Emmanuel EspinozaCHM 46012-13-17Lipid Biosynthesis andDegradationLipids play a variety of cellularroles,  some still being researched today.They are the main form of stored energy in most organisms, as well as majorpart of cell membranes. Specialized lipids serve as pigments (retinal),cofactors (vitamin K), detergents (bile salts), transporters (dolichols),hormones (vitamin D derivatives, sex hormones), extracellular and intracellularmessengers (eicosanoids and derivatives of phosphatidylinositol), and anchorsfor membrane proteins (covalently attached fatty acids, prenyl groups, andphosphatidylinositol). The ability to synthesize a variety of lipids istherefore essential to all organisms. There are many biosynthetic pathways forsome of the principal lipids present in most cells, that are used for assemblingthese water-insoluble products from simple, water-soluble precursors such asacetate.

Like other biosynthetic pathways, these reaction sequences areendergonic and reductive. They use ATP as a source of metabolic energy and areduced electron carrier, typically NADPH as a reducing agent.   During the synthesis of fatty acids,acetyl-CoA is the precursor of the methyl end in the growing chain of the fattyacid. The carbons will be derived from the acetyl group in the acetyl-CoA .This will only happen after the acetyl-CoA is modified in order to provide thesubstrate first the fatty acid synthase, which is malonyl-CoA. The malonyl-CoAhas a three carbon dicarboxylic acid derivative known as malonate which isbound to the coenzyme A. Malonate will be  formed from acetyl-CoA when theaddition of the carbon dioxide is complete.

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The biotin factor of the enzymeacetyl-CoA carboxylase will be responsible for the addition of the CO2. This isknown as the commitment step of fatty acid synthesis. This is because themalonyl-CoA has no other metabolic roles in the body other than serving as theprecursor to fatty acids, but research is being done to find out if it has anyother metabolic functions. Oneof the more important enzymes in this reaction is the fatty acid synthase. Thisenzyme is in charge of carrying out the elongation steps of the fatty acidsynthesis scheme. Fatty acid synthase is a part of a multienzyme complex; inmammals this complex will contain two subunits. Each of the subunits of thiscomplex has a variety of enzymatic activities in the cell. In bacteria andplants, some of these proteins will associate into other complexes in order tocatalyze the steps of fatty acid synthesis.

The synthesis of fatty acids will begin withacetyl?CoA; the fatty acid chain grows from the back end in order to have  the carbon 1 and the alpha?carbon of thecomplete fatty acid added at the end. In order to start synthesis, the firstreaction will be the transfer of the acetyl group to a pantothenate groupof acyl carrier protein (ACP),which is a region of the large mammalian FAS protein. The acyl carrier proteinis a small, independent peptide in bacterial fatty acid synthase. Thepantothenate group of acyl carrier protein is the same on Coenzyme A, so the transferrequires no energy input. In the previousreaction, the S and SH refer to the thio group on the end of Coenzyme A or thepantothenate groups. The bond between the carbonyl carbon of the acetyl groupand the thio group is a very high energy bond, because the activated acetylgroup is easily donated to an acceptor and the energy is very high.

The secondreaction is another acetyl group transfer, this time, from the pantothenate ofthe ACP to cysteine sulfhydral (–SH) group on fatty acid synthase. The pantothenate group will be primed inorder to accept a malonyl group from malonyl?CoA: at this point, the fatty acid synthase hastwo different activated substrates, one of which is the acetyl group bound onthe cysteine –SH and the other is the malonyl group bound on the pantothenate–SH. The transfer of the two carbon acetyl group unit from Acety S?cysteine tomalonyl?CoA has two distinct features: first,  the release of the carbon dioxide groupof malonyic acid that was originally put on by acetyl?CoA carboxylase. The nextstep will be the generation of a 4?carbon ?? keto acid derivative, boundto the pantothenate of the acyl carrier protein. This ketoacid will now be reduced to the methylene(CH 2) state in a three?step reaction sequence. This three stepreaction will first start off with the reduction by NADPH to the ?? hydroxy acidderivative.

Next, the water is removed via dehydration reaction to make thetrans-double bond. Lastly, NADPH will reduce the molecule in order to make thesaturated fatty acid. At this point, the elongated 4?carbonchain is now ready to accept a new 2?carbon unit from malonyl?CoA. The 2?carbonunit, which is added to the growing fatty acid chain, becomes carbons 1 and 2of hexanoic acid (6?carbons). The cycle of transfer, elongation, reduction,dehydration, and reduction continues until palmitoyl?ACP is made. Then the thioesterase activity ofthe FAS complex releases the 16?carbon fatty acid palmitate from the fatty acidsynthase.Fatty acid synthesis provides anextreme example of the phenomenon of metabolic channeling: neither free fatty acids with morethan four carbons nor their CoA derivatives can directly participate in thesynthesis of palmitate. Instead they must be broken down to acetyl?CoA andreincorporated into the fatty acid.

Hydrolysis of triacylglycerols into free fatty acids and glycerol willresult in production of energy. Lipases, are catalytic enzymes that willcatalyze the reaction and carry out the hydrolysis of the triacylglycerols. Thehydrolysis reaction will release the three fatty acids and the glycerol; fromhere, an intestinal carrier will absorb the glycerol which will then rejoinwith the fatty acids later, in the intestinal cells. Absorption of the fatty acids released by the lipases will require theuse of a very complex mechanism. It is known that fatty acids are poorlysoluble in water, but they are more soluble than triacylglycerols. Due to thenonpolar nature of lipids; when they come into contact, they will form lipiddroplets.  Protein based enzymes arewater soluble and will not to be able to easily access entry into the lipiddroplets.

In order for the lipids to be digested, they must emulsified intosmaller droplets, with large surface areas. With larger and more open surfacearea, the hydrophobic interaction that force lipids into large droplets will beeasier to overcome. Bile salts or bile acids are the molecules that areprimarily responsible for carrying out these functions. The liver willmetabolically create and secrete them into the gall bladder to which they willbe then be pumped into the duodenum. These bile salts are derivedfrom cholesterol and will be a major end product of the cholesterol metabolismpathway. Bile salts have strong detergent properties, with large hydrophobic componentsand the carboxylic end that has the negative charge; this charge is present onphysiological conditions of the small intestine.

The hydrophobic component ofthe bile acid will associate at a point known as the critical micelleconcentration, which well form a disk shaped micelle structure known as adroplet. Micelles in the gut all contain cholesterol, triacylglycerol, andfatty acids as well as bile salts; these are all known as mixed micelles. The bile salts form the edge of the micelle and alsoappear, in fewer numbers (when compared to the lipids),  dispersed throughout the inside of themicelle.

The lipids exist in a bilayer on the inside of the disc. Bile acidsare important for fatty acid absorption. Themixed micelles will have enough surface area for the pancreatic lipases tocomplete their actions, and digest the lipids.

Pancreatic lipases use acofactor called colipase, which is used to bind both to the lipase and to themicelle surfaces. The actions of these lipases will lead to the free fattyacids that will be in the aqueous phase when located in the gut. Cells in thesmall intestine will most likely absorb the free fatty acids and any that aremissed will be absorbed by the bacteria of the large intestine. These bacteriacan metabolize the free fatty acids as well. Bile salts are reabsorbed in the furtherend of the small intestine. Themetabolism of bile salts can help to explain the ability of certain dietaryfibers to help lower serum cholesterol. One molecule of bile salts willcirculate through the liver and the intestine a least four times, or morebefore it will be eliminated. Certain soluble fibers, like the ones found inoat bran; will bind bile acids which cannot be eliminated in this state.

Thisis the reason why they are eliminated in the stool as fiber bound bile acids. Sincebile salts are derived from cholesterol, whenever they are made, the body willdeplete its storage of cholesterols. This depletion will lead to a reduction ofserum cholesterol and will low the risk for coronary artery diseases. Ingestionof dietary oat fiber cannot alone overcome an excessive dietary cholesterolconsumption though. Using this method but continuing to eat certain amounts offoods high in cholesterol will not help overcome the effects of highcholesterol consumption.Serum albumin will complex with the freefatty acids in order to transport them. Many other lipid derived molecules includingcholesterols and phospholipids, are all transported as protein lipid complexeswhich are known as lipoproteins.

The protein complexes are sphere shaped and willhave many different kinds of proteins on the surfaces. The different componentsof the proteins are called apolipoproteins. Lipoproteins can be classified inmany different ways. Most of them are separated based on the density of each one.The lightest of proteins are known as chylomicrons and have a lower density thanwater. Chylomicrons are made up of high lipid levels by weight. Triacylglycerolsare the main part of the chylomicrons. Chylomicrons also contain some cholesteroland other apolipoproteins.

Very low density lipoproteins arenot as dense as chylomicrons. These lipoproteins are based on proteincomponents not as much lipids. Both vldl and ldl are known as bad cholesterolssince their serum concentration levels are responsible for different heart andartery diseases like strokes. HDL are about half and half when it comes to thelipid and protein ratio. They are good cholesterols since they to lower therate of artery diseases.

 High?density lipoproteins (HDLs) willcontain a different apolipoprotein form, Apolipoprotein A which is differentthan those of low density. These proteins are just about half lipid and halfprotein by weight. Phospholipids and cholesterol esters are the most importantlipid components. HDL can be sometimes referred to as “good cholesterol”because a higher ratio of HDL to LDL corresponds to a lower rate of coronaryartery disease.

Triacylglycerols in chylomicrons and will circulatethrough the blood. These triacylglycerols are used as substrates for cellularlipases, which will then hydrolyze them to make fatty acids in severaldifferent steps. Many carrier proteins transport the lipids into the cell usingmany different pathways. There are carriers that can be used for varying chain?lengthlipids.

Energy production from triacylglycerols beginswith their hydrolysis into free fatty acids. When analyzing this fat?storing tissue,we can see that a cellular lipase will be carrying out the hydrolysis. Next thefatty acid will be taken up through the bloodstream and the liver. The liver isresponsible for glycerol absorption and the fatty acids by the blood. This can besent to the glycolytic pathway by glycerol kinase and glycerol three phosphate dehydrogenase.This enzyme can be used as energy via glucose or the TCA cycle via intermediates.Fatty acids are broken down through the?? oxidation pathway thatreleases two?carbon units.

For example, palmitic acid has 16 carbons. Itsinitial oxidation produces eight acetyl?Coenzyme A (CoA) molecules, eightreduced FAD molecules, and eight NADH molecules. The fatty acid is first activated at the outermitochondrial surface by conjugating it with CoA, then transported through the innermitochondrial membrane to the matrix, and then, for each 2?carbon unit, brokendown by successive dehydrogenation,water addition, dehydrogenation, and hydrolysis reactions. The first reaction will involve thecatalization by the  isoforms ofacyl-CoA dehydrogenase (AD) on the inner-mitochondrial membrane. This reactionwill result in trans double bond, different from naturally occurringunsaturated fatty acids. Analogous to succinate dehydrogenase reaction in thecitric acid cycle; the electrons from bound FAD transferred directly to theelectron- transport chain via electron-transferring flavoprotein (ETF) which is catalyzed bytwo isoforms of enoyl-CoA hydratase. Next, water adds across the double bond yieldingalcohol, analogous to fumarase reaction in the citric acid cyclewith the same stereospecificity.

Following this reaction, the one is  catalyzed by b-hydroxyacyl-CoAdehydrogenase which  uses NAD cofactoras the hydride acceptor. In this reaction, only L-isomers of hydroxyacyl CoAact as substrates which is analogous to malate dehydrogenase reaction inthe citric acid cycle. The next reaction is catalyzed by acyl-CoA acetyltransferase(thiolase) via covalent mechanism: The carbonyl carbon in b-ketoacyl-CoAis electrophilic, active site thiolate acts as nucleophile and releasesacetyl-CoA, and the terminal sulfur in CoA-SH acts as nucleophile andpicks up the fatty acid chain from the enzyme. This will result in the netreaction of thiolysis of carbon-carbon bond.   


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