DENOVO SYNTHESIS OF FATTYACIDS BY VANA JAGAN MOHAN RAO

1. BY
VANA JAGAN MOHAN RAO M.S.Pharm, MED.CHEM
NIPER,KOLKATA
Asst. Professor, MIPER- KURNOOL
Email: jaganvana6@gmail.com

2. Beta-oxidation Fatty acid synthesis
Site Mitochondria Cytoplasm
Intermediates Present as CoA derivatives Covalently linked to SH gr of ACP
Enzymes Present as independent proteins Multienzyme complex
Sequential units 2C units released as Acetyl CoA 2C added as Malonyl CoA(3C)
Co-enzymes NAD and FAD NADPH
Transport Carnitine Citrate
End product Acetyl CoA Palmitate
Difference b/w synthesis and breakdown of fatty acids

3. Subcellular organelle
Source of carbon atoms
- Cytoplasm (extra-mitochondrial)
- Acetyl CoA
- NADPH
- ATP
Source of reducing equivalent
Source of energy
 Site :-
Liver, adipose tissue, kidney, brain and mammary glands
Source of fatty acids :-
Exogenous - Diet (major)
Denovo / Endogenous - Pathway operates – excess of caloric in the diet –
fatty acids are synthesized – and stored as Triacylglycerol (TAG)

4. Stages of fatty acids synthesis
 Transport of Acetyl CoA and NADPH into cytoplasm.
 Conversion of Acetyl CoA to Malonyl CoA.
 Reactions of Fatty acid synthase complex.

5. Transport of Acetyl CoA to cytoplasm
 Acetyl CoA is produced in the mitochondria by the oxidation of pyruvate and
fatty acids, degradation of carbon skeleton of ketogenic amino acids.
 Because it is impermeable, Acetyl CoA is converted to citrateand
transported to cytoplasm.
 This transport is coupled with the cytosomal production of NADPHand
CO2 which is also required for FAsynthesis.

7. Conversion of Acetyl CoA to Malonyl CoA / Carboxylation of Acetyl CoA
Acetyl CoA carboxylase is the rate limiting enzyme of this pathway.
The elongation of the fatty acid occurs by addition of 2C at a time. But the 2-
carbon units are added as 3-carbon, Malonyl units

8. Fatty Acid Synthase (FAS) Complex
• exists as a multi-enzyme complex
• The enzymes form a dimer with identical subunits
• Each subunit is organized into 3 domains with 7 enzymes
• Subunits independently operate & both synthesize FA simultaneously
subunits lie in Antiparallel (head to tail) orientation
 1st Domain or Condensing Unit - initial substrate bindingsite
Beta-keto acyl synthase or Condensing enzyme (CE); Acetyl transferase (AT)
and Malonyl trans acylase (MT)
2nd Domain or ReductionUnit - Dehydratase (DH); Enoyl reductase
(ER); Beta-keto acyl reductase (KR) and Acyl carrier protein (ACP)
 3rd Domain or Releasing Unit - release the FAsynthesised.
Thio-esterase (TE) or Deacylase

9. • ACP - polypeptide chain having a phospho-pantotheine gr, to which the
acyl groups are attached in thioester linkage.
• ACP acts like the CoA carrying fatty acyl groups
• Eukaryotes - ACP is a part of FAS complex
• Prokaryotes – FAS complex + separate acyl carrier protein
• Advantages of Multi-enzyme Complex
• Intermediates of the reaction can easily interact with the active sites of the
enzymes.
• One gene codes all the enzymes; so all the enzymes are in equimolecular
concentrations.
• So the efficiency of the process is enhanced.
sivaranjani

10. FAS complex
Cys
Cyspantetheine
SH
4’-phospho-
pantetheine
SH
SH
4’-phospho-
SH
Subunit
division
Thioesterase
ACP
-SH group of
phosphopantetheine
of one subunit is in
close proximity
to the -SH of
cysteine residue of
CE of the other
subunit
1
2
ThioesteraseCE
MT
AT
Acetyl
transacylase
Malonyl
transacylase
Ketoacyl
synthase
DH
ER
KR

11. Reactions of fatty acid synthase complex

17. Short-term control – rapid, with in min
 Allosteric regulation
 Covalent modification
Long-term control – slow, takes hr to manifest
 Induction
 Repression
Regulation of fatty acid synthesis
sivaranjani

18. HMPshunt
Allosteric regulation
Rate limiting enzyme –
Acetyl CoA Carboxylase

20. • Involves change in the gene expression which controls the rate of
synthesis of these enzymes.
• Insulin - induces
• Glucagon - represses
Long-term control mechanism

22. Desaturation system
Smooth endoplasmic reticulum
There are 4 fatty acyl desaturase enzymes in mammals
designated 9 , 6, 5 and 4 fatty acyl-CoA desaturase
 Palmitoyl CoA 16C– Palmitoleic acid 16:1(9)
 Stearyl CoA 18C – Oleic acid 18:1(9)
Mammals cannot incorporate a double bond beyond 9 – PUFA
cannot be synthesized so supplied in diet, but plants contains
12,15 fatty acyl CoA desaturase.

24. Summary of FA synthesis
Site:
Localization:  Cytoplasm (up to C16)
Enzymes: 3 2 Acetyl-CoA-carboxylase (HCO -
- source of CO , biotin, ATP)
 Fatty acid synthase (NADPH ,CoA)
Primary substrate:
Final product:
 Acetyl-CoA
 Palmitate
Liver, Adipose tissue, Mammary gland during lactation
(always in excess calories)

25.  2-6 Rn are repeated by 2C in each cycle to form chain length C16
(palmitate)
 Palmitate,is a precursor of saturated and unsaturated FA:
elongation systems Saturated FA (> C16)
 Unsaturated FA (=) desaturation systems