Where does FAS occur?
Cytosol
What is the 2C acetyl donor is FAS?
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
Formation of malonyl-CoA
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
- Biotin carboxylase domain activates biotin carrier protein with CO2 —> change in conformation
- Biotin carrier protein swivels to the transcarboxylase domain
- CO2 is donated from biotin to an incoming Acetyl-CoA substrate —> malonyl-CoA
- Biotin carrier protein swivels back to other domain to start the reaction over again
Sequence of events that increase levels of malonyl-CoA and drives FAS pathway forward…
Well fed state
- A-CoA made in matrix by the PDH complex (ultimately from glycolysis of glucose in cytosol)
- A-CoA + OAA —> citrate (in the CAC to generate energy)
- This continues and [ATP] rises
- This inhibits the CAC enzyme (isocitrate dehydrogenase)
- [citrate] increases in matrix
- Citrate passes through mitochondrial membrane into cytosol (higher to lower concentration)
- Citrate —> OAA + Acetyl-CoA
- ACC then converts Acetyl-CoA —> malonyl-CoA —> FAS
Enzyme involved in FAS (post malonyl-CoA formation)
FA synthase complex
Multi-subunit
All 4 (repeating) reaction take place with the help of this enzyme
The 4 repeating reactions of FAS (general)
- Condensation
- Reduction
- Dehydration
- Reduction
reactions are the inverse order and opposing directions of B-oxidation
Condensation reaction of FAS
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
First reduction reaction of FAS
Enzyme: beta-ketoacyl ACP reductase
Energy used: NADPH (—> NADP+)
Product = beta-hydroxyacyl-ACP
Beta-keto group is reduced to a -OH group
Dehydration reaction of FAS
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
2nd reduction of FAS
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
From which FA are all non-essential FAs synthesized from in the body?
Palmitate (C16:0)
Other FAs from out diet may become modified … but if made from de novo synthesis…it was modified from palmitate
What each round of FAS requires
Extends chain by 2C
Needs…2 NADPH and generates 7 CO2
