Chapter 23: Fatty Acid & Eicosanoid Synthesis

Ethanol Metabolism Step 1 {Enzyme}

• Ethanol + NAD → acetaldehyde + NADH + H⁺

• Main enzyme is alcohol dehydrogenase or MEOS

Ethanol Metabolism Step 2

Acetaldehyde + NAD → acetate + NADH + H⁺

Ethanol Metabolism Step 3

• Acetate + CoA + ATP → acetyl CoA + AMP + PPi

Fatty Acid Synthase Complex

• Strictly synthesize palmitic acid (16:0)

• Involves 2 identical dimer-complexes: 1 ACP protein + 6 enzymes

• Requires acetyl CoA, NADPH, and ATP as substrates

Acetyl CoA Transport into Cytosol

Step 1: Occurs in mitochondria

• Acetyl CoA + oxaloacetate → citrate + CoA

• High ATP inhibits α-ketoglutarate dehydrogenase in citric acid acid causing citrate buildup

• Malate shuttle moves citrate out of mitochondria into cytosol

Step 2:

• Citrate + CoA → Acetyl CoA + oxaloacetate

• Main enzyme is ATP citrate lyase

Malonyl CoA Synthesis {Enzyme}

• Acetyl CoA + CO₂ → malonyl CoA

• Main enzyme is acetyl CoA carboxylase (w/Biotin)

Fatty Acid Synthase Complex Step 1

• ACP monomer 1 binds to acetyl CoA (2C)

• ACP monomer 2 binds to malonyl CoA (3C)

Fatty Acid Synthase Complex Step 2

• Acetyl CoA disconnects from monomer 1 and breakdown

• One carbon bonds to malonyl group on monomer 2 to become ketoacyl group (4C)

• The other carbon become CO₂

Fatty Acid Synthase Complex Step 3

Ketoacyl + NADPH + H → hydroxyacyl + NADP

Fatty Acid Synthase Complex Step 4

Hydroxyacyl → unsatacyl + H₂O

Fatty Acid Synthase Complex Step 5

Unsatacyl + NADPH + H → satacyl + NADP

Fatty Acid Synthase Complex Step 6

• The satacyl group on monomer 2 transfers to monomer 1

• New malonyl CoA (3C) bonds to monomer 2

• Satacyl group combines with malonyl group (loses 1 carbon to CO₂)

• Repeat step 3-6 until palmitic acid is formed

Fatty Acid Modification Types

• Elongation: addition of 2 carbons to carboxylic end

• Desaturation: removal of 2 hydrogen to insert double bond in hydrocarbon chain

• Esterification: FA esterified to an alcohol alcohol compound

Elongation

• Occurs in smooth ER

• The main enzyme is FA elongases

• Same mechanism as fatty acid synthase

• $16:2\Delta^{5,8}$ → $18:2\Delta^{7,10}$

Desaturation

• Occurs in smooth ER

• Main enzyme is FA desaturases

• Always cis-version

Essential Vitamins

Human cannot make linoleic acid & alpha-linoleic acid since it cannot introduce double bond beyond position 9

Linoleic Acid → Arachidonic Acid

• $18:2\Delta^{9,12}$ → $18:3\Delta^{6,9,12}$ (delta-6 FA desaturase)

• $18:3\Delta^{6,9,12}$ → $20:3\Delta^{8,11,14}$ (FA elongase)

• $20:3\Delta^{8,11,14}$ → $20:4\Delta^{5,8,11,14}$ (delta-5 FA desaturase)

Alpha-Linoleic Acid → EPA

• $18:3\Delta^{9,12,15}$ → $18:4\Delta^{6,9,12,15}$ (delta-6 FA desaturase)

• $18:4\Delta^{6,9,12,15}$ → $20:4\Delta^{8,11,14,17}$ (FA elongase)

• $20:4\Delta^{8,11,14,17}$ → $20:5\Delta^{5,8,11,14,17}$ (delta-5 desaturase)