Desaturase Rules

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CH₃-(CH₂)_x-CH₂-CH₂-(CH₂)_y-C-SCoA 

1. X must be greater than or equal to 5

2. (CH₂)_x may have double bonds

3. (CH₂)_y is always saturated.

Fatty Acid Biosynthesis Differs

from Beta Oxidation How?

• Occurs in the cytoplasm, not mitochondrion
• Has ACP as its acyl group carrier, not CoA
• NADPH is electron donor, whereas FAD is electron acceptor in Beta oxidation
• C₂ unit donor is malonyl-CoA, not acetyl-CoA

What are the sources of Acetyl-CoA

in the Cytosol?

• Amino acid degradation
• Glycolysis yields cytosolic pyruvate which is converted to acetyl-DoA in mitochondria
• Citrate-malate-pyruvate shuttle provides cytosolic acetate units and reducing equivalents for fatty acid synthesis
• Fatty Acid oxidation produces mitochondrial acetyl-CoA 

How is Acetyl-CoA Carboxylase

Regulated?

• Insulin triggers activation of enzyme, dephosphorylates it.  Insulin also inhibits lipases.
• Glucagon and epinephrine trigger phosphorylation/inactivation.  Glucagon activates Lipases.
• Citrate activates.
• Fatty acyl-CoAs inhibit.

In Round One of Fatty Acid

Synthesis, what is attached to the

cys and what is attached

to the ACP?

ACP is attached to malonyl-CoA

while the cys is attached to acetyl-CoA

Where does Fatty Acid Elongation

take place?

Primarily in the endoplasmic reticulum

How is Fatty Acid metabolism regulated?

•  insulin promotes the conversion of carbohydrates to triacylglycerol.
• Glucogon and epin. stimulate mobilization of fatty acids while decreasing glycolysis and increasing gluconeogenesis.

HMG-CoA + 2NADPH ------>

Mevalonate + 2NADP⁺ + CoA

HMG-CoA Reductase

• Rate-limiting step in cholesterol biosynthesis
• site of action of cholesterol-lowering drugs

Mevalonate + 2ATP ----->

5 pyrophostphate mevalonate + 2ADP

1. Mevalonate Kinase
2. Phosphomevalonate Kinase

5 pyrophosphate mevalonate + ATP ----->

Isopentenyl pyrophosphate + ADP + Pi + CO₂

Pyrophosphate Mevalonate

Decaroxylase

Isopentenyl pyrophosphate <----->

Dimethylallyl pyrophosphate

Isopentenyl

pyrophosphate

isomerase

Dimethylallyl pyrophosephate + isopentenyl pyrophosphate ----->

Geranyl pyrophosphate + PPi

Prenyl Transferase

• Head to tail condensation reaction

Geranyl pryophosphate + isopentenyl pyrophosphate ---->

Farnesyl pyrophosphate + PPi

Prenyl transferase

• Head to tail reaction

2Farnesyl pryophosphate + NADPH + H⁺ ---->

Squalene + NADP⁺ + 2PPi

Squalene synthase

• head to head condensation reaction

How is HMG-CoA Reductase regulated?

• Inactivated by AMP-dependent kinase phosphorylation
• degraded, half-life is ~3 hours, but depends on cholesterol lvl.
• gene expression is controlled by sholesterol lvls.

Hypercholesterolemia

• Have defencies in LDL receptors.
• Use combination of HMG-CoA inhibitors and cholesterol-binding resins to treat to lower cholesterol lvls.