FATTY ACID SYNTHESIS

FATTY ACID SYNTHESIS Kshitiz Raj Shrestha Lecturer, Biochemistry

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

Where Does Cytosolic Acetyl-CoA Come From? Fig. 21-10 cytosol • Acetyl-CoA comes from citrate, which can come out of the TCA cycle .

One Transporter is Not Enough! Fig. 21-10

Acetyl-CoA carboxylase reaction • A trifunctional protein: acetyl-CoAcarboxylase • 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

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

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

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

Four step sequence Condensation Reduction Dehydration Reduction

Step 1: A Condensation & Elimination Reaction Fig. 21-2

Note: Step 2: A Reduction Reaction FAS FAS Fig. 21-2

FAS FAS Step 3: A Dehydration Reaction Fig. 21-2

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

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) Fig. 21-6

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

Think about the regulation… Fig. 21-11

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…

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?

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)

burn store Malonyl-CoA (from activation of fatty acid biosynthesis from excess glucose) High NADH Note need For NAD+ Overall Control of Fatty Acid Oxidation b-oxidation transporter II Fatty acyl-CoA I Inner mt membrane TAG’s and PL’s Fig. 17-8

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-hydroxyacyl-CoAdehydrogenase • High acetyl-CoA inhibits thiolase

References Lehninger Principle of Biochemistry 4th edition Biochemistry by U .Satyanarayan

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FATTY ACID SYNTHESIS

FATTY ACID SYNTHESIS

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