Lipid Biosynthesis

1. Lipid Biosynthesis

2. Overview of Fatty Acid Metabolism Showing The Major
Pathways and End Products

3. Acetyl-CoA Carboxylase
ACC reaction, like those of the other biotin-dependent carboxylases,
occurs in two steps, a CO2 activation and a carboxylation
• ACC is a biotin-dependent enzyme that catalyzes the first
• committed step of fatty acid biosynthesis and one of its rate controlling
steps.
• IRREVERSIBLE
• Biotin dependent carboxylases in human:
• ACC
• propionyl-CoA carboxylase
• pyruvate carboxylase
• β-methylcrotonyl-CoA carboxylase (which participates in
• the degradation of leucine).
BUT:
glutamate carboxylase
Vitamine K dependent

4. The Structure of Pyruvate Carboxylase

5. Acetyl-CoA Carboxylase Has Three
Activities in a Single Polypeptide

8. Biological Tethers

9. Critical SH-Groups Carry The Intermediates
During The Synthesis of Fatty Acids
A. Acyl Carrier Protein
The prosthetic group is 4′-phosphopantetheine, which is
covalently attached to the hydroxyl group of a Ser residue in
ACP
Phosphopantetheine contains the B5 vitamin pantothenic acid,
also found in the coenzyme A molecule:

10. Critical SH-Groups Carry The
Intermediates During The
Synthesis of Fatty Acids

11. Structural Overview of The Mammalian
(Porcine) Fatty Acid Synthase

12. Substate Shuttling By The ACP in mFAS

13. Sequence of Events During Synthesis of a
Fatty Acid
The enzyme complex must be charged
with the correct acyl groups:
A. the acetyl group of acetyl-CoA is
transferred to the Cys-SH group of the β-
ketoacyl-ACP synthase. This reaction is
catalyzed by
acetyl-CoA–ACP transacetylase (AT)
B. transfer of the malonyl group from
malonyl-CoA to the -SH group of ACP, is
catalyzed by
malonyl-CoA–ACP transferase (MT)

14. Step 1 Condensation
condensation of the activated acetyl
and malonyl groups to form
acetoacetyl-ACP, an acetoacetyl
group bound to ACP through the
phosphopantetheine-SH group;
simultaneously, a molecule of CO2 is
produced.
Enzyme: β-ketoacyl-ACP synthase
(KS)

16. The butyryl group is transferred
from the phosphopantetheine-SH
group of ACP to the Cys -SH group of
β--ketoacyl-ACP synthase (like in A
reaction).
To start the next cycle of four
reactions that lengthens the chain
by two more carbons, another
malonyl group is linked to the now
unoccupied phosphopantetheine-SH
group of ACP (like in B reaction).

17. Beginning Of The Second Round
Of The Fatty Acid Synthesis Cycle

18. The Overall Process Of Palmitate Synthesis

19. Stoichiometry

20. Shuttle For Transfer Of Acetyl Groups
From Mitochondria To The Cytosol

21. Main Sources of NADPH For
Fatty Acid Synthesis

22. Regulation of fatty acid synthesis
-regulation of Acetyl-CoA carboxylase-

23. -regulation of Acetyl-CoA carboxylase-

24. Parallel Regulation of Fatty Acid Synthesis and
Oxidation

25. Sites of Regulation of
Fatty Acid Metabolism.

26. Subcellular Localization
of Lipid Metabolism

27. Routes of Synthesis of Other Fatty Acids

28. Electron Transfer in The Desaturation
of Fatty Acids in Vertebrates
Mammalian systems contain four terminal desaturases of broad chain-length
specificities designated Δ9-, Δ6-, Δ5-, and Δ4-fatty acyl-CoA desaturases.

29. Biosynthesis of Phosphatidic Acid

30. Phosphatidic Acid in Lipid
Biosynthesis

31. Glycerogenesis
Glyceroneogenesis Is Important for Triacylglycerol
Biosynthesis
The dihydroxyacetone phosphate used to make glycerol-3-
phosphate for triacylglycerol synthesis comes either from
glucose via the glycolytic pathway or from oxaloacetate via
an abbreviated version of gluconeogenesis termed
glyceroneogenesis. Glyceroneogenesis is necessary in
times of starvation, (when glycolysis is inhibited) since
approximately 30% of the fatty acids that enter the liver
during a fast are reesterified to triacylglycerol and
exported as VLDL. Adipocytes also carry out
glyceroneogenesis in times of starvation. They do not
carry out gluconeogenesis but contain the gluconeogenic
enzyme
phosphoenolpyruvate carboxykinase (PEPCK), which is
upregulated when glucose concentration is low, and
participates in the glyceroneogenesis required for
triacylglycerol biosynthesis.

32. Flux through the triacylglycerol cycle between liver and adipose tissue is controlled to a large degree by
the activity of PEPCK, which limits the rate of both gluconeogenesis (in liver) and glyceroneogenesis (in
liver and adipose tissue). Glucocorticoid hormones such as cortisol regulate the levels of PEPCK
reciprocally in the liver and adipose tissue. Acting through the glucocorticoid receptor, these steroid
hormones increase the expression of the gene encoding PEP carboxykinase in the liver, thus increasing
gluconeogenesis and glyceroneogenesis. In adipose tissue, they inhibit PEPCK expression thus increasing
fatty acid release.

33. A class of drugs called thiazolidinediones are now used to treat type 2 diabetes. In this disease, high levels
of free fatty acids in the blood interfere with glucose utilization in muscle and promote insulin resistance.
Thiazolidinediones activate a nuclear receptor called peroxisome proliferator-activated receptor γ (PPARγ),
which induces the activity of PEP carboxykinase. Therapeutically, thiazolidinediones increase the rate of
glyceroneogenesis, thus increasing the resynthesis of triacylglycerol in adipose tissue and reducing the
amount of free fatty acid in the blood.

35. Pyridoxal phosphate is an essential cofactor in the
glycogen phosphorylase reaction as well; involved
in acid catalysis
Coenzyme Reaction Mediated
Biotin Carboxylation
Cobalamin (B12) coenzymes Alkylation
Coenzyme A Acyl transfer
Flavin coenzymes Oxidation-reduction
Lipoic acid Acyl transfer
Nicotinamide coenzymes Oxidation-reduction
Pyridoxal phosphate Amino group transfer
Tetrahydrofolate One-carbon group transfer
Thiamine pyrophosphate Aldehyde transfer

36. Thank You