FA Synthesis

Question 1

Where does FAS occur?

Answer 1

Cytosol

Question 2

What is the 2C acetyl donor is FAS?

Answer 2

Malonyl-CoA

A 3C molecule

During the condensation reaction, CO2 is removed from it and the remaining 2C acetyl group is donated to the FA chain synthesis

Question 3

Formation of malonyl-CoA

Answer 3

Enzyme: acetyl-CoA carboxylase (ACC)…
—> has a biotin carboxylase and transcarboxylase domain with a biotin carrier protein that ‘swings’ between these two domains

Substrate: Acetyl-CoA

Biotin carrier protein contains a lysine residue that covalently attaches to vitamin biotin

1. Biotin carboxylase domain activates biotin carrier protein with CO2 —> change in conformation
2. Biotin carrier protein swivels to the transcarboxylase domain
3. CO2 is donated from biotin to an incoming Acetyl-CoA substrate —> malonyl-CoA
4. Biotin carrier protein swivels back to other domain to start the reaction over again

Question 4

Sequence of events that increase levels of malonyl-CoA and drives FAS pathway forward…

Answer 4

Well fed state

1. A-CoA made in matrix by the PDH complex (ultimately from glycolysis of glucose in cytosol)
2. A-CoA + OAA —> citrate (in the CAC to generate energy)
3. This continues and [ATP] rises
4. This inhibits the CAC enzyme (isocitrate dehydrogenase)
5. [citrate] increases in matrix
6. Citrate passes through mitochondrial membrane into cytosol (higher to lower concentration)
7. Citrate —> OAA + Acetyl-CoA
8. ACC then converts Acetyl-CoA —> malonyl-CoA —> FAS

Question 5

Enzyme involved in FAS (post malonyl-CoA formation)

Answer 5

FA synthase complex

Multi-subunit

All 4 (repeating) reaction take place with the help of this enzyme

Question 6

The 4 repeating reactions of FAS (general)

Answer 6

1. Condensation
2. Reduction
3. Dehydration
4. Reduction

reactions are the inverse order and opposing directions of B-oxidation

Question 7

Condensation reaction of FAS

Answer 7

Enzyme: beta-ketoacyl ACP synthase

Products: beta-ketoacyl-ACP + CO2

Malonyl group becomes activated to the acyl carrier protein (ACP)…

Acetyl group is attached at the beta-ketoacyl-ACP enzymatic domain

—> then enzyme cleaves CO2…while condensing the acetyl group to remaining 2C portion of malonyl-CoA

**keto group on the beta-carbon of the acyl-ACP

Question 8

First reduction reaction of FAS

Answer 8

Enzyme: beta-ketoacyl ACP reductase

Energy used: NADPH (—> NADP+)

Product = beta-hydroxyacyl-ACP

Beta-keto group is reduced to a -OH group

Question 9

Dehydration reaction of FAS

Answer 9

Enzyme: beta-hydroxyacyl-ACP dehydratase

Products: trans-(delta2)-enoyl-ACP + water

Dehydration of the beta-OH group in the form of water

**note: that the product should sound familiar from beta-oxidation

Question 10

2nd reduction of FAS

Answer 10

Enzyme: enoyl-ACP reductase

Energy use: NADPH

Product: saturated acyl-ACP lengthened by 2C

…to being next round the 4+ carbon acyl group is transferred to the beta-ketoacyl-ACP synthase domain (reaction 1)…and a new malonyl-CoA becomes activated

Question 11

From which FA are all non-essential FAs synthesized from in the body?

Answer 11

Palmitate (C16:0)

Other FAs from out diet may become modified … but if made from de novo synthesis…it was modified from palmitate

Question 12

What each round of FAS requires

Answer 12

Extends chain by 2C

Needs…2 NADPH and generates 7 CO2