ࡱ> Root Entry F!|@μCompObjnWordDocumentuObjectPool|| O\"#$%&'()*+,-./0123PQRSTUVWXYZ[!]^_`aSummaryInformation( @Y@O@8M%Microsoft Word 6.010 FMicrosoft Word 6.0 Document MSWordDocWord.Document.69q_Oh+'0$ H l   D h        (C:\MSOFFICE\WINWORD\TEMPLATE\NORMAL.DOTCellular Biochemistry NotesKenneth WunchKenneth Wunch@~ܥe= $eu0$$bbbbb hvc h h hh2h4 huAfhfh"hhhhhhiiii(ijhkTuTuIk bhhhhhkhbbhfhhhhhbhbhib>chbbbbhihhCellular Biochemistry Notes Chapter 19 "Lipid Metabolism" Lipid Digestion, Absorption, and Transport -Triacylglycerides constitute both ~90% of the dietary lipid and the major form of metabolic energy storage in humans; the oxidative metabolism of fats yields over twice the energy of an equal weight of dry carbohydrate or protein -Since triacylglycerols are water insoluble, whereas digestive enzymes are water soluble, triacylglycerol digestion takes place at lipid-water interfaces; rate of digestion therefore depends on the surface area of the interface and is greatly increased by the emulsifying action of bile acids -Enzymatic activity of pancreatic lipase greatly increases when it contacts the lipid-water interface, a phenomenon known as interfacial activation; however, the enzyme does not bind unless it is in complex with pancreatic colipase -Phospholipids are degraded by pancreatic phospholipase A2, which hydrolytically excises the fatty acid residue at C2 to yield the corresponding lysophospholipids (powerful detergents); disrupt membranes and can lyse cells -Bile acids and fatty acid-binding protein facilitate the intestinal absorption of lipids; bile acids not only aid lipid digestion but are essential for the absorption of lipid digestion products; inside intestinal cells, fatty acids form complexes with intestinal fatty acid-binding protein (I-FABP), a cytoplasmic protein which increases the solubility of these water-insoluble substances and protects the cell from their detergent-like effects Lipids are transported in lipoprotein complexes Fig. 19-5 Dietary Lipids -The lipid digestion products absorbed by the intestinal mucosa cells are converted to triacylglycerols and cholesterols and then packaged into chylomicrons. -Triacylglycerols and cholesterols synthesized by the liver are packaged into very low density lipoproteins (VLDL) -Triacylglycerol components of chylomicrons and VLDL are hydrolyzed to free fatty acids and glycerol in the capillaries of adipose tissue and skeletal muscle by lipoprotein lipase; in the liver and kidneys, it is further converted to DHAP; VLDLs that have lost fatty acids are LDLs Adipose Lipids -Mobilization of triacylglycerols stored in adipose tissue involves hydrolysis to glycerol and free fatty acids by triacylglycerol lipase -Free fatty acids are released into the bloodstream where they bind to albumin, a soluble protein that comprises about half of the blood serum protein; rare individuals who suffer from analbuminemia, severely depressed levels of albumin, suffer no apparent adverse symptoms, their fatty acids are transported in complex with other serum proteins Fatty Acid Oxidation -Before fatty acids can be oxidized, they must be "primed" for reaction in an ATP-dependent acylation to form fatty acyl-CoA this process is catalyzed by a family of at least 3 acyl-CoA synthetases; these enzymes catalyze the following reaction: Fatty acid + CoA + ATP ( ( acyl-CoA + AMP + PPi -These enzymes are associated with the ER or the outer mitochondrial membrane Transport across the Mitochondrial Membrane -A long-chain fatty acyl-CoA cannot directly cross the inner mitochondrial membrane--its acyl portion is first transferred to carnitine -Translocation process itself is mediated by a specific carrier protein that trans. Biosynthesis of ceramide occurs in four reactions from the precursors palmitoyl-CoA and serine 4. Galactocerebroside and glucocerebroside are the two most common cerebrosides and are common components of brain lipids 5. Sulfatides account for 15% of the lipids of white matter in the brain 6. Biosynthesis of globosides and gangliosides is catalyzed by a series of glycosyl transferases 15 (hydroxymethylglutaryl)-nthsized from HMG-CoA in a 26--either synthesize it from HMG-''''''''''',(-(0(1(@(v(x(y())))2)5)\)]))))))****+++G+R+T+U++++,,u,v,1-T-U-^-_-`-a-b-----..q..////6/R/r/// 0)01#1$1n1o122223364N4P4Q444445,7U^c ^c Uc c `,73:A@@ApDqFF~I/NHNbOQQQQQQQQQQQQQ` `8`;`>`A`C`Y`b`c`i`j`````````DaEaYaZa[abamaaaaaa1b3bYbZbbbbbb^c U^c Uc uPc Aw(x(())[)\)))))g***++S+T++++++,t,u,,0-1-_-`-..///0m1n11p22222S3!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t-S35464O4P444f5g55`6a666,7t7u7777w88999:2:3:h:i:::;;;;;+<,<z<{<<<K===!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t-=>O>P>>>>>T???@@@A@@@A3A4AQARAvAwAAAAABB;B"?"<#=##$%%&&&&'''a(b({(|((())**]*^**P+y+z+,,,,,,n-o--*.+........//3////000001!!t!t!t!t!t!x!t!t!t!t!t!t!t!t!!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t ',7b)*$w(S3=7E.Nb+,-./ !! Kenneth Wunch A:\BCHP18.DOC Kenneth Wunch A:\BCHP19.DOC Kenneth Wunch A:\BCHP19.DOC Kenneth Wunch A:\BCHP19.DOC ken wunch A:\BCHP19.DOC ken wunch A:\BCHP19.DOC ken wunch A:\BCHP19.DOC Kenneth Wunch A:\BCHP19.DOC Kenneth Wunch A:\BCHP19.DOC Kenneth Wunch A:\BCHP19.DOC@Canon Bubble-Jet BJ-200eLPT1:CANON800Canon Bubble-Jet BJ-200e@fyyhRoot Entry F!|9= CompObjnWordDocumentG]uObjectPool||"#$%&'()*+,-./0123456789:;<=>?@ABCDEFHIJKLMNOPQRSTUVWXYZ[!SummaryInformation( @Y@z9O@2!Microsoft Word 6.09 FMicrosoft Word 6.0 Document MSWordDocWord.Document.69q_Oh+'0$ H l   D hories=no,status=no,menubar=no,sc(C:\MSOFFICE\WINWORD\TEMPLATE\NORMAL.DOTCellular Biochemistry NotesKenneth WunchKenneth Wunch@~product of the fatty acid synthase pathway, is the precursor of longer chain saturated and unsaturated fatty acids through the actions of elongases and desaturases -Elongases are present in both the mitochondrion and the ER but the mechanisms differ to add or remove carbons -Unsaturated fatty acids are produced by terminal desaturases -Linoleic acid must be obtained in the diet and is therefore and essential fatty acid because it is a required precursor of prostaglandins Synthesis of Triacylglycerols -Triacylglycerols are synthesized from fatty acyl-coA esters and glycerol-3-phosphate or dihydroxyacetone phosphate -The initial step in this process is catalyzed either by glycerol-3-phosphate acyltransferase (in mitochondria or ER) or dihydroxyacetone phosphate acyltransferase (in ER or peroxisomes) Regulation of Fatty Acid Metabolism Fig 19-27 -Synthesis and breakdown of glycogen and triacylglycerols concern the whole organism, with its organs and tissues forming an interdependent network connected by the blood stream -Hormones also regulate the rates of the opposing pathways of lipid metabolism and therefore control whether fatty acids will be oxidized or synthesized; their targets are the regulatory enzymes of fatty acid synthesis and breakdown in specific tissues -Short term regulation controls occur in a matter of minutes or less; examples include substrate availability, allosteric interactions, and covalent modification -Long term regulation such as alteration of the amount of enzyme present by changes in the rates of protein synthesis and/or breakdown requires hours or days; starvation and/or regular exercise, by decreasing the glucose concentration in the blood, change the body's hormone balance--this situation results in long-term increases in the levels of fatty acid oxidation enzymes accompanied by long-term decreases in those of lipid biosynthesis -Fatty acid oxidation is regulated largely by the concentration of fatty acids in the blood, which is, in turn, controlled by the hydrolysis rate of triacylglycerols in adipose tissue by hormone-sensitive triacylglycerol lipase; glucagon-insulin ratio is of prime importance in determining the rate and direction of fatty acid metabolism Cholesterol Metabolism -Cholesterol is a vital constituent of cell membranes and the precursor of steroid hormones and bile acids--it is clearly essential to life, yet its deposition in arteries has been associated with CV disease and stroke; intricate balance between the biosynthesis, utilization, and transport of cholesterol keeps its harmful deposition to a minimum Cholesterol Biosynthesis -All of the carbon atoms of cholesterol are derived from acetate that form isoprene units--C5 -HMG-CoA is a key cholesterol precursor; HMG-CoA reductase mediates the rate-determining step of cholesterol biosynthesis and is the most elaborately regulated enzyme of this pathway 3. Squalene was demonstrated to be the linear intermediate in cholesterol biosynthesis by the observation that feeding isotopically labeled squalene to animals yields labeled cholesterol; squalene is formed by the condensation of six isoprene units 4. Cholesterol is synthsized from lanosterol in a 19-step process embedded in the ER membrane 5. Cholesterol is transported in the blood and taken up by cells in lipoprotein complexes--very low density lipoproteinsintermediate density lipoproteinslow-density lipoproteins 6. Chylomicrons are lipoprotein complexes that transport dietary cholesterol, cholesterol esters, and triacylglycerols in the blood 7. Liver and peripheral tissues have two ways of obtaining cholesterol: either synthesize it from acetyl-CoA by the de novo pathway, or obtain it from the bloodstream by receptor-mediated endocytosis; a small amount of cholesterol also enters the cells by a non-receptor-mediated pathway 8. While LDL transports cholesterol from the liver, cholesterol is transported back to the liver by high density lipoproteins (HDL); surplus cholesterol is disposed of by the liver as bile acids thereby protecting body from an overaccumulation of this water-insoluble substance B. Control of cholesterol biosynthesis and transport 1. 3 ways of maintaining cellular cholesterol supply a. By regulating the activity of HMG-CoA reductase, the enzyme catalyzing the rate-limiting step in the de novo pathway b. By regulating the rate of LDL receptor synthesis; high intracellular concentrations of cholesterol suppress LDL receptor synthesis, whereas low cholesterol concentrations stimulate it c. By regulating the rate of esterification and hence the removal of free cholesterol 2. HMG-CoA reductase is the primary control site for cholesterol biosynthesis 1. Long-term feedback regulation of HMG-CoA reductase is its primary means of control 2. HMG-CoA reductase exists in interconvertible more active and less active forms, thus short-term regulation of HMG-CoA reductase constitutes a means of cellular energy conservation 3. The serum concentration of LDL therefore depends on the rate that liver removes IDL from the circulation, which, in turn, depends on the # of functioning LDL receptors on the liver cell surface 4. Overexpression of LDL receptor prevents diet-induced hypercholesterolemia (high blood cholesterol) at least in mice C. Cholesterol Utilization 1. Steroid hormones, derivatives of cholesterol, are grouped into five catagories: progestins, glucocorticoids, mineralocorticoids, androgens, and estrogens 2. The quantitatively most important pathway for the excretion of cholesterol in mammals is the formation of bile acids (bile salts); this is the body's only route for cholesterol excretion VII. Arachidonate metabolism: prostaglandins, prostacyclins, thromboxanes, and leukotrienes A. Almost all mammalian cells except RBCs produce prostaglandins and their related compounds known collectively as eicosanoids; eicosanoids mediate: 1. The inflammatory response 2. The production of pain and fever 3. The regulation of blood pressure 4. The induction of blood clotting 5. The control of several reproductive functions such as the induction of labor 6. The regulation of the sleep/wake cycle Eicosanoids are hormonlike in that many of their effects are intracellularly mediated by cAMP; they are local mediators, that is, they act in the same environment in which they are synthesized. 7. Prostaglandins are all derivatives of the hypothetical C20 fatty acid prostanoic acid in which carbon atoms 8 to 12 comprise a cyclopentane ring; in humans, the most important prostaglandin precursor is arachidonic acid 1. Aspirin inhibits prostaglandin synthesis from arachidonic acid which serves as a precursor of leukotrienes, thromboxanes, and prostacyclins B. The Cyclic pathway of Arachidonate Metabolism: Prostaglandins, Prostacyclins, and Thromboxanes 1. PGH2 is the immediate precursor of all series-2 prostaglandins, prostacyclins, and thromboxanes 2. The fate of PGH2 depends on the relative activities of the enzymes catalyzing the specific interconversions 3. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of the prostaglandins, prostacyclins, and thromboxanes by inhibiting or inactivating the cyclooxygenase activity of PGH2 synthase C. The Linear Pathway of Arachidonate Metabolism: Leukotrienes 1. Leukotrienes, derived from the 5-lipoxygenase reaction, are synthesized by a variety of white blood cells, mast cells, as well as lung, spleen, brain, and heart 2. The first reaction in the conversion of arachidonate to leukotrienes is its 5-lipoxygenase-catalyzed oxidation to form 5-hydroperoxyeicosatetraenoic acid (5-HPETE) 3. 5-HPETE is converted to peptidoleukotrienes by first forming an unstable epoxide; glutathionie-S-transferase then catalyzes the addition of the glutathione sulfhydryl group to the epoxide, forming leukotriene C4 4. -Glutamyl-transferase removes glutamic acid converting LTC4 to leukotriene D4 5. LTD4 is converted to leukotriene E4 which can also be converted to leukotriene B4 VIII. Phospholipid and Glycolipid Metabolism A. Glycerophospholipids 1. Significantly asymmetrical in their C1 and C2 linked fatty acyl groups; C 1 substituents are mostly saturated fatty acids, whereas those at C2 are by and large unsaturated fatty acids 2. The triacylglycerol precursors 1, 2-diacyl-sn-glycerol and phosphatidic acid are also the precursors of certain glycerophospholipids 3. Phosphatidylserine is synthesized from phosphatidyl-ethanolamine by a head group exchange reaction catalyzed by phosphatidylethanolamine:serine transferase 4. In the synthesis of phosphatidylinositol and phosphatidylglycerol, the hydrophobic tail is activated rather than the polar head group 5. Cardiolipin is an important phospholipid first isolated from heart tissue and is synthesized from 2 molecules of phosphatidylglycerol 6. Enzymes that synthesize phosphatidic acid have a general preference for saturated fatty acids at C1 and for unsaturated fatty acids at C2 7. Plasmalogens: a glycerophospholipid that contains a hydrocarbon chain linked to glycerol C1 via a vinyl ether linkage 8. Alkylacylglycerophospholipids: the alkyl substituent at glycerol C1 is attached via an ether linkage B. Sphingophospholipids 1. Only one major phospholipid contains ceramide as its hydrophobic tail--sphingomyelin, an important structural lipid of nerve cell membranes 2. Main route of sphingomyelin synthesis occurs through donation of the phosphocholine goupr of phosphatidylcholine to N-acylsphingosine C. Sphingoglycolipids 1. Polar head groups consist of carbohydrate units 2. Major classes include: cerebrosides, sulfatides, globosides, and gangliosides 3. Biosynthesis of ceramide occurs in four reactions from the precursors palmitoyl-CoA and serine 4. Galactocerebroside and glucocerebroside are the two most common cerebrosides and are common components of brain lipids 5. Sulfatides account for 15% of the lipids of white matter in the brain 6. Biosynthesis of globosides and gangliosides is catalyzed by a series of glycosyl transferases 15''''''''''',(-(0(1(@(v(x(y())))2)5)\)]))))))****+++G+R+T+U++++,,u,v,1-T-U-^-_-`-a-b-----..q..////6/R/r/// 0)01#1$1n1o122223364N4P4Q444445,7U^c ^c Uc c `,73:A@@ApDqFF~I/NHNbOQQQQuPc w(x(())[)\)))))g***++S+T++++++,t,u,,0-1-_-`-..///0m1n11p22222S3!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t-S35464O4P444f5g55`6a666,7t7u7777w88999:2:3:h:i:::;;;;;+<,<z<{<<<K===!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t-=>O>P>>>>>T???@@@A@@@A3A4AQARAvAwAAAAABB;B"?"<#=##$%%&&&&'''a(b({(|((()) *****X+++,&,',,-G-H--D.^._.....D/E//00W0X00000w11132{2|22233333,4l4m444=5_5`5}5~5555555<6=6g6h6677+7,77 8 888888b9c999D:::::_;;;;)<*<<==S=T=======o>>> ?5?6????T@_@`@@@@kAwAxAAAZB[BsBtBBCC{CCCCCCC*D+DDDEE ERESEEE!t!t!t!t!t!x!t!t!t!t!t!t!t!t!!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t ',7Q)*$w(S3=7E.NQ+,-./ !! Kenneth Wunch A:\BCHP18.DOC Kenneth Wunch A:\BCHP18.DOC Kenneth Wunch A:\BCHP19.DOC Kenneth Wunch A:\BCHP19.DOC Kenneth Wunch A:\BCHP19.DOC ken wunch A:\BCHP19.DOC ken wunch A:\BCHP19.DOC ken wunch A:\BCHP19.DOC Kenneth Wunch A:\BCHP19.DOC Kenneth Wunch A:\BCHP19.DOC@Canon Bubble-Jet BJ-200eLPT1:CANON800Canon Bubble-Jet BJ-200e@fyyhh@MSUDCanon Bubble-Jet BJ-200edCanon Bubble-Jet BJ-200e@fyyhh@MSUDCanon Bubble-Jet BJ-200ed)) ))&',L STWX|} XY\]l:;EG^a &?ABs~ * , - ]!!!!!!!!!!!!?"@"""=#>#[#b#~####5$U$>%O%P%%%&'''''b(z(|(}((((()H)X+_.m44=58::=[BtBCEEEEEEEE$$$% %o%p%%%%%%%^&q&s&t&&&&&&''('+','P'Q'''''''''''',(-(0(1(@(v(x(y())))2)5)\)]))))))****+++G+R+T+U++++,,u,v,1-T-U-^-_-`-a-b-----..q..////6/R/r/// 0)01#1$1n1o122223364N4P4Q444445,73:A@@ApDqFF~I/NHNbOQQATimes New Roman Symbol &ArialWingdings"AhSSTF O +ICellular Biochemistry Notes Kenneth Wunch Kenneth Wunchܥe= e]uE$$`````j ajjjj&j4jtAZjZj"|j|j|j|j|j|jkkkk(kl\mtTuIzm`|j|j|j|j|jzm|j``|jZj|j|j|j|j`|j`|jk`\p`````|jk|j|jCellular Biochemistry Notes Chapter 19 "Lipid Metabolism" Lipid Digestion, Absorption, and Transport -Triacylglycerides constitute both ~90% of the dietary lipid and the major form of metabolic energy storage in humans; the oxidative metabolism of fats yields over twice the energy of an equal weight of dry carbohydrate or protein -Since triacylglycerols are water insoluble, whereas digestive enzymes are water soluble, triacylglycerol digestion takes place at lipid-water interfaces; rate of digestion therefore depends on the surface area of the interface and is greatly increased by the emulsifying action of bile acids -Enzymatic activity of pancreatic lipase greatly increases when it contacts the lipid-water interface, a phenomenon known as interfacial activation; however, the enzyme does not bind unless it is in complex with pancreatic colipase -Phospholipids are degraded by pancreatic phospholipase A2, which hydrolytically excises the fatty acid residue at C2 to yield the corresponding lysophospholipids (powerful detergents); disrupt membranes and can lyse cells -Bile acids and fatty acid-binding protein facilitate the intestinal absorption of lipids; bile acids not only aid lipid digestion but are essential for the absorption of lipid digestion products; inside intestinal cells, fatty acids form complexes with intestinal fatty acid-binding protein (I-FABP), a cytoplasmic protein which increases the solubility of these water-insoluble substances and protects the cell from their detergent-like effects Lipids are transported in lipoprotein complexes Fig. 19-5 Dietary Lipids -The lipid digestion products absorbed by the intestinal mucosa cells are converted to triacylglycerols and cholesterols and then packaged into chylomicrons. -Triacylglycerols and cholesterols synthesized by the liver are packaged into very low density lipoproteins (VLDL) -Triacylglycerol components of chylomicrons and VLDL are hydrolyzed to free fatty acids and glycerol in the capillaries of adipose tissue and skeletal muscle by lipoprotein lipase; in the liver and kidneys, it is further converted to DHAP; VLDLs that have lost fatty acids are LDLs Adipose Lipids -Mobilization of triacylglycerols stored in adipose tissue involves hydrolysis to glycerol and free fatty acids by triacylglycerol lipase -Free fatty acids are released into the bloodstream where they bind to albumin, a soluble protein that comprises about half of the blood serum protein; rare individuals who suffer from analbuminemia, severely depressed levels of albumin, suffer no apparent adverse symptoms, their fatty acids are transported in complex with other serum proteins Fatty Acid Oxidation -Before fatty acids can be oxidized, they must be "primed" for reaction in an ATP-dependent acylation to form fatty acyl-CoA this process is catalyzed by a family of at least 3 acyl-CoA synthetases; these enzymes catalyze the following reaction: Fatty acid + CoA + ATP ( ( acyl-CoA + AMP + PPi -These enzymes are associated with the ER or the outer mitochondrial membrane Transport across the Mitochondrial Membrane -A long-chain fatty acyl-CoA cannot directly cross the inner mitochondrial membrane--its acyl portion is first transferred to carnitine -Translocation process itself is mediated by a specific carrier protein that transports acyl-carnitine into the mitochondrion while transporting free carnitine in the opposite direction Oxidation -Fatty acids are dismembered through the oxidation of fatty acyl-CoA, a process that occurs in 4 reactions Fig. 19-9 1) Formation of a trans-, double bond through dehydrogenation by the flavoenzyme acyl-CoA dehydrogenase; reoxidized via the electron-transport chain 2) Hydration of the double bond by enoyl-CoA hydratase to form a 3-L-hydroxyacyl-CoA 3)NAD+-dependent dehydrogenation of this -hydroxyacyl-CoA by 3-L-hydroxyacyl-CoA dehydrogenase to form the corresponding -ketoacyl-CoA 4) C--C cleavage in a thiolysis reaction with CoA as catalyzed by -ketoacyl-CoA thiolase (also called thiolase) to form acetyl-CoA and a new acyl-CoA containing 2 less C atoms than the original -Acyl-CoA dehydrogenase deficiency has fatal consequences such as: sudden infant death sydrome some 10% are deficient in acyl-CoA dehydrogenase and the infants can't take the switch from glucose to fatty acid metabolism. Symptoms are hypoglycemia, vomiting, lethargy, encephalopathy, respiratory arrest, seizures, apnea, cardiac arrest, coma, and sudden and unexpected death. Long-term outcomes include developmental and behavioral disability, chronic muscle weakness, failure to thrive, cerebral palsy, and attention deficit disorder Jamaican vomiting sickness unripe ackee fruit contain hypoglycin A an unusual amino acid that is metabolized to methylenecyclopropyllacetyl-CoA. This compound is a mechanism-based inhibitor of acyl-CoA dehydrogenase -Fatty acid oxidation is highly exergonic; oxidation of acetyl-CoA via th CAC generates additional FADH2 and NADH which are reoxidized through oxidative phosphorylation to form ATP Oxidation of Unsaturated Fatty Acids -Double bonds in fatty acids of biological origin are cis bonds and occur at three-carbon intervals -Double bonds at these positions pose problems for the -oxidation pathway and are solved through the action Enoyl-CoA isomerase which converts the cis double bond to the more stable trans form -Natural substrate for enoyl-CoA hydratase Oxidation of Odd-Chain Fatty Acids -Final round of oxidation of these fatty acids forms propionyl-CoA which is converted to succinyl-CoA for entry into the CAC Peroxisomal Oxidation -Oxidation of fatty acids occurs in the peroxisome as well as in the mitochondrion; peroxisomal oxidation in animals functions to shorten very long chain fatty acids so as to facilitate their degradation by the mitochondrial -oxidation system Ketone Bodies -Ketogenesis which occurs primarily in liver mitochondria converts acetyl-CoA to acetoacetate or D--hydroxybutyrate; these compounds together with acetone are referred to as ketone bodies and serve as important metabolic fuels for many peripheral tissues, particularly heart and skeletal muscles; ketone bodies are water-soluble equivalents of fatty acids -Brain uses ketone bodies during periods of starvation (Chp 21) PAGE  PAGE 5 Fatty Acid Biosynthesis Pathway Overview -9;f. 7 8 9 G v k #isg<WEg$$$% %o%p%%%%%%%^&q&s&t&&&&&&''('+','P'Q'']c uP uDP Jac Jac ^c U^c Uc c Uc$T:;fgNOtu]^=>8 9 H Z [ u v    j k wx$!!!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t-$%,hist]^_`a#gh<=WXEhi|!t!t!t!t!t!t!t!t!t!!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t!t-uden%o%%%%]&^&r&s&&&('P''''-(?(@(w(!t!t!t!t!t!t!t!t!t!t!td!!t!t!t!t!t!x!t!t!t!t!t!t!t!t!!t!t!t!t!t!t!t!t!t!th`%+K@Normala "A@"Default Paragraph Font @ Header !)@ Page NumberFatty acid biosynthesis occurs through condensation of C2 units, the reverse of the B-oxidation process; it occurs in the cytosol with the growing fatty acids esterified to acyl-carrier protein (ACP) -Involves two steps: 1) The ATP-dependent carboxylation of acetyl-CoA by acetyl-CoA carboxylase to form malonyl-CoA (3C) 2) The exergonic decarboxylation of the malonyl group in the condensation reaction catalyzed by fatty acid synthase Fatty Acid Synthase -The synthesis of fatty acids from acetyl-CoA and malonyl-CoA involves 7 enzymatic reactions: Fig 19-19, 19-22 -1 & 2 are priming reactions in which the synthase is "loaded" with the condensation reaction precursors -3 the condensation reaction--malonyl-ACP is decarboxylated with the resulting carbanion attacking the acetyl-thioester to form a ketoacyl-ACP -4-6 are the reduction and dehydration that convert this ketone to an alkyl group Transport of Mitochondrial Acetyl-CoA into the cytosol -Acetyl-CoA enters the cytosol in the form of citrate via the tricarboxylate transport system; cytosolic ATP-citrate lyase then catalyzes the reaction. Fig 19-20 Citrate + CoA + ATP <----> acetyl-coA + oxaloacetate + ADP + Pi -When the need for ATP synthesis is low, this mitochondrial acetyl-CoA may be stored for future use as fat Elongases and Desaturases Palmitate (16:0), the normal h@MSUDCanon Bubble-Jet BJ-200edCanon Bubble-Jet BJ-200e@fyyhh@MSUDCanon Bubble-Jet BJ-200ed | &',L STWX|} XY\]l:;EG^a &?ABs~ * , - ]!!!!!!!!!!!!?"@"""=#>#[#b#~####5$U$>%O%P%%%&'''''b(z(|(}((((((@)`)))))))**\*^*_*****z+{+++\,t,,,,,,o-r-+.............///2/3/5//////// 000000t0v000000 11111$$$% %o%p%%%%%%%^&q&s&t&&&&&&''('+','P'Q'''''''''''',(-(0(1(@(v(x(y())))2)5)\)]))))))****+++G+R+T+U++++,,u,v,1-T-U-^-_-`-a-b-----..q..////6/R/r/// 0)01#1$1n1o122223364N4P4Q4444Q445Qd6QQQ6Q6s7Q7Qc8o8v8Q9`9 `:6:g:l:8`:;`;>`;A`C`Y`=b`c`i`j`````````DaEaYaZa[abamaaaO>aaa1b3bYbZbbbb>ATimes New Roman Symbol &ArialWingdings"AhSQ Tf O +ICellular Biochemistry Notes Kenneth Wunch Kenneth Wunch