Kshitiz Raj Shrestha Lecturer, Biochemistry FATTY ACID SYNTHESIS Kshitiz Raj Shrestha Lecturer, Biochemistry 03/12/010
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 03/12/010
Where Does Cytosolic Acetyl-CoA Come From? Fig. 21-10 cytosol Acetyl-CoA comes from citrate, which can come out of the TCA cycle . 03/12/010
One Transporter is Not Enough! Fig. 21-10 03/12/010
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 03/12/010
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 03/12/010
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 03/12/010
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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 03/12/010
Four step sequence Condensation Reduction Dehydration 03/12/010
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Step 1: A Condensation & Elimination Reaction Fig. 21-2 03/12/010
Step 2: A Reduction Reaction Note: FAS FAS Fig. 21-2 03/12/010
Step 3: A Dehydration Reaction FAS Fig. 21-2 03/12/010
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 03/12/010
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) 03/12/010 Fig. 21-6
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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 03/12/010
Think about the regulation… Fig. 21-11 03/12/010
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… 03/12/010
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? 03/12/010
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) 03/12/010
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 03/12/010
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 03/12/010
References Lehninger Principle of Biochemistry 4th edition Biochemistry by U .Satyanarayan 03/12/010
THANK YOU FOR YOUR KIND ATTENTION 03/12/010