Synthesis of Fatty Acids
step 3
acetyl CoA goes into lipogenesis (becomes fuel for lipogenesis) with the help of NADH, oxaloacetate produces malate Oxaloacetate + NADH ---> malate + NAD+ enzyme: malate dehydrogenase
elongation to palmitate step 2
acetyl group (2C) on monomer 1 binds to malonyl group (3C) on monomer 2 -----> CO2 + CoA + Ketoacyl (acetoacetyl ACP) (4C compound) enzyme: ketoacyl synthase
elongation to palmitate step 6
enzyme, thioesterase, (part of FA synthase complex) releases palmitate (16:0) from ACP of enzyme complex
step 2
once in cytosol: citrate undergoes reverse or its formation to regenerate acetyl CoA, ATP & oxaloacetate. Citrate + ATP +CoA ---> acetyl CoA + Oxaloacetate + ADP +Pi enzyme: ATP citrate lyase
step 4
once in the cytosol: malate produces pyruvate, CO2, n NADPH with the help NADP+ malate + NADP+ ---> pyruvate + CO2 + NADPH enzyme: malic anezyme
step 5
pyruvate is shuttled back to the inner mitochondrial membrane by a pyruvate transporter protein, where it makes oxaloacetate with the help of ATP and CO2, the whole cycle continues pyruvate + ATP + CO2 ---> oxaloacetate + ADP + Pi enzyme: pyruvate carboxylase
synthesis of omega-3 PUFAs
the body cannot make alpha-linolenate (18:3 delta 9,12,15) from linoleate (18:2 delta 9,12), thus it is essential -however other omega-3 can be made from alpha-linoleate -alpha-linoleate (18:3 delta 9,12,15) can be desaturated (delta 6 desaturase) to form 18:4 delta 6,9,12,15 -18:4 can be elongated by 2 carbons to from 20:4 delta 8,11,14,17 -20:4 can be desaturated (delta 5 desaturase) to from EPA (20:5 delta 5,8,11,14,17) -EPA can then be elongated by 2 carbons to form 22:5 delta 7,10,13,16,19 -22:5 can be desaturated (delta 4 desaturase) to form DHA (22:6 delta 4,7,10,13,16,19)
synthesis of omega-6 PUFAs
the body cannot make linoleate (18:2 delta 9,12) from oleate (18:1), thus it is essential -however, other omega-6 can be made from linoleate linoleate (18:2 delta 9,12) can be desaturated (delta 6 desaturase) to form gamma linolenate (18:3 delta 6,9,12) -gamma linolenate is elongated (elongase) by 2 Carbons to form 20:3 (detla 8,11,14) -20:3 (delta 8,11,14) can be desaturated (delta 4 desaturase) for form arachidonate (20:4 delta 5,8,11,14)
major steps
-formation of malonyl CoA (helps with the process of delivery) -ACP complex formation -chain elongation lipogenesis can convert glucose to fatty acids via acetyl CoA but humans cannot reverse the process
desaturation
-liver microsomal system -always start at next largest number, i.e., if fatty acid is saturated (16:0 or 18:0) then largest point for mammals is delta 9, then delta 6, delta 5, and detla 4 -thus to form 16:1 from palmitate or 18:1 from stearate we would desaturate at carbon #9, as delta 9 desaturase
synthesis of stearate 18:0
-palmitate (16:0) is converted into palmitoyl CoA (addition of CoA) -palmitate CoA is added to malonyl CoA with a loss of CO2 (FA elongase) -new fatty acid is rearranged, same as before (step 3), to form stearoyl CoA -stearoyl CoA then forms stearate (18:0) with the loss of CoA
synthesis of oleate (18:1)
-stearoyl CoA (18:0) plus the delta desaturase enzyme will form stearoyl-enzyme-complex with the loss of CoA -stearoyl-enz complex with be converted into hydroxystearoyl-enz complex with the addition of one molecule of oxygen at the 9th carbon -hydroxystearoyl-enz will form oleyl-enz complex with the addition of CoA and removal of enzyme -oleyl CoA can then form oleate (18:1 omega-9)
elongation to palmitate step 1
A) acetyl group binds to monomer 1 (acetyl transcyclase) forming acetyl ACP B) malonyl group binds to monomer 2 (malonyl transacyclase) forming malonyl ACP
elongation to palmitate step 4
A) this new butyryl-ACP on monomer 2 is transferred to monomer 1 b) a new malonyl CoA is formed from another acetyl CoA and is placed on monomer 2 C) the new butyryl-ACP on monomer 1 is added to malonyl group on monomer 2 with the loss of CO2 producing a 6 C structure (repeat of step 2) D) repeat step 3
fatty acid synthase complex
all intermediates in lipogenesis are bound to acyl carrier proteins (ACP) rather than CoA a "head-to-tail" arrangement of the two monomers. Though each monomer contains all the partial activities of the reaction sequence, the actual functional unit consists of one-half of one monomer interacting with the complementary half of theother. Thus, two acyl chains are produced simultaneously. -dimer (2 identical parts) enzyme complex made of 8 proteins (7 enzymes + 1 acyl carrier protein ACP) -fatty acid attaches to ACP (thiolester) as it is made -final product is always palmitate (16:0)
problem in diet
americans east so little alpha-linolenate that EPA and DHA also become essential for health this problem is usually not true for omega-6 PUFAs because same enzymes are used, a competition exist between the synthesis of omega-3 and omega-6
fate of palmitate
chain elongation (FA elongase) to 18:00, etc add malonyl CoA as before -desaturation: removes Hs with desaturases -esterification: FAs are added to other compounds, i.e. glycerol, cholesterol with ester linkage
elongation to palmitate step 3
rearrangement Rx of acetoacetyl- ACP: A) Ketoacyl + NADPH + H^+ (h donor) ---> hydroxyacyl (hydrobutryl)+ NADP^+ enzyme: ketoacyl reductase - forming hydrobutyrl- ACP B) lose water (hydratase) forming crotonyl ACP hydroxyacyl ----> unsat acyl + H2O enzyme: hydratase C) unsat acyl + NADPH + H^+ ---> sat acyl NADP^+ enzyme: enoyl reductase (forming butyryl ACP)
elongation to palmitate step 5
repeat 5 more times until the structure is 16 carbons
step 1
since acetyl CoA is produced in the mitochondria (pyruvate dehydrogenase) and lipogenesis occurs in the cytosol, first step is to get acetyl CoA out of mitochondria Acetyl CoA + Oxaloacetate ---> citrate + CoA enzyme: citrate synthase outer mitochondrial membrane is freely permeable to acetyl CoA as well as many other substances like citrate, malate, pyruvate inner membrane is not permeable to acetyl CoA thus we need an indirect shuttle system involving citrate transporter (protein)
Lipogenesis
the metabolic pathway by which fatty acids are synthesized from acetyl CoA -occurs in cytosol -fatty acid synthase complex -fatty acid is bonded to acyl carrier protein (ACP) -Needs NADPH as a reducing agent - upto 2 carbons are synthesized at a time -acetyl CoA forms malonyl CoA (3 carbons), which becomes the carrier of the two carbon units -excess calorie intake from carbohydrates and alcohl leading to excess amount of acetyl CoA -takes place in liver, adipose tissue and mammary tissue
formation of malonyl CoA
to make this molecule, we need acetyl CoA, ATP, and carboxylase acetyl CoA + HCO^-_3 -----> malonyl CoA -ATP ----> ADP + Pi -acetyl CoA carboxylase ( W/ Biotin) -activated by citrate and insulin in the well fed state. -inhibited by long chain unsaturated fatty acids, thus eating a diet higher in mono- and polyunsaturated fat may prevent fatty acid synthesis.
