11 biosynthesis of other lipids 20141115

Biosynthesis of Membrane Lipids

Glycerolipids and Sphingolipids Synthesis of new membrane requires production of phospholipids On smooth ER surfaces

CTP

PPi Phosphatic acid phosphatase

Pi

CMP

Glycerophospholipids

Head group HO

CTP

PPi

CMP

Biosynthesis of Glycerolipids (glycerol backbone)

Glycerophospholipids

Phosphodiester linkage

Examples of head groups: - inositol in phosphatidylinositol - glycerol in phosphatidylglycerol

Non-polar (hydrophobic)

Polar (hydrophilic)

Amide linkage

N-acylation

(C-18)

Biosynthesis of sphingolipids (backbone: C-18 amino alcohol)

(C-16)

C

O

R

C

O

R

(N-acyl-sphingosine)

choline

Head-group attachment

(Sphingophospholipid)

(Glycosphinolipid)

Desaturation

(ARA)

ARA is a precursor for Eicosanoids

Eicosanoids - Potent signaling molecules - e.g. Prostaglandins and thromboxanes

Arachidonic acid (ARA)

Prostaglandins - Trigger pain and inflammation - Regulate the release of mucins for stomach protection

Thromboxanes - Induces constriction of blood vessels, platelet aggregation,

blood clotting

Biosynthesis of Eicosanoids

Prostaglandin H2 synthase (COX) - 2 enzyme activities (1 and 2) - 2 isozymes: COX-1 and COX-2, very similar in structure (both with

activities 1 and 2) - COX-1: making prostaglandins for regulation of gastric mucin secretion - COX-2: making prostaglandins for induction of inflammation, pain, fever

Thromboxanes

Prostagladin H2 Other prostaglandins

Different pain killers/anti-inflammatory drugs targeting COX

- Inhibition of cycloxygenase of COX-1 and COX-2 - Side effects: stomach ulcers - Low dosage of aspirin: reduces risks of heart attack and stroke due to

lowered thromboxane production - Vioxx: COX-2 specific; no side effects on stomach but increased risks

of cardiovascular disease; taken off the market - Structural analysis of COX-1 and COX-2 for design of COX-2 specific

pain killers.

Salicylic acid - Natural pain-killer found in bark of willow trees used by ancient Greek - Structure similar to aspirin - Bitter tasting and unpleasant side effects including severe stomach irritation - Plant hormone to suppress diseases and wilting

Salicylic acid

Cholesterol Biosynthesis

Condensation of 3 acetate units

Conversion to a C-5 unit

(C-6 intermediate)

condensation of 6 isoprene units

3 acetyl-CoAs to 1 isoprene 6 isoprenes to 1 cholesterol 18 acetyl CoAs

Ring closure

4 fused rings: steroid nucleus

OVERVIEW OF BIOSYNTHESIS (acetyl-CoA)

(C-30)

(C-27)

Formation of mevalonate and activated isoprene units

3 acetyl-CoA 1 activated isoprene unit

Target for cholesterol-

lowering drug

CO2

Same as the first 2

steps in ketone body

formation

Cholesterol-lowering drugs - Statins - Competitive inhibitor of HMG-CoA reductase - HMG-CoA reductase converts HMG-CoA to mevalonate

5 3

Isomerization

Formation of Squalene

(C-10)

(C-15)

Tail Head Tail Head

Head

Head

Tail Tail

(C-15)

(C-15)

(C-30 unit, first discovered in sharks, Squalus spp.)

HO

Ring closure converts squalene to steroids

3 3 3

~20 rxns

Removal of methyl groups (CH3)

Reduction of double bonds

Cholesterol

3

3

Fatty acyl-CoA

CoA-SH

Acyl-CoA-cholesterol

acyl transferase

Lipoprotein

particles

(chylomicrons,

VLDL, LDL, HDL)

(C-30)

(C-27)