De Novo Synthesis of Fatty Acids

DE NOVO SYNTHESIS OF FATTY ACIDS

Occurs mainly in the liver, kidney, lactating mammary glands & Adipose tissues

Pyruvate dehydrogenase 1 Glucose → Pyruvate -- → Acetyl-CoA

In the mitochondria, while FAA synthesis occurs in the cytosol

1.a Acetyl-CoA + OAA Citrate Corsses mitochondiral membrane Citrate Acetyl-CoA

(Part of TCA cycle in Mitochondira) in Cytosol / Cytoplasm Citrate lyase (requires ATP) Induced by Insulin

OAA NADH cytosolic malate dehydrogenase

Pyruvate NAD+ Malate NADP+

Malic enzyme (NADP+-Dependent malate dehydrogenase) NADPH

Reenters the mitochondria Pyruvate

Regulartory enzyme: (Rate limiting & regulated step) Acetyl-CoA Carboxylase 2 Acetyl-CoA Malonyl-CoA 1) Acetyl-CoA Carboxylase: Biotin (+) Insulin, Citrate. High carbohydrate diets (-) Phosphorylation, AMP-activated protein kinase CO2 + ATP ADP + Pi (AMPK, not protein kinase A or PKA) & long chain fatty Acyl-CoA.

3 Fatty acid synthase, a multi-enzyme complex composed of 2 identical subunits (dimer), each with seven catalytic activities

phosphopantetheine residue form thioesters with (Located on the Acyl Carrier Protein of actyl groups Both Contain Sulfhydryl groups (-SH) FA synthetase complex) and are derived into

pantothenic acid Cysteine residue (Sulphur-containing Amino Acid) (Vitamin B5) Fatty Acid Synthase Complex (Structures are only there to help understanding)

it is composed of:

Acyl Carrier Protein (ACP) & Seven Enzymes (mentioned below)

phosphopantetheine-SH residue (sulfhydryl) pantothenic acid on ACP (Acyl Carrier Protein) (Vitamin B5)

Cysteine-SH (sulfhydryl) Cysteine residue on Ketoacyl synthases (Sulphur-containing Amino Acid)

1 Acetyl - CoA is transfered to the Cysteine-SH (sulfhydryl) on Ketoacyl synthases (essential for step 3)

Acety Transacylase Binds to phosphopantetheine-SH Binds to Ketoacyl synthases (KS) Acetyl-CoA on ACP (FAS is now primed)

1.b MalonylTransacylase Binds to phosphopantetheine-SH Malonyl-CoA on ACP

Acetyl-CoA (2C) Malonyl-CoA (3C) Ketoacyl synthases (KS) 3-ketoacyl-ACP(4C) 2 + (bound to KS) (bound to ACP) (bound to ACP)

CO2

Acetyl transferase & Malonyl transferase are often collectively refered to as Malonyl/Acetyl Transferase (MAT)

ketoacyl reductase (KR) Dehydrase (DH) 3-ketoacyl-ACP (4C) 3-hydroxyacyl-ACP (4C) 3-4 Enoyl-ACP (bound to ACP) (bound to ACP)

NADPH NADP+ H2O

ACP

Enoyl Reductase (ER) acyl residue 5 Enoyl-ACP (Transported to the Cysteine-SH (sulfhydryl) on Ketoacyl synthases) NADPH NADP+

ACP

thioesterase (TE) 6 Repeat steps 1.b to 5 untill a 16C chain is obtained Palmitate-ACP (16C) Palmitate Fatty Acid (16C)

Hormonal Regulation

1. ↑↑↑ Glucose → ↑ Insulin → Inhibition of AMP-Kinase, ↑ FAS Expression, ↑ Glycolysis → ↑ Acetyl-CoA 2. ↑ Insulin → Activates Pyruvate dehydrogenase → ↑ Acetyl-CoA 3. ↑ Insulin → ↑ Acetyl-CoA Carboxylase, FAS & ATP citrate lyase (↑ Cytosolic Acetyl-CoA)