De Novo Synthesis of fatty acids | Biosynthesis Of Fatty Acids |

This presentation contains De Novo Synthesis of fatty acids & Regulation of fatty acid synthesis

Books referred: https://www.amazon.in/Biochemistry-2019-Satyanarayana-Satyanarayana-Author/dp/B07WGHCTKZ/ref=sr_1_1?dchild=1&keywords=satyanarayan+books+biochemistry&qid=1590834248&sr=8-1

2. Fatty acids
•Fatty acids are carboxylic acids with
hydrocarbon side chain.
•Simplest form of lipids.•Simplest form of lipids.
•Mainly occur in the esterifiedform.
•Some are present as free fatty acids
(unesterified).

3. •Most fatty acids: Even carbons (usually 14C -20C).
•Because the biosynthesis of fatty acids occurs with
the sequential addition of 2 carbon units.
Even Carbon fatty acids: Palmiticacid (16C) and
stearicacid (18C).
Odd chain fatty acids: Propionicacid (3C) and
Valericacid (5C).

4. De novo synthesis of fatty acids
•Occurs in liver, kidney, adipose tissue and
lactating mammary glands.
•Enzyme for fatty acid production: Cytosomal
fraction of the cell. fraction of the cell.
Acetyl CoA: Source of carbon atoms
NADPH:provides the reducing equivalents
ATP:supplies energy.

5. 3 stages of fatty acid synthesis
•Production of acetyl CoAand NADPH.
•Conversion of acetyl CoAto malonylCoA.
•Reactions of fatty acid synthasecomplex.•Reactions of fatty acid synthasecomplex.

6. Production of acetyl CoAand NADPH
•Prerequisites: Acetyl CoAand NADPH.
•Acetyl CoAis produced in the mitochondria:
By the oxidation of pyruvateand fatty acids By the oxidation of pyruvateand fatty acids
Degradation of carbon skeleton of certain amino acids
From ketonebodies.

7. Stage 1Stage 1

8. Production of acetyl CoAand NADPH
•Mitochondria are not permeable to acetyl CoA.
•That’s why acetyl CoAis converted to Citrate.
Acetyl CoA+ OxaloacetateCitrate.Acetyl CoA+ OxaloacetateCitrate.•Citrate is freely transported to cytosol.
•In cytosol: CitrateAcetyl CoAand Oxaloacetate
by “Citrate Lyase”
•And Oxaloacetateis converted to malate.

9. •Malate
Pyruvateby “MalicEnzyme”
•NADPH and CO2 generated in this reaction are
utilized for fatty acid synthesis.utilized for fatty acid synthesis.

11. Stage 2Stage 2

12. Formation of malonylCoA
•Acetyl CoAMalonylCoAby “Acetyl CoA
Carboxylase”
•Reaction requires ATP, CO2 and biotin. •Reaction requires ATP, CO2 and biotin.
•Acetyl CoAcarboxylase: Regulatory enzyme in
fatty acid synthesis.

14. Stage 3Stage 3

15. Reactions of fatty acid synthase
complex
•Remaining reactions: catalysedby a
multifunctional enzyme “fatty acid synthase
(FAS) complex”.
•It exists as a dimerwith two identical units.

16. •Each monomer possesses the activities of seven
different enzymes and an acylcarrier protein
(ACP) bound to 4’-phosphopantetheine.
•Fatty acid synthasefunctions as a single unit
catalysingall the seven reactions. catalysingall the seven reactions.
•Dissociation of the synthasecomplex results in
loss of the enzyme activities.

17. Reaction 1
•The two carbon fragment of acetyl CoAis
transferred to ACP of fatty acid synthase,
catalysedby the enzyme, acetyl CoA-ACP
transacylasetransacylase
•The acetyl unit is then transferred from ACP
to cysteineresidue of the enzyme. Thus ACP
site falls vacant.

19. •The enzyme malonylCoA-ACP transacylase
transfers malonatefrom malonylCoAto bind
to ACP.
Reaction 2

21. •The acetyl unit attached to cysteineis transferred
to malonylgroup (bound to ACP). The malonyl
moiety loses CO2 which was added by acetyl CoA
carboxylase. Thus, CO2 is never incorporated into
Reaction 3
carboxylase. Thus, CO2 is never incorporated into
fatty acid carbon chain. The decarboxylationis
accompanied by loss of free energy which allows
the reaction to proceed forward. This reaction is
catalyzed by β -ketoacylACP synthase.

23. •β-KetoacylACP reductasereduces ketoacyl
group to hydroxyacylgroup. The reducing
equivalents are supplied by NADPH.
Reaction 4

25. •β -HydroxyacylACP undergoes dehydration. A
molecule of water is eliminated and a double
bond is introduced between αand βcarbons.
Reaction 5

27. •A second NADPH-dependent reduction, catalysedby
enoyl-ACP reductaseoccurs to produce acyl-ACP. The
four-carbon unit attached to ACP is butyrylgroup. The
carbon chain attached to ACP is transferred to cysteine
residue and the reactions 2-6 are repeated 6 more
Reaction 6
residue and the reactions 2-6 are repeated 6 more
times. Each time, the fatty acid chain is lengthened by
a two-carbon unit (obtained from malonylCoA). At the
end of 7 cycles, the fatty acid synthesis is complete and
a 16-carbon fully saturated fatty acid—namely
palmitate—bound to ACP is produced.

29. •The enzyme palmitoylthioesteraseseparates
palmitatefrom fatty acid synthase. This
completes the synthesis of palmitate.
Reaction 7

31. Overall reactionOverall reaction

34. Summary of palmitatesynthesis
•Of the 16 carbons present in palmitate, only
two come from acetyl CoAdirectly. The
remaining 14 are from malonylCoAwhich, in
turn, is produced by acetyl CoA. The overall turn, is produced by acetyl CoA. The overall
reaction of palmitatesynthesis is summarized
•8 Acetyl CoA + 7 ATP + 14 NADPH + 14 H+ 
Palmitate + 8 CoA + 7 ADP + 7 Pi + 6H2O

35. Regulation of fatty acid synthesis
Acetyl CoAcarboxylase: Acetyl CoAcarboxylase: protomer(monomer) or an
active polymer.
Citrate promotespolymerformation, henceincreases fatty acid synthesis.
PalmitoylCoAand MalonylCoAcause depolymerizationof the enzyme and
inhibit fatty acid synthesis.
Hormonal influence : Hormones regulate acetyl CoAcarboxylaseby Hormonal influence : Hormones regulate acetyl CoAcarboxylaseby
phosphorylation(inactive form) and dephosphorylation(active form) of
the enzyme.
Glucagon, epinephrine and norepinephrineinactivate the enzyme by
cAMPdependentphosphorylation.
Insulin dephosphorylatesand activates the enzyme.
Thus, insulin promotes fatty acid synthesis while glucagon inhibits.
Insulin stimulates tissue uptake of glucose, and conversion of pyruvateto
acetyl CoA. This also facilitates fatty acid formation.

36. Dietary regulation :
Consumption of high carbohydrate or fat-free diet
increases the synthesis of acetyl CoAcarboxylaseand fatty
acid synthase, which promote fatty acid formation.
Fasting or high fat diet decreases fatty acid production.
Availability of NADPH :
The reducing equivalents for fatty acid synthesis are The reducing equivalents for fatty acid synthesis are
provided by NADPH which come either from citrate (acetyl
CoA) transport or hexosemonophosphateshunt.
About 50-60% of required NADPH is obtained from HMP
shunt, which significantly influences fatty acid synthesis.