1. Kshitiz Raj Shrestha Lecturer, Biochemistry
FATTY ACID SYNTHESIS
Kshitiz Raj Shrestha
Lecturer, Biochemistry
03/12/010

2. Breaking vs. Making Fatty Acids: It’s Just Not the Same…!
They utilize different enzymes
They occur in different cellular compartments
They exploit different size “unit blocks”: 2-carbon for breakdown, 3-carbon for building
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3. Where Does Cytosolic Acetyl-CoA Come From?
Fig
cytosol
Acetyl-CoA comes from citrate, which can come out of the TCA cycle .
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4. One Transporter is Not Enough!
Fig
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5. Acetyl-CoA carboxylase reaction
A trifunctional protein: acetyl-CoA carboxylase
One subunit carries the biotin, attached via the amino group of a lysine residue
One subunit activates CO2 by transferring it to the biotin
Which serves as a long flexible arm to carry the CO2 to the third subunit
Fig. 21-1
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6. Acetyl-CoA Activation: Making Malonyl
This third subunit, a transcarboxylase, does exactly that: transfers the CO2 to acetyl-CoA, converting it into malonyl-CoA, to be used in the next step of the reaction
Fig. 21-1
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7. After Activation, Biosynthesis!
To make a fatty acid, first a 2-carbon unit is activated, becoming malonyl-CoA
Conceptually mirroring b-oxidation, a four-step process then lengthens the nascent fatty acid chain by 2 carbons
Employing a remarkable enzyme complex containing 7 different activities
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11. At “Start”, Who’s Holding Whom? And How?
The acetyl- and malonyl-CoA thio-esters can “load” onto the thiol groups of a cysteine residue in KS (b-ketoacyl-ACP synthase) and ACP-4’PPT respectively
This primes the system for the subsequent reactions
FAS
Fig. 21-3
Fig. 21-4
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12. Four step sequence
Condensation
Reduction
Dehydration
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14. Step 1: A Condensation & Elimination Reaction
Fig. 21-2
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15. Step 2: A Reduction Reaction
Note:
FAS
FAS
Fig. 21-2
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16. Step 3: A Dehydration Reaction
FAS
Fig. 21-2
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17. Step 4: A Reduction Reaction (Again)
Observe that all of the previous four reactions have been carried out tethered to the 4’PPT of ACP
And that the original acetyl group attached to KS is at the terminal end of the chain
Note:
FAS
FAS
Fig. 21-2
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18. Now Go Back to Start…
After the first complete cycle, the fully reduced butyryl group is now transferred back to the Cys residue of KS,
Thus freeing up the 4’PPT tether of ACP to accept another moiety of malonyl-CoA
…and the cycle can continue (see Fig. 21-5)
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Fig. 21-6

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22. Recall: Characteristics of Fatty Acid Biosynthesis
As is typical for biosynthetic pathways, the reaction sequences are
Endergonic
Reductive
And they employ
ATP as the metabolic energy source
The electron carrier NADPH as reductant
Large and sophisticated enzyme complexes
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23. Think about the regulation…
Fig
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24. How Are Choices About Fatty Acid Metabolism Made?
Fatty acids are a valuable fuel, and are burned only when their energy is needed
In the cytosol of liver cells, fatty acyl-CoA’s are
Either taken into mitochondria for b-oxidation
Or converted into TAGs and phospholipids by cytosolic enzymes
This metabolic fork is governed by the rate of uptake of fatty acyl-CoA’s into mitochondria
Which can be inhibited by malonyl-CoA…
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25. Recall the Acyl-Carnitine/ Carnitine Transporter
Responsible for the magic trick of supplying fatty acyl-CoA’s to the mitochondrial matrix, where b-oxidation takes place
Transport is the rate-limiting step in fatty acid oxidation
This is the point of regulation by malonyl-CoA, which inhibits acyl-carnitine transferase I
Why malonyl-CoA?
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26. The Crosstalk Between Two Pathways
With plentiful energy from carbohydrates, when not all the glucose can be oxidized or stored as glycogen,
The excess is channeled into biosynthesis of fatty acids (for storage as TAGs)
As often, this is not simply the reverse of b-oxidation, but entails as its first step
Carboxylation of acetyl-CoA to produce malonyl-CoA (see Ch. 21)
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27. Overall Control of Fatty Acid Oxidation
transporter
b-oxidation II
Fatty acyl-CoA
burn I
store
Malonyl-CoA
(from activation
of fatty acid bio-
synthesis from
excess glucose)
Inner mt
membrane
TAG’s and PL’s
High
NADH
Note need
For NAD+
Fig. 17-8
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28. Summary of Control Points
Mobilization from TAGs in the adipocyte by TAG-lipase is under hormonal control – epinephrine and glucagon.
The carnitine shuttle (which controls entry of fatty acids to the mitochondrial matrix) is inhibited by malonyl-CoA (the first intermediate in fatty acid biosynthesis). Malonyl-CoA is high when carbo-hydrate is plentiful.
High NADH inhibits b-hydroxy acyl-CoA dehydrogenase
High acetyl-CoA inhibits thiolase
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29. References Lehninger Principle of Biochemistry 4th edition
Biochemistry by U .Satyanarayan
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30. THANK YOU FOR YOUR KIND ATTENTION
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