 ATP
• glycerol 3-phosphate - dihydroxyaceton phosphate
2.5ATP (1 NADH)
• glyceraldehyde 3-phosphate – pyruvate
• 4,5 ATP (1NADH + 2 ATP)
• pyruvate – acetyl CoA 2.5 ATP (1 NADH)
• acetyl CoA in Krebs cycle
10 ATP (3NADH + 1 FADH2 + 1GTP)
• Total 19,5-1 = 18,5 ATP

14. Reaction
sequence in
the b-
oxidation

15. Connections to Electron Transport and ATP.
One turn of the fatty acid spiral produces ATP from the interaction of the
coenzymes FAD (step 1) and NAD+ (step 3) with the electron transport chain.
• Total ATP per turn of the fatty acid spiral is
• Step 1 - FAD into e.t.c. = 2 ATP
Step 3 - NAD+ into e.t.c. = 3 ATP
Total ATP per turn of spiral = 5 ATP
• Example with Palmitic Acid = 16 carbons = 8 acetyl
groups
• Number of turns of fatty acid spiral = 8-1 = 7 turns
• ATP from fatty acid spiral = 7 turns and 5 per turn = 35 ATP.
• NET ATP from Fatty Acid Spiral = 35 - 1 = 34 ATP

18. Fatty Acid Synthesis
• Occurs mainly in liver and adipocytes, in
mammary glands during lactation
• Occurs in cytoplasm
• FA synthesis and degradation occur by two
completely separate pathways

19. • Three stages of fatty acid synthesis:
• A. Transport of acetyl CoA into cytosol
Acetyl CoA from catabolism of carbohydrates and
amino acids is exported from mitochondria via
the citrate transport system
Cytosolic NADH also converted to NADPH
Two molecules of ATP are expended for each round
of this cyclic pathway
• B. Carboxylation of acetyl CoA
• C. Assembly of fatty acid chain

21. Sources of NADPH for Fatty Acid Synthesis
1. One molecule of NADPH is generated for each molecule of
acetyl CoA that is transferred from mitochondria to the
cytosol (malic enzyme).
2. NADPH molecules come from the pentose phosphate
pathway.

22. B. Carboxylation of Acetyl CoA
Enzyme: acetyl CoA carboxylase
Prosthetic group - biotin
A carboxybiotin intermediate is formed.
ATP is hydrolyzed.
The CO2 group in carboxybiotin is transferred to acetyl CoA to
form malonyl CoA.
Acetyl CoA carboxylase is the regulatory enzyme.

23. C. The Reactions of Fatty Acid Synthesis
n Five separate stages:
(1) Loading of precursors via thioester
derivatives
(2) Condensation of the precursors
(3) Reduction
(4) Dehydration
(5) Reduction

24. • The elongation phase of fatty acid synthesis starts with the
formation of acetyl ACP and malonyl ACP.
• Acetyl transacylase and malonyl transacylase catalyze these
reactions.
• Acetyl CoA + ACP  acetyl ACP + CoA
Malonyl CoA + ACP  malonyl ACP + CoA

25. • Condensation
reaction.
• Acetyl ACP and
malonyl ACP react to
form acetoacetyl ACP.
• Enzyme - acyl-
malonyl ACP
condensing enzyme.

26. • Reduction.
• Acetoacetyl ACP is
reduced to D-3-
hydroxybutyryl ACP.
• NADPH is the
reducing agent
• Enzyme: -ketoacyl
ACP reductase

27. • Dehydration.
• D-3-hydroxybutyryl
ACP is dehydrated to
form crotonyl ACP
• Enzyme:
3-hydroxyacyl ACP
dehydratase

28. • Reduction.
• The final step in the
cycle reduces crotonyl
ACP to butyryl ACP.
• NADPH is reductant.
• Enzyme - enoyl ACP
reductase.
• This is the end of first
elongation cycle (first
round).

29. • In the second round
butyryl ACP
condenses with
malonyl ACP to form a
C6--ketoacyl ACP.
• Reduction,
dehydration, and a
second reduction
convert the C6--
ketoacyl ACP into a
C6-acyl ACP, which is
ready for a third
round of elongation.

30. Final reaction of FA synthesis
• Rounds of synthesis continue until a
C16 palmitoyl group is formed
• Palmitoyl-ACP is hydrolyzed by a thioesterase

31. 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.

32. Ketogenesis
• The ketone bodies
are
• acetoacetate
• b-
hydroxybutyrate
• acetone

33. Ketogenesis is the process by which ketone bodies are
produced as a result of fatty acid breakdown

36. The ways of formation of active form of glycerol.
There are two ways of formation of active form of
glycerol.
• 1. Phosphorilation of glycerol through the
action of glycerol kinase:
ATP + glycerol  glycerol 3-phosphate + ADP
• 2. Reduction of dihydroxyacetone phosphate
which is the product of the aldolase reaction
of glycolysis. Dihydroxyacetone phosphate is
reduced to glycerol 3-phosphate by the NAD-
linked glycerol-3-phosphate dehydrogenase of
the cytosol:
• Dihydroxyacetone phosphate + NADH + H+ 
glycerol 3-phosphate + NAD

37. Biosynthesis of triacylglycerols
• The first stage in
triacyglycerol
formation is the
acylation of the free
hydroxyl groups of
glycerol phosphate
by two molecules of
fatty acyl-CoA to yield
first a
lysophosphotidic acid
and then a
phosphatidic acid:
H2C
HC
OH
OH
H2C O P
R1 - COSKoA KoA - SH H2C
HC
O
OH
H2C O P
C
O
R1

38. Lysophosphotidic acid Phosphatidic acid
H2C
HC
O
OH
H2C O P
R2 - COSKoA KoA - SH
H2C
HC
O
O
H2C O P
C
O
R1
C
O
R1
C R2
O

39. • The activity of acetyl-CoA
carboxylase depends on its
phosphorylation status .
In its inactive form acetyl-CoA
carboxylase is phosphorylated in
serine, whereas the active form is
not phosphorylated.

40. The phosporylation of acetyl CoA carboxylase is catalyzed by an AMP-
dependent protein kinase (AMPK).
High AMP levels induce the phosphorylation and inactivation of acetyl-
CoA carboxylase.

41. Pathway of cholesterol biosynthesis

42. Bile acids perform such functions:
1. eliminating cholesterol from the body;
driving the flow of bile to eliminate
catabolites from the liver;
2. emulsifying lipids and fat soluble vitamins in
the intestine;
3. and aiding in the reduction of the bacteria
flora found in the small intestine and biliary
tract.

45. Obesity is a major risk factor for coronary heart
disease, which can lead to heart attack.

46. Atherosclerosis
• Atherosclerosis - the process in which deposits
of fatty substances, cholesterol, cellular waste
products, calcium and other substances build up
in the inner lining of an artery. It usually affects
large and medium-sized arteries.
• Plaques can grow large enough to significantly
reduce the blood's flow through an artery. But
most of the damage occurs when they become
fragile and rupture. Plaques that rupture
cause blood clots to form that can block blood
flow or break off and travel to another part of the
body. If either happens and blocks a blood vessel
that feeds the heart, it causes a heart attack. If it
blocks a blood vessel that feeds the brain, it
causes a stroke. And if blood supply to the arms
or legs is reduced, it can cause difficulty walking
and eventually lead to gangrene.