fatty acid biosynthesis MUHAMMAD MUSTANSAR FJMC LAHORE
DR MUHAMMAD MUSTANSAR Fatty Acid Synthesis
Fatty acids Fatty acids are a class of compounds containing a long hydrophobic hydrocarbon chain and a terminal carboxylate group They exist free in the body as well as fatty acyl esters in more complex molecules such as triglycerides or phospholipids. Fatty acids can be oxidized in all tissues, particularly liver and muscle to provide energy They are also structural components of membrane lipids such as phospholipids and glycolipids. Esterified fatty acids, in the form of triglycerides are stored in adipose cells Fatty acids are also precursors of Eicosanoids
Sources of Fatty acids Diet Adipolysis De novo synthesis(from precursors)- Carbohydrates, protein, and other molecules obtained from diet in excess of the body’s need can be converted to fatty acids, which are stored as triglycerides
Biosynthesis of Fatty acidsThe excess dietary Carbohydrates & Proteinscan be converted to fatty acids and are stored asTri acyl Glycerol.Denovo synthesis of Fatty acids takes place inLiver, Kidney, adipose tissue and LactatingMammary glands.Site: Cytoplasm of the cellRequirements:Acetyl CoA – source of Carbon atomsNADPH – provides reducing equivalentsATP – energy
═ Fatty acid synthesis in 3 stages(i) Production of Acetyl CoA & NADPH(ii) Conversion of acetyl CoA to Malonyl CoA(iii) Reactions of Fattyacid synthase complex.
De novo fatty Acid Synthesis-extraFatty acids are synthesized by an Introductionmitochondrial systemThis system is present in many tissues, includingliver, kidney, brain, lung, mammary gland, andadipose tissue.Acetyl-CoA is the immediate substrate, and freepalmitate is the end product.Its cofactor requirements include NADPH, ATP,Mn2+, biotin, and HCO3– (as a source of CO2).
Location of fatty acid synthesis FA synthase complex is found exclusively in the cytosol. The location segregates synthetic processes from degradative reactions.
Sources of NADPHNADPH is involved as donor of reducingequivalentsThe oxidative reactions of the pentose phosphatepathway are the chief source of the hydrogenrequired for the reductive synthesis of fatty acids.Tissues specializing in active lipogenesis—ie, liver,adipose tissue, and the lactating mammary gland—possess an active pentose phosphate pathway.Other sources of NADPH include the reaction thatconverts malate to pyruvate catalyzed by the "Malicenzyme" (NADP malate dehydrogenase) and the extramitochondrial isocitrate dehydrogenase reaction(probably not a substantial source, except inruminants).
Acetyl co A- Sources and Fate Acetyl co A, the precursor for fatty acid synthesis is produced from pyruvate, ketogenic amino acids, fatty acid oxidation and by alcohol metabolism It is a substrate for TCA cycle and a precursor for fatty acids, ketone bodies and sterols.
Transportation of Acetyl co AFattyacid synthesis requires considerableamounts of acetyl-CoANearly all acetyl-CoA used in fatty acidsynthesis is formed in mitochondria Acetyl co A has to move out from themitochondria to the cytosol Cytosol – site of acetate utilization Mitochondria – site of acetate synthesis
Transportation of Acetyl co AAcetate is shuttled out of mitochondria as citrateThe mitochondrial inner membrane isimpermeable to acetyl-CoAIntra-mitochondrial acetyl-CoA first reacts withoxaloacetate to form citrate, in the TCA cyclecatalyzed by citrate synthaseCitrate then passes into the cytosol throughthe mitochondrial inner membrane on thecitrate transporter.In the cytosol, citrate is cleaved by citratelyase regenerating acetyl-CoA.
Enzymes and cofactors involved in theprocess of Fatty acid synthesisTwo main enzymes-Acetyl co A carboxylaseFatty acid SynthaseBoth the enzymes are multienzyme complexesCoenzymes and cofactors are-BiotinNADPHMn++Mg++
Steps in Fatty acid synthase complex1) Acetyl CoA is transferred to ACP by Acetyl CoA ACP transacylase (CoA is removed). The two carbon unit acetate which is attached to ACP is shifted to cysteine residue of keto acyl synthase enzyme.
2) Now Malonyl CoA is transferred to ACP by Malonyl CoA ACP transacylase where Co A is removed
3) The acetyl unit (2) which is attached to cysteine combines with malonyl unit (3 ‘C’) where Co2 is released to form keto acyl, ACP, Enzyme is keto acyl synthase.
4) Ketoacyl ACP undergoes reduction to form β-hydroxy acyl ACP, enzyme is keto Acyl reductase NADPH provides Hydrogens.
5) β-hydroxy acyl ACP undergoes dehydration where one water molecule is removed to form Enoyl ACP (double bond between 2 & 3 Carbons) enzyme is dehydratase.
6) Enoyl ACP undergoes reduction to form acyl ACP or butryl ACP, enzyme is enoyl ACP reductase, NADPH provides Hydrogens.
7) The 4 carbon butryl acid attached to ACP is shifted to cysteine residue and reactions 2 – 6 are repeated
Series of ReactionsAfter activation, the processes involved are-1. Condensation2. Reduction3. Dehydration4. ReductionThese steps are repeated till a fatty acid with 16 carbonatoms is synthesized
Repetition of these four steps leadsto fatty acid synthesis
The overall reaction for thesynthesis of palmitate fromacetyl-CoA can be consideredin two parts.
Part 1First, the formation of seven malonyl-CoA molecules: 7Acetyl-CoA + 7CO2 + 7ATP 7malonyl CoA + 7ADP + 7Pi
Part 2Then the seven cycles of condensation andreductionAcetyl-CoA + 7malonyl-CoA + 14NADPH + 14H+ palmitate + 7CO2 + 8CoA + 14NADP+ + 6H2OThe biosynthesis of FAs requires acetyl-CoA andthe input of energy in the form of ATP and reducingpower of NADPH.
Rxn for palmitate synthesis is: Acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 7 H+ palmitate + 7 CO2 + 14 NADP+ + 8 CoASH + 6H2OBut malonate is made from acetyl CoA7 acetyl-CoA + 7 CO2 + 7 ATP 7 malonyl-CoA + 7 ADP + 7 Pi + 7 H+So overall:8 acetyl-CoA + 7 ATP + 14 NADPH palmitate +14 NADP+ + 8 CoASH + 6 H2O + 7 ADP + 7 PiThe NADPH comes from the pentose phosphateshunt. The source of acetyl-CoA is more complex.
Comparison of β-Oxidation & Fatty AcidSynthesis Βeta Oxidation Fatty acid Synthesis pathwayLocation Mitochondrial CytoplasmicAcyl Carriers(Thiols) Coenzyme A 4’ Phosphopantetheine and CysteineElectron acceptors and FAD/NAD NADPHdonorsOH Intermediates L D2 Carbon Acetyl co A Acetyl co A/ Malonyl coproduct/donor A