Lipids, lipoproteins and integrated metabolism Flashcards
Kennedy Pathway
Synthesis of phosphatidylcoline (PC) and phosphatidylethinolamine (PE)
- Uses CTP as a substrate
- CDP-choline + DAG –> PC+CMP
- CDP-ethanolamine + DAG –> PE + CMP
Alternate Pathway
Synthesis of Phosphatidylglycerol (PG) and phosphatidylinositol-4,5-bisphosphate (PI)
- Use specific CTP for PG and PI
- CDP-DAG + glycerol –> PG + CMG
- CDP-DAG + inositol –> PI + CMP
*PG is essential for cardiolipin
Exchange
Synthesis of Phosphatidylserine (PS)
PE + Serine –> PS + ethanolamine
Exchanges ethanolamine for serine
Decarboxylation
Synthesis of Phosphatidylethanolamine (PE)
PS–> PE+ CO2
Methylation
Synthesis of phosphatidylcholine
PE + 3SAM –> PC
Phospholipase A1
Cuts the ester linkage at Sn1 position of the phospholipid
Phospholipid + H2O –> Lysophospholipid + R1-COOH
ex: PE + H2O –> Free fatty acid (FFA) + lysophosphatidylethanolamine
* Phospholipase A2 cuts at Sn2
Phospholipase C
Cuts the phosphate with its head group at sn3 from the phospholipid.
End up with a DAG
Ex: PS + PLC –> DAG + phosphoserine
Phospholipase D
Cuts the Head group attached to the phosphate at Sn3 of the phospholipid.
End up with phosphatidic acid (PA)
Sphingolipids
Sn2 has amide instead of ester linkage.
Sn1 has an ether instead of C-C linkage attached to X
Ceramide
Sphingolipid with H as X
1-Start from palmitoyl-CoA + Serine .
2-Use of NADPH in the pathway to reduce ketone of Sn3 into hydroxyl
3-Add fatty-acyl group into Sn2
4- Reduce C-C of Sn3 into C=C with FAD.
Cerebrosides
Sphingolipids with one sugar molecule as the X group
Globoside
Sphingolipids with 2 or more sugars attached (not branched) as the X group
Gangliosides
Sphingolipids with branched sugars+NANA group branching with sugar as the X group
Plasmalogen
Difference with phospholipids:
- Sn1 has an ether-linked alkene instead of acetyl ester
- The X group attached to Sn3 PO4 is a choline group
Platelet-activating factor
Differences with phospholipids:
- Sn1 has an ether -linked alkane instead of an acetyl ester
- Sn2 has an acetyl ester group instead of FA
- Sn3 has a choline group attached to PO4
Cholesterol Synthesis
1st step: 2Acetyl-CoA –> Acetoacetyl-CoA (4C)
2nd step (HMG-CoA synthase): Acetoacetyl-CoA + Acetyl CoA –> HMG-CoA (6C)
3rd step (HMG-CoA reductase inhibited by statins): HMG-CoA + 2NADPH –> Mevalonate (6C)
1-: Add 2 activated isoprine (5C+5C)= geranyl (10C) –>–> cholesterol (in humans), stigmasterol in plants or ergosterol in fungi
Products upstream of cholesterol biosynthesis
Activated isoprene (∆3-Isopentyl pyrophosphate) –> Vitamin A,E,K, carotenoids, plant hormones, rubber, phytol chain of chlorophyll, dolichols, quinone electron carrier: ubiquinone and plastoquinone, isoprene, cholesterol
Products downstream of cholesterol biosynthesis
Cholesterol –> Bile acids, Vitamin D , Steroid hormones.
Steroid hormones biosynthesis:
Cholesterol –> pregnenolone –> progesterone –> cortisol, corticosterone or testosterone .
- Corticosterone –> aldosterone
- Testosterone (reduction + demethylation) –> Estradiol
Cholesterol ester biosynthesis
1- LCAT enzyme (in plasma!):
Phosphatidylcholine (lecithin) + cholesterol –> Cholesteryl ester + Lysolecithin
2- ACAT enzyme (intracellular!):
Acyl-CoA + Cholesterol –> Cholesteryl ester + CoA
-Cholesteryl ester is hydrohphobic –> can be packed and transported or stored
Vitamin D biosynthesis
7-Dehydrocholesterol + UV light –>–> Cholecalciferol (Vit. D3) –>–> 1,25 D3
Tags to drive proteins into membranes
- Palmitoyl group on interanal Cys(or Ser) (inside)
- N-Myristoyl gorup on amino-terminal Gly (inside)
- Farnesyl group on carboxy-terminal Cys (inside)
- GPI anchor on carboxyl terminus (located on the outside)
HMG-CoA reductase regulation
- Activated by insulin
- Product inhibition (endogenous and exogenous cholesterol).
Can inhibit product inhibition by converting cholesterol into cholesteryl esters using ACAT. - Inhibited by glucagon and statin
Cholesterol regulation in the ER
1- SCAP has a sterol sensing domain. When cholesterol is present, it binds to SCAP, preventing the release of SREBP.
When cholesterol is not present, SCAP releases SREBP which can go to the Golgi complex
2- In the golgi, SREBP is cleaved by S1P and S2P proteases.
3- The released domain of SREBP migrates to the nucleus and increases synthesis of HMG-CoA reductase (endogenous cholesterol) and LDL receptors synthesis (exogenous cholesterol)
Uptake of exogenous cholesterol
LDL receptor receptor-mediated endocytosis –> Endosome (LDL receptor recycling)–> Lysosome (degradation into a.a, FAs and cholesteryl ester droplets
Chylomicrons
- Lipoprotein
- Lowest density
- Highest TAG content
- Lowest protein content (as well as phospholipids, free cholesterol and cholesteryl esters)
VLDL
- lipoprotein
- low density
- has a little bit more protein content that chylomicrons and a little less TAG
LDL
- lipoprotein
- Second-highest density
- Has more proteins, less TAG and many cholesteryl esters (bad cholesterol)
HDL
- Lipoprotein
- Highest density
- Highest protein content
- Lowest TAG content
- Less cholesteryl esters than in LDL
ApoA-1
- Exchangeable Apolipoprotein
- Associates with HDL
- Activates LCAT (which generates cholesteryl esters)
- Interact with ABC transporters
ApoB-48
- Integral Apolipoprotein
- very large integral protein
- associates with chylomicrons
ApoB-100
- Largest apolipoprotein
- Integral
- Associates with VLDL and LDL.
- Binds to LDL receptor
- It contains a ligand-binding domain
ApoC-II
- Exchangeable Apolipoprotein
- low molecular weight
- Found on chylomicrons, VLDL and HDL
- Activates lipoprotein lipase
ApoE
- Exchangeable Apolipoprotein
- Associates with chylomicrons, VLDL and HDL.
- Triggers clearance of VLDL and chylomicrons remnants.
Ketone bodies biosynthesis
- 1st Step (thiolase): 2 acetyl-CoA Acetoacetyl-CoA (4C)
- 2nd step (HMG-CoA synthase): Acetoacetyl-CoA + Acetyl-CoA + H2O –> HMG-CoA (6C)
- 3rd Step (HMG-CoA lyase): HMG-CoA –> Acetoacetate + Acetyl CoA
- 4th Step (acetoacetate decarboxylase or D-ß-hydroxybutyrate dehydrogenase), formation of ketone bodies:
Acetoacetate –> Acetone + CO2
or
Acetoacetate + NADH –> D-ß-Hydroxybutyrate
- First 2 steps are similar than cholesterol biosynthesis
- Ketone bodies formation is not inhibited by statins because they target HMG-CoA reductase.
