#3 FA synthesis

What is the basic premise of FA synthesis?

When nutrient/energy levels are high, Acetyl-CoA converted into FA and then stored as TAGs

FA synthesis steps

Occurs in liver, brain, mammary glands and adipose tissue, builds FA 2C at a time using AcetylCoA as carbon source

1) Condensation

2) Reduction

3) Dehydration

4) Reduction

What is Acetyl CoA Carboxylase? (AAC)

Enzyme that converts Acetyl CoA into Malonyl CoA (Biotin dependent) by adding CO2 to AceCoA in 2 step process, ATP hydrolyzed

Second step is IRREVERSIBLE, committed step in FA synth

What is Malonyl CoA?

Similar to Acetyl CoA, Has Malonyl group attached to CoA via high energy thioester bond

Think of it as ‘activated’ Acetyl CoA, REQ with AceCoA for initiating FA synthesis, and FA elongation

Fatty Acid Synthase (FAS)

Performs mammal FA synthesis, single polypeptide with 7 functional domains and 2 key thiol centres

ALL Acetyl and Malonyl groups loaded onto ACP domain first

Key thiol groups on FAS

Acyl Carrier Protein (ACP): Binds acyl groups via flexible thiol group, can transfer acyl groups to different active sites

Beta ketoacyl ACP Synthase (KS): Has reactive Cys residue which can bind Acyl groups

FAS charging

MAT (Malonyl/Acetyl CoA ACP transferase) domain transfers Acetyl from Acetyl CoA to ACP, ACP transfers Acetyl to KS domain

MAT transfers Malonyl from Malonyl CoA onto ACP

FAS Condensation (#1)

KS domain transfers Acetyl group via FAS onto Malonyl group, Carboxyl group lost as CO2, forms beta ketoacyl ACP synthase

FAS Reduction (#2)

ACP arm moves to KR (ketoacyl ACP reductase) active site, beta C3 reduced to form beta hydroxylacyl ACP (e donor NADPH)

FAS Dehydration (#3)

ACP arm moves to DH (beta hydroxyacyl ACP dehydratase), water removed to form trans delta² enoyl ACP

FAS Reduction (#4)

ACP arm moves to ER (enoyl ACP reductase) to form acyl ACP (e donor NADPH)

Enzyme naming conventions

Synthase build stuff, named after what they build aka the product

Reductase reduce stuff, named after what they reduce aka substrate

Dehydratase dehydrate stuff, named after what they dehydrate

FAS Chain lengthening (#5)

MAT moves acyl group to KS domain (Cys residue) (Reposition of acyl group)

MAT transfers fresh Malonyl group to ACP and cycle continues

How does the FA chain grow?

Grows outwards, OG acetyl group at END of acyl chain

When does the FA chain stop?

Almost ALWAYS at C16 acyl ACP (Palmitoyl ACP) after 7 rounds of synthesis

What is the overall reaction of FAS and ACC to create a Palmitate?

8 AceCoA + 7 ATP + 14 NADPH + 6 H+ + H2O

= Palmitate + 8 CoASH + 7 ADP + 7 Pi + 14 NADP+

What is the overall FAS rxn to create Palmitate?

1 AceCoA + 7 Malonyl CoA + 14 NADPH (reductions) + 20 H+

= Palmitate + 7 CO2 + CoA + 8 CoASH + 14 NADP+ + 6 H2O (1 H2O for thioesterase rxn)

What is the overall ACC reaction for palmitate?

7 AceCoA + 7 CO2 + 7 ATP + 7 H2O

= 7 Malonyl CoA + 7 ADP + 7 Pi + 14 H+

Where does Acetyl CoA come from?

Generated by carb and protein breakdown in mit matrix

FA synth occurs in cytoplasm so Acetyl is moved via citrate transporter into cytosol

How to make longer FA than Palmitate?

Using elongases enzymes to add C (similar to FAS but req various separate enz)

How to desaturate palmitate FA?

Desaturases use O2 and NADH/NADPH to generate cis db in a SPECIFIC location

Mammals CANNOT create db past C9

What are the 3 fates of FA?

Stored as TAGs

Incorporated into phospholipid bilayer

Beta oxidation (FA breakdown)