METABOLISM OF ACYLGLYCEROLS AND SPHINGOLIPIDS
BIOMEDICAL IMPORTANCE
Acyglycerols – constitute majority of lipids in the body
Triacylglycerols – major lipids in fat deposits and in food
Phospholipids & sphingolipids – amphipathic nature makes them suitable as main lipid component of cell membranes
- Phospholipids take part in metabolism of many other lipids
- Dipalmitoyl lecithin: lung surfactant (lacking in respiratory distress syndrome)
- Inositol phospholipids: precursors of hormone second messengers
- Platelet activating factor (PAF): alyklphospholipid
- Glycosphingolipids: spingosine + sugar residues + FA in outer leaflet of plasma membrane with oligosaccharide chains facing outward → GLYCOCALYX:
o Cell adhesion and cell recognition
o Receptors for bacterial toxins (e.g. cholera)
o ABO blood group substances
Glycolipid storage diseases – Gaucher’s disease, Tay-Sachs disease → defect in glycolipid degradation in lysosomes
HYDROLYSIS INITIATES CATABOLISM OF TRIACYLGLYCEROLS
Lipase – hydrolyzes TAG ➔ FA + glycerol
- Hydrolysis (lipolysis) occurs in adipose tissue → release of FA into plasma → combine with serum albumin → FFA uptake into tissues (liver, heart, kidney, muscle, lung,
testis, adipose tissue, but not readily by brain) → oxidized or reesterified
- Utilization of glycerol depends whether tissues possess glycerol kinase (liver, kidney, intestine, brown adipose tissue, lactating mammary gland)
TAG & PHOSPHOGLYCEROLS ARE FORMED BY ACYLATION OF TRIOSE PHOSPHATES
- Significant branch points: phosphatidate and diacylglycerol steps
- DHAP → phosphoglycerols containing ether link (-C-O-C-) → PLASMALOGENS & PAF
- Glycerol 3-P and DHAP→ intermediates in glycolysis → connection between CHO and lipid metabolism
➢ Phosphatidate is the common precursor in the biosynthesis of TAG, many phosphoglycerols, & cardiolipin
- activity of enzymes resides in ER but some in mitochondria
- regulation of TAG, phosphatidylcholine, and phosphatidylethanolamine biosynthesis driven by: availability of FFA → those that escape oxidation → converted to
phospholipids → requirement satisfied → used for TAG synthesis
o Biosynthesis of TAG
Enzyme Substrates and products Description
Glycerol kinase Glycerol + ATP →sn- glycerol 3 – P + ADP >glycerol and FA must be activated by ATP before
incorporated into acylglycerols
Glycerol 3 – P acyltransferase Glycerol 3 – P + acyl-CoA (mainly saturated) → 1-acylglycerol-3-P >glycerol phosphate pathway
(lysophosphatidate) + CoA
Glycerol 3-P dehydrogenase Glycerol 3-P + NAD+ ↔ dihydroxyacetone phosphate (DHAP) + NADH + >if activity of glycerol kinase is low (muscle or adipose
H+ ↔ glycolysis tissue), glycerol 3-P formed from DHAP
1-acylglycerol-3-P acyltransferase 1-acylglycerol-3-P + acyl-CoA (usually unsaturated) → 1,2-diacylglycerol >2 molecules of acyl-CoA (formed by activation of FA by
phosphate (phosphatidate) + CoA acyl-CoA synthetase) combine with glycerol 3-P in two
stages to form phosphatidate
Phosphatidate phosphohydrolase 1,2-diacylglycerol phosphate + H2O → 1,2 diacylglycerol + Pi >enzyme mainly in cytosol but active form is membrane
bound
Monoacylglycerol acyltransferase (intestinal 2-monoacylglycerol + acyl-CoA → 1,2 diacylglycerol + CoA >monoacylglycerol pathway
mucosa)
Diacylglycerol acyltransferase (DGAT) 1,2 diacylglycerol + acyl – CoA → TRIACYLGLYCEROL + CoA >catalyzes the only step specific for TAG synthesis
>rate limiting in most circumstances
Choline kinase Choline + ATP → phosphocholine + ADP >choline and ethanolamine first activated by
phosphorylation by ATP
>choline considered an essential nutrient in many
mammalian species (not established in humans)
CTP: phosphocholine cytidyl transferase Phosphocholine + CTP → CDP-choline + PPi >linkage with CDP
CDP-choline:diacylglycerol phosphocholine CDP-choline + 1,2 diacylglycerol → CMP + PHOSPHATIDYLCHOLINE >phosphatidylethanolamine also formed
transferase
Serine + phosphatidylethanolamine → phosphatidylserine + >phosphatidylethanolamine formed from ethanolamine by a
ethanolamine pathway similar to that shown for formation of
phosphatidylcholine
Phosphatidylserine → PHOSPHATIDYLETHANOLAMINE + CO2 >reformation of phosphatidylethanolamine from
phosphatidylserine by decarboxylation
Phosphatidylethanolamine N – Phosphatidylethanolamine + (-CH3)3 → phosphatidylcholine >alternative pathway in liver by progressive methylation
methyltransferase
CDP-DG synthase 1,2-diacylglycerol phosphate (phosphatidate) + CTP → CDP-
diacylglycerol + PPi
Phosphatidyl-inositol synthase CDP-diacylglycerol + inositol → PHOSPHATIDYLINOSITOL (PIP) +
CMP
Kinase PIP + ATP → PIP-4-phosphate + ADP
kinase PIP-4-P + ATP → PIP 4,5 bisphosphate + ADP
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BIOMEDICAL IMPORTANCE
Acyglycerols – constitute majority of lipids in the body
Triacylglycerols – major lipids in fat deposits and in food
Phospholipids & sphingolipids – amphipathic nature makes them suitable as main lipid component of cell membranes
- Phospholipids take part in metabolism of many other lipids
- Dipalmitoyl lecithin: lung surfactant (lacking in respiratory distress syndrome)
- Inositol phospholipids: precursors of hormone second messengers
- Platelet activating factor (PAF): alyklphospholipid
- Glycosphingolipids: spingosine + sugar residues + FA in outer leaflet of plasma membrane with oligosaccharide chains facing outward → GLYCOCALYX:
o Cell adhesion and cell recognition
o Receptors for bacterial toxins (e.g. cholera)
o ABO blood group substances
Glycolipid storage diseases – Gaucher’s disease, Tay-Sachs disease → defect in glycolipid degradation in lysosomes
HYDROLYSIS INITIATES CATABOLISM OF TRIACYLGLYCEROLS
Lipase – hydrolyzes TAG ➔ FA + glycerol
- Hydrolysis (lipolysis) occurs in adipose tissue → release of FA into plasma → combine with serum albumin → FFA uptake into tissues (liver, heart, kidney, muscle, lung,
testis, adipose tissue, but not readily by brain) → oxidized or reesterified
- Utilization of glycerol depends whether tissues possess glycerol kinase (liver, kidney, intestine, brown adipose tissue, lactating mammary gland)
TAG & PHOSPHOGLYCEROLS ARE FORMED BY ACYLATION OF TRIOSE PHOSPHATES
- Significant branch points: phosphatidate and diacylglycerol steps
- DHAP → phosphoglycerols containing ether link (-C-O-C-) → PLASMALOGENS & PAF
- Glycerol 3-P and DHAP→ intermediates in glycolysis → connection between CHO and lipid metabolism
➢ Phosphatidate is the common precursor in the biosynthesis of TAG, many phosphoglycerols, & cardiolipin
- activity of enzymes resides in ER but some in mitochondria
- regulation of TAG, phosphatidylcholine, and phosphatidylethanolamine biosynthesis driven by: availability of FFA → those that escape oxidation → converted to
phospholipids → requirement satisfied → used for TAG synthesis
o Biosynthesis of TAG
Enzyme Substrates and products Description
Glycerol kinase Glycerol + ATP →sn- glycerol 3 – P + ADP >glycerol and FA must be activated by ATP before
incorporated into acylglycerols
Glycerol 3 – P acyltransferase Glycerol 3 – P + acyl-CoA (mainly saturated) → 1-acylglycerol-3-P >glycerol phosphate pathway
(lysophosphatidate) + CoA
Glycerol 3-P dehydrogenase Glycerol 3-P + NAD+ ↔ dihydroxyacetone phosphate (DHAP) + NADH + >if activity of glycerol kinase is low (muscle or adipose
H+ ↔ glycolysis tissue), glycerol 3-P formed from DHAP
1-acylglycerol-3-P acyltransferase 1-acylglycerol-3-P + acyl-CoA (usually unsaturated) → 1,2-diacylglycerol >2 molecules of acyl-CoA (formed by activation of FA by
phosphate (phosphatidate) + CoA acyl-CoA synthetase) combine with glycerol 3-P in two
stages to form phosphatidate
Phosphatidate phosphohydrolase 1,2-diacylglycerol phosphate + H2O → 1,2 diacylglycerol + Pi >enzyme mainly in cytosol but active form is membrane
bound
Monoacylglycerol acyltransferase (intestinal 2-monoacylglycerol + acyl-CoA → 1,2 diacylglycerol + CoA >monoacylglycerol pathway
mucosa)
Diacylglycerol acyltransferase (DGAT) 1,2 diacylglycerol + acyl – CoA → TRIACYLGLYCEROL + CoA >catalyzes the only step specific for TAG synthesis
>rate limiting in most circumstances
Choline kinase Choline + ATP → phosphocholine + ADP >choline and ethanolamine first activated by
phosphorylation by ATP
>choline considered an essential nutrient in many
mammalian species (not established in humans)
CTP: phosphocholine cytidyl transferase Phosphocholine + CTP → CDP-choline + PPi >linkage with CDP
CDP-choline:diacylglycerol phosphocholine CDP-choline + 1,2 diacylglycerol → CMP + PHOSPHATIDYLCHOLINE >phosphatidylethanolamine also formed
transferase
Serine + phosphatidylethanolamine → phosphatidylserine + >phosphatidylethanolamine formed from ethanolamine by a
ethanolamine pathway similar to that shown for formation of
phosphatidylcholine
Phosphatidylserine → PHOSPHATIDYLETHANOLAMINE + CO2 >reformation of phosphatidylethanolamine from
phosphatidylserine by decarboxylation
Phosphatidylethanolamine N – Phosphatidylethanolamine + (-CH3)3 → phosphatidylcholine >alternative pathway in liver by progressive methylation
methyltransferase
CDP-DG synthase 1,2-diacylglycerol phosphate (phosphatidate) + CTP → CDP-
diacylglycerol + PPi
Phosphatidyl-inositol synthase CDP-diacylglycerol + inositol → PHOSPHATIDYLINOSITOL (PIP) +
CMP
Kinase PIP + ATP → PIP-4-phosphate + ADP
kinase PIP-4-P + ATP → PIP 4,5 bisphosphate + ADP
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