Fatty Acid Synthesis

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Fatty acid and triacyl glycerol synthesis

    • Glucoseis converted toacetylCoAforfattyacidsynthesis
      • Glucose enters liver cells and is converted via glycolysis to pyruvate, which enters mitochondria.(MCQ)
      • Pyruvate is converted to (MCQ)
        • acetyl coenzyme A (CoA) by pyruvatedehydrogenase
        • oxaloacetate(OAA) by pyruvate carboxylase.
      • Because acetyl CoA cannot directly cross the mitochondrial membrane and enter the cytosolto be used for the process of fatty acid synthesis, acetyl CoA and OAA condense to form citrate,which can cross the mitochondrial membrane.(MCQ)
      • In the cytosol, citrate is cleaved to OAA and acetyl CoA
        • Enzyme :citrate lyase
        • citratelyaserequires ATP
        • citratelyase is induced by insulin.(MCQ)
      • OAA from the citrate lyase reaction is reduced in the cytosol by NADH, producing NAD+and malate.
        • Enzyme is cytosolic malate dehydrogenase.(MCQ)
      • Malate is converted to pyruvate
        • NADPH is produced, and CO2 isreleased.
        • The enzyme is malic enzyme (or NADP+-dependent malate dehydrogenase).
        • Pyruvate reenters the mitochondrion and is reutilized.
        • NADPH supplies reducing equivalents for reactions on the fatty acid synthase complex
        • NADPH is produced by malic enzymeand the pentose phosphate pathway.(MCQ)
      • Acetyl CoA(from the citrate lyase reaction or from other sources) supplies carbons for fatty acid synthesis in the cytosol.(MCQ)
    • Synthesisoffattyacidsbythefattyacidsynthasecomplex
      • Fatty acid synthase
        • amultienzyme complex
        • located in the cytosol(MCQ)
        • It has two large identicalsubunits with seven catalytic activities.
        • Thisenzymecontainsaphosphor pantetheineresidue,derivedfromthevitaminpantothenicacid, and a cysteine residue; both contain sulfhydryl groups that can form thioesters withacyl groups.(MCQ)
        • The growing fatty acyl chain moves during the synthesis of two carbon units from one tothe other of these sulfhydryl residues as it is elongated.
      • Additionoftwo-carbonunits
        • Initially,acetylCoAreactswiththephosphopantetheinylresidue,andthentheacetylgroupis transferred to the cysteinyl residue.
        • A malonyl group from malonyl CoA forms a thioesterwith the phosphopantetheinylsulfhydryl group.
        • Acetyl CoA carboxylase
          • Malonyl CoA (two carbons) is formed from acetyl CoA by a carboxylation reaction that requires biotin and ATP. (MCQ)
          • The enzyme catalyzing this reaction is acetyl CoA carboxylase
          • inhibited by phosphorylation(MCQ)
          • activated by dephosphorylation and by citrate(MCQ)
          • induced by insulin.(MCQ)
        • The acetyl groupon the fatty acid synthase complex condenses with the malonyl group;the CO2 that was added to the malonyl group by acetyl CoA carboxylase is released; and a b-ketoacyl group, now containing four carbons, is produced.
      • Reduction of the b-keto acy lgroup
        • Theb-ketogroupisreducedbyNADPHtoab-hydroxygroup.
        • Thendehydrationoccurs,producingadoublebondbetweencarbons2and3.
        • Finally,thedoublebondisreducedbyNADPH,andafour-carbonacylgroupisformed
        • NADPHisproducedbythepentosephosphatepathwayandmalicenzyme.(MCQ)
      • Elongation of the growing fatty acylchain
        • Theacylgroupistransferredtothecysteinylsulfhydrylgroup,andmalonylCoAreactswiththe phosphopantetheinyl group. Condensation of the acyl and malonyl groups releases CO2, followed by three reactions reducing the b-keto group.
        • The chain grows by two carbons.
        • Thissequenceofreactionsrepeatsuntilthegrowingchainis16carbonsinlength.
        • Palmitate, a 16-carbon saturated fatty acid, is the final product released by hydrolysis fromthe fatty acid synthase complex.(MCQ)
      • Elongation and desaturation of fatty acids
        • Palmitate can be elongated and desaturated to form long-chain saturated and unsaturated fatty acids.
        • Elongation of long-chain fatty acids occurs on the endoplasmic reticulum by reactions similar to those that occur on the fatty acid synthase complex.(MCQ)
        • MalonylCoAprovidestwo-carbonunitsaddingtopalmitoylCoA.
        • Malonyl CoA condenses with the carbonyl group of the fatty acyl residue, and CO2 isreleased.(MCQ)
        • The beta-keto group is reduced by NADPH to a beta-hydroxy group; dehydration occurs; and adouble bond is formed, which is reduced by NADPH.
        • Desaturation of fatty acids requires O2, NADPH, and cytochrome b5.(MCQ)
        • In humans, desaturases may add double bonds at the 9 to 10 position of a fatty acyl CoA and between carbon 9 and the carboxyl group.
        • Plants introduce double bonds between carbon 9 and theOmega-carbon; animals cannot. These unsaturated fatty acidsfrom plants are essential in the human diet.
        • Linoleate(18:2, 9,12) and alpha-linolenate(18:3, 9,12,15) are the major sources of the essential fatty acids, required for synthesis of arachidonic acidand other polyunsaturated fatty acids of the eicosanoid (e.g., prostaglandins) family.(MCQ)
    • Synthesis of triacylglycerols
      • In intestinal epithelial cells, triacylglycerol synthesis occurs by a different pathway than inother tissues.
      • This triacylglycerol becomes a component of chylomicrons(MCQ)
      • Ultimately, the fattyacyl groups are stored in adipose triacylglycerols.
      • In liver and adipose tissue
        • glycerol 3-phosphate provides the glycerol moiety that reacts withtwo fatty acyl CoA molecules to form phosphatidic acid.
        • The phosphate group is cleaved to form a diacylglycerol, which reacts with another fatty acyl CoA to form a triacylglycerol.
        • The liver can use glycerol to produce glycerol 3-phosphate by a reaction that requires ATP and is catalyzed by glycerol kinase.
      • Adipose tissue
        • lacks glycerol kinase
        • cannotgenerate glycerol 3-phosphate from glycerol.
        • Both liver and adipose tissue can convert glucose, through glycolysis, to dihydroxyacetone phosphate (DHAP),which is reduced by NADH to glycerol 3-phosphate.(MCQ)
    • Triacyl glycerolis stored in a diposetissue.
      • In the liver, triacylglycerol is incorporated into very-low-density lipoprotein (VLDL), entering blood. (MCQ)
      • Ultimately, fatty acyl groups are stored in adipose triacylglycerols.
    • Regulation of triacylglycerol synthesis from carbohydrate
      • Synthesis of triacylglycerols from carbohydrate occurs in the liver in the fed state
      • Key regulatory enzymes are activated and induced by carbohydrate.
        • The glycolytic enzymes glucokinase, phosphofructokinase 1, and pyruvate kinase are active.
        • Pyruvatedehydrogenaseisdephosphorylatedandactive.
        • PyruvatecarboxylaseisactivatedbyacetylCoA.
        • Citratelyaseisinducible.(MCQ)
        • AcetylCoAcarboxylaseisinduced,activatedbycitrate,andconvertedtoitsactive,dephosphorylated state by a phosphatase that is stimulated by insulin.(MCQ)
        • Thefattyacidsynthasecomplexisinducible.
      • NADPH
        • thereductant for fatty acid synthesis
        • produced by the
          • induciblemalic enzyme
          • pentose phosphate pathway enzymes: glucose 6-phosphate dehydrogenase and 6-phos- phogluconate dehydrogenase.(MCQ)
      • Carnitineacyltransferase I(carnitinepalmitoyltransferase I)
        • Malonyl CoA,the product of the acetyl CoA carboxylase reaction ,inhibits it
        • Preventsnewly synthesized fatty acids from entering mitochondria and undergoing beta-oxidation.(MCQ)
      • Formation of triacyl glycerol stores in adipose tissue
          • Hydrolysis of triacylglycerols of chylomicrons and VLDL
            • The triacylglycerols of chylomicrons and VLDL are hydrolyzed to fatty acids and glycerolbylipoprotein lipase in the capillary walls of adipose tissue.
            • Lipoprotein lipase
              • synthesized in adipose cells
              • secretedfrom the cell in response to insulin.(MCQ)
              • This results in elevated lipoprotein lipase levels after consuming a meal.
              • Apoprotein C-II,which is transferred from HDL to chylomicrons and VLDL once those particles enter the circulation, activates lipoprotein lipase.(MCQ)
          • Synthesisoftriacylglycerolsinadiposetissue
            • Fatty acids released from chylomicrons and VLDL by lipoprotein lipase are taken up by adipose cells and converted to triacylglycerols, but glycerol is not used because adipose tissue lacks glycerol kinase (MCQ)
            • Transportofglucoseintoadiposecellsisstimulatedbyinsulin.
            • Glucose is converted to DHAPand reduced by NADH to form glycerol 3-phosphate, which produces the glycerol moiety of the triacylglycerol.
            • The triacylglycerols are stored in large fat globules in adipose cells.(MCQ)
          • Applied aspects :
            • Elevated triglyceride (triacylglycerol) > 1000 mg/dL can cause pancreatitis(MCQ)
            • Chylous ascites
                • extravasation of milky chyle (lymph) with a triglyceridelevel of more than 200 mg/dL into the peritoneal cavity of the abdomen.
                • occurs in abdominal surgery, abdominal trauma, and cancers such as lymphomas, in which the lymphatic system is obstructed.

                 

                1.         All of the following are required for the de novo synthesis of fatty acids. EXCEPT:

                A.        PLP

                B.        NADPH

                C.        ATP

                D.        Bicarbonate

                ANS:   1.          A. De novo synthesis of fatty acids require NADPH (reduced nicotinamideadenine dinucleotide phosphate), ATP and bicarbonate. HMP shunt (Hexose mono phosphate shunt) anilcitrate shuttle (malic enzyme) are the main source for NADPH. The first step of fatty acid synthesis is carboxylation of acetyl CoA to malonyl CoA, which requires ATP and bicarbonate (source of CO2).

                2.         Which vitamins are required for biosynthesis of fatty acids:

                A.        Biotin and vitamin K

                B.        Pantothenic acid and thiamin

                C.        Biotin and folic acid

                D.        Biotin and pantothenic acid

                ANS:   2.         D. Carboxylation of acetyl CoA to malonyl CoA. Carbondioxidei> covalently bounded to biotin using the energy from the hydrolysis of ATP. In the presence of acetyl CoA carboxylase, carbondioxidr is transferred to acetyl CoA to produce malonyl CoA.

                1

                Acyl carrier protein is a component of fatty acid synthase compplex. possesses a phosphopantetheine group , which is derived in mi the vitamin pantothenic acid.

                3.         Pick out the correct statement regarding regulation of acetyl CoA carboxylase:

                A.        Enzyme is inactivated allosterically by high concentration of citrate

                B.        Phosphorylation of acetyl CoA carboxylase favours fatty acid synthesis

                C.        Insulin favours fatty acid synthesis by dephosphorylation of acetyl CoA carboxylase

                D.        Acetyl CoA carboxylase is activated by malonyl CoA

                ANS:   3. C. When the concentration of ATP is high, enzymes of TCA c v i li-especially isocitrate dehydrogenase is inhibited (no need to generate energy). High concentration of citrates will be transported into cytosol by tri carboxylate transporter. Acetyl CoA carboxylase is activated allosterically by high concentration of citrate. Glucagon and epinephrine favours the formation of inactive phosphorylated form of acetyl CoA carboxylase and inhibit fatty acid synthesis. Dephosphorylation of acetyl CoA carboxylase is favoured by insulin, which increases the enzyme activity. Palmitoyl CoA is the inhibitor of acetyl CoA carboxylase.

                4.         Which one of the following statement is correct regarding fatty acid synthase complex in mammals:

                A.        It is a dimer with unidentical subunits

                B.        Each subunit composed of six enzymes

                C.        Two subunits are in antiparallel direction

                D.        They catalyze the same enzymatic steps

                 ANS:  4.         C. Fatty acid synthase is a multi- enzyme complex. It composed of two identical dimer, which each subunit has seven catalytic activities and acyl carrier protein (ACP) segment in a continuous polypeptide chain. Two subunits lie in antiparallel direction. The ACP segment contains a phosphopantetheine residue derived from the cleavage of coenzyme A. The -SH group of phosphopantetheine of one sub unit is linked to the -SH of cysteine residue of the other subunit. Each cycle of fatty acid synthesis employs one acyl carrier protein and seven enzymes: acetyl transacylase, malonyltransacylase, P-ketoacylsynthetase, dehydratase, enoylreductase, ketoacylreductase and thioesterase.

                5.         Camitine:

                A.        It is synthesized from lysine and methionine in liver and kidney

                B.        It is chemically p-hydroxy y-trimethyl amino butyrate

                C.        It is a transpoter for short chain fatty acids

                D.        Acyl carnitine is transported across the membrane by the translocase to the mitochondrial matrix

                ANS:   5.C. p-oxidation enzymes are in the mitochondrial matrix, but the inner mitochondrial membrane is impermeable for activated long chain fatty acyl CoA molecules. Carnitine is chemically p- hydroxy y-trimethylaminobutyrate, synthesised from lysine and methionine in liver and kidney. The acyl group is transferred from acyl CoA to carnitine by carnitine acyl transferase I, an enzyme found on the cytosolic side of inner mitochondrial membrane. Acyl carnitine is transported across the membrane by translocase to the mitochondrial matrix. The acyl group is transferred back to CoA by carnitine acyl transferase n, located on the inner surface of the inner mitochondrial membrane. Carnitine is returned to cytosol for reuse.

                11.       All of the following hormones activate hormone sensitive lipase EXCEPT:

                A.        Glucagon

                B.        Adrenaline

                C.        Insulin

                D.        Noradrenaline

                ANS:   11.       C. In the adipose tissue, hormone sensitive lipase is in an inactive form, which is activated (phosphorylated) by a cyclic AMP dependent protein kinase. Glucagon, Adrenaline and nora-drenaline activate hormone sensitive lipase by enhancing the activity of adenylatecyclase and thus increases lipolysis. Insulin inactivates the hormone sensitive lipase by decreasing cyclic AMP levels.

                12 .Carnitinedeficiency can occur in a number of ways. Secondary carnitinedeficiency can be distinguished from primary carnitinedeficiency by measuring which of the following in the blood?

                (A)       Fatty acids

                (B)       Acyl-carnitine

                (C)       Lactic acid

                (D)       Glucose

                (E)       Ketone bodies

                8 The answer is B:

                acyl-carnitine. Primary carnitine deficiency is a lack of carnitine within the cell (such as a mutation in the carnitine transporter); secondary carnitine deficiency occurs when the carnitine is sequestered in the form of acyl-carnitine (the carnitine cannot be removed from the acyl group, such as a defect in carnitine acyl transferase 2). Thus, elevated levels of acylcarnitine would be expected in a secondary carnitine deficiency, but not in a primary carnitine deficiency. In both types of carnitinedeficiencies, fatty acid oxidation is significantly reduced, so the levels of ketone bodies, glucose, lactate, and fatty acids would be similar under both conditions.


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