Classes of lipids 1. fatty acids 2. triglycerides = glycerol + 3 f.a. 3. phosphoglycerides = gly. + 2 f.a. 4. steroids 5. sphingolipids=sphingosine+x+f.a. hosphogluconate pathway (pentose shunt) Main functions: 1. formation of NAD: for lipid synthesis 2. formation of ribose- Location in cell: enzymes found in cytoplasm hosphogluconate pathway (pentose shunt) Regulation: glucose-6- Dase catalyzes the first step NAD: inhibits g-6-d activity hosphogluconate pathway Substrate: glucose-6- End-products: depends on needs of cell - in adipose cells, NAD: is required for reducing lipid intermediates - in rapidly dividing cells, DNA syn. requires pentose- 4 s C- : g-6- G-6- Dase NAD + C- = 6--gluconolactone NAD: + + C-= 6-phosphogluconolactone Lactonase =.. ::.. - C= -C- -C- -C- -C- -C--= 6-phosphogluconate
6-hosphogluconate Dase -C= -C- -C- -C- -C- -C--= =C= NAD + NAD: + + -C- C= - C- - C- - C--= ribulose-5- glu glycogen c.acetyl CoA glu g-6- NAD: r-5- c.citrate f-6- gly. f-1,6-di DA 3-G DA gly. AA E pyr pyr acetyl Co A AA citrate malate pyr malate isocitrate malate AA succinate G succ.coa G-6- D deficiency isozymes catalyze G-6- D reaction in red blood cells one isozyme is stable and produces most of NAD: 2nd isozyme is absent in many people whose ancestors survived in malarial areas Regions of endemic malaria function of NAD: in rbc NAD: formed in red blood cells by pentose shunt supplies : ions for reducing oxidants and repairing damaged molecules high fever, or ingestion of drugs, e.g. aspirin, causes extra NAD: to be used in rbc G-6-D deficient humans increased demands for NAD: occur after large doses of quinones, aspirin, sulphonimides or high fever if unusually large demands for NAD: in rbc, then damaged proteins not repaired anemia results due to fewer rbc
Nitrates in diet NAD: is used to form b-fe++ from b-fe+++ (met-b) in rbc in some individuals, the enzyme, met-b reductase is inhibited by nitrates and the [functional b- Fe++] drops significantly, and anemia results Main function: storage of acetyl residues for future energy needs Substrate: cytoplasmic acetyl CoA C 3 - C~S-CoA End-product: palmitate 16:0 (16 C : 0 =) C 3 - (C 2 ) - C _ 14 C-C-C-C-C-C-C-C-C-C-C-C C-C- C - C ~S-CoA 16 1 Regulation: acetyl CoA carboxylase - catalyzes rate-limiting step - activated by cytopl. citrate allosterically - inactivated by active protein kinase Regulation: Citrate shuttle - moves acetyl residues to cytoplasm m. acetyl CoA + AA citrate Rate of triglyceride formation also regulates f.a. synthesis Location: cytoplasm of adipose and liver cells citrate + cytopl. CoA + AT citrate lyase acetyl CoA + AA + AD + i
m. acetyl~s CoA + AA _ -C - C~S-CoA C C= -C-_ C C - C ~S CoA + c. acetyl CoA Citrate shuttle citrate lyase C C= -C- C Citrate - C= -C- C C -C- C Ō cytoplasm 1. acetyl CoA carboxylase C 3 -C~S-CoA -C-C 2 -C~S - CoA malonyl CoA N-carboxybiotin biotin AD + i AT C 3 - - cytoplasmic citrate is required for activation of acetyl CoA carboxylase 2. Transfer of acetyl and malonyl residues to carrier proteins C 3 -C ~ S-CoA synthase-s - - C - C 2 - C ~S-CoA AC-S CoA -S - C 3 -C ~ S-synthase CoA-S - C - C 2 - C ~S - AC 3. Condensation reaction C 3 -C ~ S-synthase + -C - C 2 -C ~S -AC acetyl synthase malonyl acyl carrier protein S-synthase C 2 + C 3 - C - C 2 - C ~ S-AC acetoacetyl AC 4. Reduction reactions NAD+ NAD: + + C 3 - C-.. C 2 - C ~ S-AC C 3 - C- C 2 - C ~ S-AC C 3 - C = C - C ~ S-AC C 3 - C - C - C ~ S-AC NAD: + + NAD+ Second condensation C 3 -C 2 - C 2 -C ~ S - AC - C - C 2 - C ~ S - AC C 3 -C 2 -C 2 -C ~S-synthase malonyl AC C S-synthase 2 C 3 - C 2 - C 2 - C -C 2 - C ~ S -AC
Reduction reactions NAD: + + NAD+ R - C- C 2 - C ~ S-AC R - C - C - C ~ S-AC R - C-.. C 2 - C ~ S-AC R- C = C - C ~ S-AC NAD: + + NAD+ palmityl CoA C-C-C-C-C-C-C-C-C-C-C-C C-C- C - C ~ S - CoA 16 1 end product of fatty acid synthesis Fatty acids in human cells fatty acid C:= palmitoleic 16:1 oleic 18:1 linoleic 18:2* linolenic 18:3* arachidonic 20:4 *essential fatty acids Elongation of palmityl CoA -C-C 2 C ~ S-CoA malonyl CoA R - C 2 - C ~ S-CoA palmityl CoA R - C = C - C ~ S-AC NAD: + + R- C- C 2 -C ~ S-CoA NAD: + + NAD+ R- C -C -C ~ S-AC Elongation reaction R - C 2 - C 2 - C ~ S-AC stearyl 18:0 Desaturation of fatty acids (double bond formation) - by enzymes miniature ETS systems C 3 - (C 2 ) 16 -C ~ S-CoA + NAD: = stearyl CoA NAD 2 2 C 3 -(C 2 ) 7 -C=C-(C 2 ) 7 -C~ S-CoA oleyl CoA
Triglyceride synthesis Main function: storage of fatty acids for energy Regulation: Location: rate depends on availability of fatty acids and = cytoplasm of adipose cells (also liver) Triglyceride synthesis Substrates: fatty acyl CoA s + glycerol 4 Endproduct: triglycerides tri-palmitate tri-oleate fatty acids NEVER free in the cell fatty acids may be stored in triglycerides, may be made into phosphoglycerides for cell membranes or put onto cholesterol to form cholesterol esters fatty acid Triglyceride pathway DA glycerol NAD: NAD C 3 (C 2 ) 14 -C~S-CoA C 3 (C 2 ) 14 -C~S-CoA 2 -C--C-(C 2 ) 14 -C 3 2 CoA-S 2 -C--C-(C 2 ) 14 -C 3 -- 2 -C--- phosphatidate Triglyceride pathway Triglyceride pathway 2 -C--C-(C 2 ) 14 -C 3 -C--C-(C 2 ) 14 -C 3 2 -C--- phosphatidate -- i 2 -C--C-(C 2 ) 14 -C 3 -C--C-(C 2 ) 14 -C 3 2 -C-- diacylglycerol 2 -C--C-(C 2 ) 14 -C 3 -C--C-(C 2 ) 14 -C 3 2 -C--C-(C 2 ) 14 -C 3 tripalmitate CoA-S 2 -C--C-(C 2 ) 14 -C 3 -C--C-(C 2 ) 14 -C 3 2 -C-- diacylglycerol C oa-s~c-(c 2 ) 14 -C 3
ormonal control of lipid synthesis 1. Glucagon and epinephrine act through cam to inhibit acetyl CoA carboxylase. glucagon G cam AT protein kinase active ac.coa carboxylase inactive ormonal control of lipid synthesis 2. Insulin acts through other proteins (e.g. irs-1) to stimulate activity of: irs-1 pyruvate Dase insulin citrate lyase binds to receptor protein to cause irs-1 to form glu glycogen c.acetyl CoA glu g-6- NAD: r-5- c.citrate f-6- gly. f-1,6-di DA 3-G DA gly. AA E pyr pyr acetyl Co A AA citrate malate pyr malate isocitrate malate AA succinate G succ.coa