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SPHINGOLIPIDS

SPHINGOLIPIDS. Head piece. Hydrophobic Tails. Sphingomyelin. Ganglioside G M1. H. OH. H. CH 3 (CH 2 ) 12 C=C-CH- C -CH 2. H. NH. O. C=O. R. HO. H. C. H. OH. 2. O. H. +. CH 3 -(CH 2 ) 12 -C=C-CH- C -CH 2 -OPO-CH 2 CH 2 N(CH 3 ) 3. O. H. O. NH. C=O.

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SPHINGOLIPIDS

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  1. SPHINGOLIPIDS Head piece Hydrophobic Tails Sphingomyelin Ganglioside GM1

  2. H OH H CH3(CH2)12C=C-CH-C-CH2 H NH O C=O R HO H C H OH 2 O H + CH3-(CH2)12-C=C-CH-C-CH2-OPO-CH2CH2N(CH3)3 O H O NH C=O R Sphingomyelin Cerebroside

  3. O Antigen GalNAc A Antigen Gal B Antigen Blood Group Antigens, A,B,O -Lacto- O = Universal donor -Lacto- AB = Universal acceptor Glycosphingolipids (no Sialic acid) -Lacto- (What if ‘O’ was the acceptor and ‘AB’ the donor?)

  4. 1 2 3 3 4 Gangliosides (with Sialic acid) Head Piece of Ganglioside Core Oligosaccharide

  5. Palmitoyl-CoA + Serine 3-Ketosphinagnine Sphinganine Dihydroceramide Ceramide

  6. Sphingolipid Biosynthesis OH CH3(CH2)12CH2-CH2-CH-C-CH2OH O O +NH3 CH3(CH2)12CH2-CH2-C-C-CH2OH CH3(CH2)12CH2-CH2-C-S-CoA HS-CoA CO2 H H3N+ H H HO-CH2C-COO- H3N+ Palmitoyl-CoA Serine Sphinganine 3-keto NADPH Sphinganine (dihydrosphingosine)

  7. H OH CH3(CH2)12CH2-CH2-CH-C-CH2OH +NH3 O R-CH2C-S-CoA H OH CH3(CH2)12CH2-CH2-CH-C-CH2OH NH C=O C=O Only trans double bond in any lipid R R H OH H CH3(CH2)12C=C-CH-C-CH2OH H NH Sphinganine (dihydrosphingosine) Dihydroceramide FAD Dihydroceramide (N-acylsphinganine) Ceramide (N-Acylsphingosine)

  8. All modifications occur here H OH H CH3(CH2)12C=C-CH-C-CH2OH H O NH O HC-O-C-R O R-C-O-CH + HC-OPO-CH2CH2N(CH3)3 O C=O R H OH O H + CH3-(CH2)12-C=C-CH-C-CH2-OPO-CH2CH2N(CH3)3 H O NH C=O R Ceramide Lecithin Donates Phosphocholine + DAG Sphingomyelin

  9. H H OH OH H H CH3(CH2)12C=C-CH-C-CH2 CH3(CH2)12C=C-CH-C-CH2OH H H NH NH UDP-Glucose UDP O C=O C=O R R HO C H 2 O Cerebroside

  10. Sphingolipid Turnover Tay-Sachs Disease Hexosamindase A is missing Sphinolipids must turnover to prevent accumulation in neuronal cells

  11. Cholesterol Biosynthesis • Synthesis of mevalonate • Synthesis of isopentenyl-PPi • Synthesis of squalene • Cyclization of squalene to lanosterol • Lanosterol to cholesterol

  12. 2 NADPH + 2H+ 2 NADP+ + HS-CoA OH O OOC-CH2-C-CH2-C~SCoA OH CH3 OOC-CH2-C-CH2-CH2OH CH3 HMG-CoA HMG-CoA reductase mevalonate Rate controlling step in cholesterol biosynthesis Inhibited by glucagon (phosphorylation) Stimulated by insulin Inhibited by lovastatin and compactin (fungus)

  13. HO C COO- X O OH HO O CH3 C COO- H3C CH3 OH R Mevalonate STATINS (Competitive inhibitors of HMG-CoA Reductase) R = H X = H Compactin R = CH3 X = H Lovastatin (MevacorTM) R = OH X = H Pravastatin (PravacholTM) R = CH3 X = CH3 Simvastatin (ZocorTM)

  14. ATP ATP ATP ADP ADP ADP OP OOC-CH2-C-CH2-CH2OP~P OH OH OH CH3 OOC-CH2-C-CH2-CH2OP~P OOC-CH2-C-CH2-CH2OH OOC-CH2-C-CH2-CH2OP CH3 CH3 CH3 Mevalonate

  15. CH3 H2C=CH-CH=CH2 CO2 CH3 CH3 Pi CH2=C-CH2-CH2OP~P CH3-C=CH-CH2OP~P OP OOC-CH2-C-CH2-CH2OP~P CH3 Isoprene (2 methyl- 1,3 butadiene) Isopentenyl-P~P Dimethylallyl-P~Pi

  16. PPi CH3 CH3 CH3 CH3 CH2=C-CH2-CH2OP~P CH3-C=CH-CH2OP~P CH3-C=CH-CH2 CH2-C=CH-CH2OP~P carbon-carbon bond 10 carbons Geranyl-P~Pi

  17. PPi CH3 CH3 CH3 CH3 CH3 CH3-C=CH-CH2 CH2-C=CH-CH2OP~P CH3-C=CH-CH2 CH2-C=CH-CH2 CH2=C-CH2-CH2OP~P CH3 CH2-C=CH-CH2OP~P CH2OPP Farnesyl-P~Pi

  18. CH2OPP PPOCH2 Squalene C30

  19. Cyclization of Squalene to Lanosterol Lanosterol is the first fully closed ring compound

  20. HO Cholesterol

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