Anabolism of Fatty acids (Anabolic Lynen spiral) Glycerol and Triglycerides

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1 Anabolism of Fatty acids (Anabolic Lynen spiral) Glycerol and Triglycerides Anabolism of fatty acids Fatty acids are not stored in the body free. They are a source of energy in the form of triglycerides (1) They are precursors of phospholipids, which are constituents of membranes. The synthesis of saturated fatty acids is done from acetylcoa issue from the degradation of glucose (2). Unsaturations in fatty acids chain occurs by oxidation of saturated fatty acids. The synthesis of fatty acids occurs mainly in the cytosol (3). However the end of the synthesis of fatty acids in C18 or more takes place in the endoplasmic reticulum. Comments (1) Triglycerides are firstly stored in some organs such as the liver, then in adiposites. (2) This explains that fatty acids always have an even number of carbon. However in certain ruminants, the synthesis can use a propionylcoa (C3) in addition to the AcetylCoA. They contain fatty acids with odd number of carbons. (3) This route is so different from degradation. 1

2 Synthesis of saturated fatty acids GLOBAL SYNTHETIC BALANCE: n CH 3 COSCoA 4(n-1) e CH 3 (CH 2 ) 2n-2 COO - + HSCoA (Anabolic Lynen spiral ). The synthesis involves only two enzymes: the malonyl-coa synthase (or acetyl-coa carboxylase) and fatty acid synthase. (Involved coenzymes are not indicated) NB : The synthesis involves 2 (n-1) reductions, n-1 synthesis of skeletons and n hydrolyses. Each round involves two reductions, a synthesis of skeleton, and hydrolysis. On the last step an extra hydrolysis releases the fatty acid. AcetylCoA carboxylase (ACC) ACC transforms the AcetylCoA in MalonylCoA under a mechanism similar to that of pyruvate carboxylase. CO 2 CH 3 COSCoA COO - -CH 2 -COSCoA ATP ADP + P Biotine 2

3 Fatty acid synthase (FAS) The FAS of mammals consists of two subunits of molecular mass g/mol each bearing all active sites. It synthesizes two fatty acid molecules. A rotating arm: FAS H S CH 2 CH 2 NH CO CH 2 CH 2 NH CO CHOH C(CH 3 ) 2 O P O Ser Enzyme pantheteine The arm consists of a pantheteine molecule formed by a chain of 11 atoms of carbon and nitrogen. It is condensed on a phosphoserine belonging to acid fat synthase forming pantothenate (-PantSH). See the thiol. Comments The panthetein is also constitutive of the HSCoA. 3

4 Reactions FAS has several active sites corresponding each to a different activity. The rotating arm swings to get the fatty acid in building a site to another. 1. Transferase activity Simple transfer of malonyl CO-CH 2 -COO Synthase activity: coupled reaction Synthesis, skeleton breakdown, hydrolysis. 3. DH activity (NADP dependent). Reduction. 4. Dehydratase activity 5. DH activity (NADP dependent) Reduction alkene to alkane. NB : FADH 2 reduces the alkene and is the regenerated by NADPH. 6. Transferase activity Simple transfer Other sites : Starting site: transfer of acetyl (CH 3 CO) groupe from acetyl-coa to PantSH. Ending site: hydrolysis of the fatty acid 4

5 Synthesis of fatty acids of more of 18C Fatty Acid Synthase (FAS) present in the cytosol synthesizes fatty acids not longer than the palmitate (C16). For longer acids, palmitate is transported from cytosol to endoplasmic reticulum (ER). An isofas at ER fixes palmitate and continues the elongation. 5

6 Unsaturated fatty acids synthesis Unsaturated fatty are obtained by O2 involving oxidation of saturated fatty acids. Oxydase CH 3 -(CH 2 ) 16 -COO - CH 3 -(CH 2 ) 7 -CH=CH-(CH 2 ) 7 -COO- 1/2 O2 H2O Comments Oxidases are oxido-reductases using O 2. Biosynthesis of glycerol Glycerol-P is produced by reduction of dihydroxy-ketone P (glycolysis) A phosphatase (Pase) is then involved to produce glycerol. C=O CH 2 OP DH CHOH CH 2 OP NADH NAD + Pase P CHOH The synthesis and degradation of glycerol differ only by the action of a phosphatase in the case of synthesis and of a kinase in the case of degradation 6

7 Anabolism of triglycerids Glycerides are synthetized from glycerol-p and acylcoa : Step 1 : Acyl-CoA are synthetized from free fatty acids by the same ligases than in anabolism. Steps 2 and 3 : 2 transferases condensate acyl group on glycerol-p to form a phosphatidic acid Step 4 : A 3rd transferase forms the triglyceride Remark Phosphatidic acids are precursors of phospholipides Phospholipide 7