Fatty Acid Synthesis. Sources of Fatty Acids: Sites of Fatty Acid Synthesis:

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1 Fatty Acid Sythesis Sources of Fatty Acids: Diet (pricipal source) Coversio of carbohydrates ad proteis to fatty acids. Sites of Fatty Acid Sythesis: Liver Lactatig mammary glads Adipose tissues. Fatty acid sythesis Additio of carbos (from Acetyl-CoA) to fatty acid chai. ATP- ad NADPH-depedet.

2 FATTY ACID SYNTHESIS & DEGRADATION SYNTHESIS Cytoplasmic process Phosphopatetheie-boud itermediates Requires NADPH Eergy cosumig Requires CO 2 Resposive to citrate Two carbo uits added as maloyl CoA DEGRADATION Occurs i mitochodria Coezyme A boud itermediates NAD + ad FAD Eergy yieldig CO 2 yieldig Two carbo uits removed as acetate Note: FATTY ACID SYNTHESIS DOES NOT OCCUR BY REVERSAL OF THE FATTY ACID DEGRADATION PATHWAY.

3 Cytosolic Acetyl CoA First but ot committed step i fatty acid sythesis. Occurs i mitochodria. Ivolves trasfer of acetate uits from mitochodria acetyl CoA to the cytosol. Sice the CoA part ca ot cross the mitochodria chage to citrate. Traslocatio of citrate: Cleavage by ATP-citrate lyase. Produces cytosolic acetyl CoA ad oxaloacetate (OAA). Ehaced by ATP ad citrate.

4 Formatio of Maloyl-CoA The first committed step i sythesis of fatty acids is the formatio of the maloyl-coa. Acetyl-CoA, is carboxylated to maloyl-coa i a reactio catalyzed by Acetyl-CoA Carboxylase usig HCO3 ad ATP ad bioti as co-ezyme ATP-depedet carboxylatio of the bioti, carried out at oe active site, followed by trasfer of the carboxyl group to acetyl-coa at a secod active site. HCO 3- + ATP + acetyl-coa ADP + Pi + maloyl-coa

5 Acetyl-CoA Carboxylase (ACC) Commits acetate to fatty acid sythesis Carboxylatio of acetyl-coa to form maloyl- CoA is the irreversible, committed step i fatty acid biosythesis ACC uses bicarboate ad ATP (AND bioti) O ATP O O + HCO 3- + C S CoA C H2 H 3 O S CoA

6 NADPH Sources of NADPH eeded for FA sythesis, iclude: 1. Petose phosphate pathway (PPP) 2. Citrate (Cyotosolic) Acetyl-CoA + Oxaloacetate, Oxaloacetate (reduced by NADH) malate, Malate (oxidatively decarboxylated) pyruvate + NADPH

7 Fatty Acid Sythase Catalyzes fatty acid sythesis from acetyl CoA, maloyl CoA ad NADPH. Multi-ezyme complex, cosistig of two idetical peptide chais. Each chai is subdivided ito: Domai I: cotais acetyl ad maloyl trasferase ad codesig ezyme. Forms acetyl-acp ad maloyl-acp, ad iduces their codesatio. Domai II: acyl carrier protei (ACP) [carries substrate from oe active site to aother]. Mediates both reductio ad dehydratio reactios. Domai III: cotais thioesterase [releases plamitate after elogatio cycle].

8 Fatty Acid Sythase

9 Elogatio Phase A 2-step process ivolvig repetitio of the followig four reactios: Codesatio: formatio of acetyl-acp ad maloyl-acp followed by their codeatio (mediated by acyl-maloyl-acp) acetoacetyl- ACP. Reductio: Formatio of D-3-hydroxybutyryl- ACP; catalyzed by b-ketoacyl-acp reductase (NADPH-depedet) Dehydratio: formatio of crotoyl-acp (catalyzed by 3-hydroxyacyl-ACP dehydratase) Reductio: Formatio of butyryl-acp from crotoyl-acp (catalyzed by eoyl-acp reductase). New cycle uses maloyl-acp as a source of 2C uits cotiues, util the 16-C palmitate-acp is produced

10 Further Processig Additioal elogatio (for >16C FA) & desaturatio (for usaturated FA) uses ezymes i mitochodria ad ER. Elogatio: additio of 2-carbo uits, mediated by elogases: Foud i ER ad mitochodria Have specific mechaisms of actio Destauratio: mediated by termial desaturases (mixed-fuctio oxidases): Itroductio of double bods NADPH ad O 2 depedet

11 Regulatio of FA Sythesis Allosteric modifiers, phosphorylatio ad hormoes Maloyl-CoA blocks the caritie acyltrasferase ad thus ihibits b-oxidatio. Acetyl CoA Carboxylase (ACC) Activated by citrate Ihibited by fatty acyl-coas Hormoes regulate ACC Glucago activates lipases/ihibits ACC Isuli ihibits lipases/activates ACC