24-Metabolism of Acylglycerols & Sphingolipids

What constitutes the majority of lipids in the body?

Acylglycerols

What are the major lipids in the body?

Triacylglycerols

What are the main lipids of cell membranes?

Phospholipids and sphingolipids

Dipalmitoyl Lecithin

Lung surfactant

Where are glycosphingolipids located?

On cell surfaces with oligosaccharide chains facing outward

What must happen to triacylglycerols before further catabolism?

They must be hydrolyzed by a lipase to fatty acids and glycerol

Where does much of the hydrolysis (lipolysis) of triacylglycerols occur?

In adipose tissue

How are free fatty acids transported in the plasma?

They combine with serum albumin

Free fatty acids are uptake into tissues for

catabolism.

What determines the utilization of glycerol in tissues?

The presence of glycerol kinase

What is the common precursor of triacylglycerols and many phosphoglycerols?

Phosphatidate

What is the primary source of glycerol-3-phosphate?

Dihydroxyacetone phosphate, formed by glycerol-3-phosphate dehydrogenase

Formation of sn-Glycerol 3-phosphate

a. From Glycerol

Enzyme:

Reaction:

a. From Glycerol

Enzyme: Glycerol kinase

Reaction: Glycerol + ATP → sn-Glycerol 3-phosphate + ADP

b. From Dihydroxyacetone Phosphate (DHAP)

Enzyme:

Reaction:

Note: This is the primary source of glycerol-3-phosphate (as highlighted in the green box)

Enzyme: Glycerol-3-phosphate dehydrogenase

Reaction:DHAP + NADH + H⁺ → sn-Glycerol 3-phosphate + NAD⁺

2. Formation of Lysophosphatidate

Reactants:

Enzyme:

Product:

Reactants: sn-Glycerol 3-phosphate + Acyl-CoA (mainly saturated)

Enzyme: Glycerol-3-phosphate acyltransferase

Product: 1-Acylglycerol-3-phosphate (lysophosphatidate)

Name one of the acyltransferase enzymes involved in the biosynthesis of triacylglycerols.

Glycerol-3-phosphate acyltransferase

Three acyltransferase enzymes to add fatty acid to glycerol:

•glycerol-3-phosphate acyltransferase

•1-acylglycerol-3-phosphate acyltransferase

•Diacylglycerol acyltransferase

Step: Formation of Phosphatidate

Reactants

Enzyme

Reaction

Reactants

1-Acylglycerol-3-phosphate (lysophosphatidate)

Acyl-CoA

Enzyme

1-Acylglycerol-3-phosphate acyltransferase

Reaction

Adds a second fatty acid (R₂) to the glycerol backbone

What is the role of monoacylglycerol acyltransferase?

It is involved in the monoacylglycerol pathway

Monoacylglycerol pathway:

1. Formation of Diacylglycerol (DAG) from Monoacylglycerol

Substrate:

Enzyme:

Reactants:

Product:

Substrate: 2-Monoacylglycerol

Enzyme: Monoacylglycerol acyltransferase (active in the intestine)

Reactants: Acyl-CoA + CoA

Product: 1,2-Diacylglycerol (DAG)

Monoacylglycerol pathway:

2. Alternative DAG Formation from Phosphatidate

Substrate:

Enzyme:

Reactants:

Product:

Phosphatidate

Substrate: 1,2-Diacylglycerol phosphate (phosphatidate)

Enzyme: Phosphatidate phosphohydrolase

Reactants: H₂O → releases Pᵢ (inorganic phosphate)

Product: 1,2-Diacylglycerol (DAG)

Monoacylglycerol pathway:

3. Final Step: Triacylglycerol Synthesis

Substrate:

Enzyme:

Reactants:

Product:

Substrate: 1,2-Diacylglycerol

Enzyme: Diacylglycerol acyltransferase

Reactants: Acyl-CoA + CoA

Product: Triacylglycerol (TAG)

What are the two main phospholipids synthesized?

Phosphatidylcholine and phosphatidylethanolamine

Biosynthesis of phospholipids:

Phosphatidylethanolamine (PE) Pathway

Step 1: Ethanolamine Activation

Ethanolamine + ATP → Phosphoethanolamine Enzyme:

Ethanolamine kinase (EK)

Biosynthesis of phospholipids:

Phosphatidylethanolamine (PE) Pathway

Step 2: CDP-Ethanolamine Formation

Phosphoethanolamine + CTP → CDP-Ethanolamine + PPi

Enzyme:

CTP:phosphoethanolamine cytidylyltransferase (ECT)

Biosynthesis of phospholipids:

Phosphatidylethanolamine (PE) Pathway

Step 3: PE Synthesis

CDP-Ethanolamine + Diacylglycerol (DAG) → Phosphatidylethanolamine (PE)

Enzyme:

Ethanolamine phosphotransferase (EPT)

Biosynthesis of phospholipids:

Phosphatidylethanolamine (PE) Pathway

Optional Step: Conversion to PC

Phosphatidylethanolamine + 3CH₃ → Phosphatidylcholine

Enzyme:

PE N-methyltransferase (PEMT)

2. Phosphatidylcholine (PC) Pathway

Step 1: Choline Activation

Choline + ATP → Phosphocholine

Enzyme:

Choline kinase

Step 2: CDP-Choline Formation

Phosphocholine + CTP → CDP-Choline + PPi Enzyme:

CTP:phosphocholine cytidylyltransferase

Step 3: PC Synthesis

CDP-Choline + DAG →

Phosphatidylcholine

Additional Note

DAG can also be converted to ______ depending on cellular needs.

triacylglycerol

•Synthesis of cardiolipin:

Triacylglycerol (TAG) Synthesis

Phosphatidate is converted to Diacylglycerol (DAG) via phosphatidate phosphohydrolase

DAG then reacts with Acyl-CoA to form Triacylglycerol Enzyme: Diacylglycerol acyltransferase

2. Phospholipid Synthesis via CDP-Diacylglycerol

Phosphatidate reacts with CTP to form CDP-Diacylglycerol

Enzyme: CDP-diacylglycerol synthase

CDP-Diacylglycerol is a precursor for: Cardiolipin (important for mitochondrial membranes)

Other phospholipids like phosphatidylinositol and phosphatidylglycerol

(3) Biosynthesis of glycerol ether phospholipids:

Section 1: Formation of Dihydroxyacetone Phosphate

Step 1: Glycerol → sn-Glycerol 3-phosphate

Enzyme: Glycerol kinase

Reaction:Glycerol + ATP → sn-Glycerol 3-phosphate + ADP

Step 2: sn-Glycerol 3-phosphate → Dihydroxyacetone phosphate

Enzyme: Glycerol-3-phosphate dehydrogenase

Reaction:NAD⁺ → NADH + H⁺

Section 2: Ether Lipid Pathway

Step 3: Dihydroxyacetone phosphate → 1-Acyldihydroxyacetone phosphate

Enzyme: Acyltransferase

Step 4: 1-Acyldihydroxyacetone phosphate → 1-Alkyldihydroxyacetone phosphate

Enzyme: Synthase

Step 5: 1-Alkyldihydroxyacetone phosphate → 1-Alkylglycerol 3-phosphate

Enzyme: Reductase

Cofactor: NADPH → NADP⁺

•Synthesis of plasmalogens:

1. Formation of 1-Alkyl-2-acylglycerol

Starting compound: 1-Alkyl-2-acylglycerol 3-phosphate

Enzyme: Phosphohydrolase

Reaction: Removal of phosphate group → 1-Alkyl-2-acylglycerol

2. Addition of Phosphoethanolamine

Reactants: 1-Alkyl-2-acylglycerol CDP-Ethanolamine

Enzyme: CDP-ethanolamine:alkylacylglycerol phosphoethanolamine transferase

Product: 1-Alkyl-2-acylglycerol 3-phosphoethanolamine

3. Desaturation to Form Plasmalogen

Enzyme: Desaturase

Cofactors: NADPH, O₂, Cytochrome b₅

Reaction: Introduces a double bond at the sn-1 ether linkage

Product: 1-Alkenyl-2-acylglycerol 3-phosphoethanolamine plasmalogen

•Synthesis of platelet-activating factor (PAF):

Key Molecules & Reactions

Starting Molecule:

1-Alkyl-2-acylglycerol Structure: Glycerol backbone with an alkyl group at position 1 and an acyl group at position 2.

Step 1: Formation of PAF Precursor

Enzyme: CDP-choline: alkylacylglycerol phosphocholine transferase

Reactants: CDP-choline + 1-Alkyl-2-acylglycerol

Products: 1-Alkyl-2-acylglycerol 3-phosphocholine + CMP

Step 2: Hydrolysis

Enzyme: Phospholipase A₂

Reactants: 1-Alkyl-2-acylglycerol 3-phosphocholine + H₂O

Products: 1-Alkyl-2-lysoglycerol 3-phosphocholine + R₃-COOH

Step 3: Acetylation

Enzyme: Acetyltransferase

Reactants: Acetyl-CoA + 1-Alkyl-2-lysoglycerol 3-phosphocholine

Products: PAF (1-Alkyl-2-acetylglycerol 3-phosphocholine)

Final Product

Platelet-Activating Factor (PAF): A bioactive phospholipid with roles in: Platelet aggregation Inflammation Allergic responses

3. Metabolism of phospholipids:

Phospholipase A₁ (PLA₁):

Cleaves the ester bond at the first carbon of glycerol.

Releases the fatty acid at position 1.

Phospholipase A₂ (PLA₂):

Cleaves the ester bond at the second carbon of glycerol.

Releases the fatty acid at position 2.

Important in inflammatory responses (e.g., arachidonic acid release).

Phospholipase B (PLB):

Can act on both positions 1 and 2, removing both fatty acids.

Phospholipase C (PLC):

Cleaves before the phosphate group, releasing diacylglycerol (DAG) and the phosphorylated head group.

Plays a role in signal transduction.

Phospholipase D (PLD):

Cleaves after the phosphate group, releasing phosphatidic acid and the free head group.

Also involved in cell signaling.

4. Sphingolipids synthesis:

•all sphingolipids are formed from

ceramide

From what is ceramide synthesized?

From the amino acid serine in the endoplasmic reticulum

What is ceramide's role in the cell?

It is an important signaling molecule regulating apoptosis, the cell cycle, and cell differentiation

Where is sphingomyelin mainly synthesized?

In the Golgi apparatus

What are gangliosides synthesized from?

Ceramide, activated sugars (e.g., UDPGlc and UDPGal), and a sialic acid (e.g., N-acetylneuraminic acid)

How does the metabolism of phospholipids vary?

Each portion of the phospholipid turns over at a different rate and is attacked by different phospholipases

Synthesis of sphingomyelins:

mainly in the

Golgi apparatus

1. Sphingomyelin Synthesis

Reactants:

Enzyme:

Products:

Reactants: Ceramide

Phosphatidylcholine

Enzyme: Sphingomyelin synthase

Products:

Sphingomyelin (a major component of cell membranes, especially in the myelin sheath)

Diacylglycerol (DAG)

This reaction transfers the phosphocholine head group from phosphatidylcholine to ceramide.

2. Glycosphingolipid Synthesis

Reactants:

Enzyme:

Products:

Reactants:

Ceramide

UDP-Galactose (UDP-Gal)

Enzyme: Galactosyltransferase

Products:

Galactosylceramide (a type of cerebroside)

UDP

Synthesis of gangliosides:

______

•activated sugars

•a sialic acid

Ceramide