脂肪酸的代谢1.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,一、脂质的消化、吸收和传送,甘油三酯被胰脏和十二指肠分泌的酯酶分解。,胰脏和十二指肠接头处胰脏分泌液进入十二指肠的通道。,脂肪的消化发生在脂质,-,水的界面处。,胆汁盐促进脂类在小肠中被吸收。,在小肠脂肪酸与胆酸盐结合形成微囊,将脂肪酸运输到小肠上皮细胞,在小肠上皮细胞再合成甘油三酯。,In the small intestine,fatty acids combine with bile salts in mixed micelles,which deliver fatty acids to epithelial cells that cover the intestinal villi.Triacylglycerols are formed within the epithelial cells.,4.,脂肪组织释放脂肪酸受激素的调控,Liberation of fatty acids from,triacylglycerols in adipose tissue is hormonedependent.,When low levels of glucose in the blood trigger the release of glucagon,（,1,）,the hormone binds its receptor in the adipocyte membrane and thus,（,2,）,stimulates adenylyl cyclase,via a G protein,to produce cAMP.This activates PKA,which phosphorylates,（,3,）,the hormone-sensitive lipase and,（,4,）,perilipin molecules on the surface of the lipid droplet.Phosphorylation of perilipin permits hormonesensitive lipase access to the surface of the lipid droplet,where,（,5,）,it hydrolyzes triacylglycerols to free fatty acids.,（,6,）,Fatty acids leave the adipocyte,bind serum albumin in the blood,and are carried in the blood;they are released from the albumin and,（,7,）,enter a myocyte via a specific fatty acid transporter.,（,8,）,In the myocyte,fatty acids are oxidized to CO,2,and the energy of oxidation is conserved in ATP,which fuels muscle contraction and other energy requiring metabolism in the myocyte.,Mobilization of triacylglycerols stored in adipose tissue,Entry of glycerol into the glycolytic pathway.,(,一,),脂肪酸的活化,二、脂肪酸的氧化,The conversion is catalyzed by fatty acylCoA synthetase and inorganic pyrophosphatase.Fatty acid activation by formation of the fatty,acylCoA derivative occurs in two steps.In step,（,1,）,the carboxylate ion displaces the outer two(,and)phosphates of ATP to form a fatty acyladenylate,the mixed anhydride of a carboxylic acid and a phosphoric acid.The other product is PPi,an excellent leaving group that is immediately hydrolyzed to two Pi,pulling the reaction in the forward direction.In step,（,2,）,the thiol group of coenzyme A carries out nucleophilic attack on the enzyme-bound mixed anhydride,displacing AMP and forming the thioester fatty acylCoA.The overall reaction is highly exergonic.,Conversion of a fatty acid to a fatty acylCoA,(,二,),脂肪酸转入线粒体,Fatty acid entry into mitochondria via the acyl-carnitine/carnitine transporter.,After fatty acylcarnitine is formed at the outer membrane or in the intermembrane space,it moves into the matrix by facilitated diffusion through the transporter in the inner membrane.In the matrix,the acyl group is transferred to mitochondrial coenzyme A,freeing carnitine to return to the intermembrane space through the same transporter.Acyltransferase I is inhibited by malonyl-CoA,the first intermediate in fatty acid synthesis.This inhibition prevents the simultaneous synthesis and degradation of fatty acids.,The formation of acylcarnitines and their transport across the inner mitochondrial membrane.The process involves,the coordinated actions of carnitine acyltransferases on both sides of the membrane and of a translocase that shuttles O-acylcarnitines across the membrane.,(,三,),-,氧化,Franz Knoops labeling Experiments(1904):fatty acids are degraded by oxidation at the,carbon,i.e.,oxidation,.,Enzymes of fatty acid oxidation in animal cells were localized in the mitochondria matrix.Revealed by Eugene Kennedy and Albert Lehninger in 1948.,Stages of fatty acid oxidation.,Stage 1:A long-chain fatty acid is oxidized to yield acetyl residues in the form of acetyl-CoA.This process is called oxidation.Stage 2:The acetyl groups are oxidized to CO,2,via the citric acid cycle.Stage 3:Electrons derived from the oxidations of stages 1 and 2 pass to O,2,via the mitochondrial,respiratory chain,providing the energy for ATP synthesis by oxidative phosphorylation.,脂肪酸,-,氧化的反应途径,The-oxidation of saturated fatty acids involves a cycle of four enzyme-catalyzed reactions.Each cycle produces single molecules of FADH,2,NADH,and acetyl-CoA and yields a fatty acid shortened by two carbons.(The delta,symbol connotes a double bond,and its superscript indicates the lower-numbered carbon involved.),脂酰,-CoA,脱氢酶的作用,ETF:Electron transfer flavoprotein,The acyl-CoA dehydrogenase reaction.The two electrons removed in this oxidation reaction are delivered to the electron transport chain in the form of reduced coenzyme Q(UQH,2,).,The mechanism of acyl-CoA dehydrogenase.Removal of a proton from the,-C is followed by hydride transfer from the,-carbon to FAD.,从猪肝脏线粒体分离的脂酰辅酶,A,脱氢酶中间链的亚基结构,The subunit structure of medium chain acyl-CoA dehydrogenase from pig liver mitochondria.Note the location of the bound FAD(red).,存在于,akee,未成熟果实中的降糖氨酸,A(hypoglycinA),对脂酰辅酶,A,脱氢酶有抑制作用，可引起呕吐、昏迷甚至死亡。,可以与脂酰辅酶,A,脱氢酶的,FAD,辅基反应，抑制酶的活性。,The conversion of hypoglycin from akee fruit to a form that inhibits acyl-CoA dehydrogenase.,The Akee Tree,烯酰,-CoA,水合酶的作用,The conversion of,trans-,and,cis,-enoyl CoA derivatives to L-and D-,-hydroxyacyl CoA,respectively.These reactions are catalyzed by enoyl-CoA hydratases(also called crotonases),enzymes that vary in their acyl-chain length specificity.A recently discovered enzyme converts,trans-,enoyl-CoA directly to D-,-hydroxyacyl-CoA.,L-,-,羟酰,-CoA,脱氢酶的作用,硫解酶催化的反应,The mechanism of the thiolase reaction.Attack by an enzyme cysteine thiolate group at the,-carbonyl carbon produces a tetrahedral intermediate,which decomposes with departure of acetyl-CoA,leaving an enzyme thioester intermediate.Attack by the thiol group of a second CoA yields a new(shortened)acyl-CoA.,The enzymes of,oxidation.,Shown here are the different subunit structures of the enzymes of,oxidation in gram-positive and gram-negative bacteria,mitochondria,and plant peroxisomes and glyoxysomes.Enz1 is acyl-CoA dehydrogenase;Enz2,enoyl-CoA hydratase;Enz3,L-,-,hydroxyacyl-CoA dehydrogenase;Enz4,thiolase;Enz5,D-3-hydroxyacyl-CoA epimerase,and Enz6,3,2,-enoyl-CoA isomerase.,(a),The four enzymes of,oxidation in gram-positive bacteria are separate,soluble entities,as are those of the short-chain-specific system of mitochondria.,(b),In gram-negative bacteria,the four enzyme activities reside in three polypeptides;enzymes 2 and 3 are parts of a,single polypeptide chain.,(c),The very-long-chain-specific system of mitochondria is also composed of three polypeptides,one of which includes the activities of enzymes 2 and 3;in this case,the system is bound to the inner mitochondrial membrane.,(d),In the peroxisomal and glyoxysomal,-,oxidation systems of plants,enzymes 1 and 4 are separate polypeptides,but enzymes 2 and 3,as well as two auxiliary enzymes,are part of a single polypeptide chain,the multifunctional protein,MFP.,(,四,),脂肪酸氧化生成,ATP,的总结算,脂肪酸,氧化,1,次生成,FADH,2,和,NADH,各,1,个，电子经呼吸链传递给氧，可生成,4,个,ATP,。,1,个乙酰,CoA,经柠檬酸循环可生成,10,个,ATP,。,以软脂酸为例，,16,个碳原子，经,7,次,氧化生成,8,个乙酰,CoA,。,ATP,的生成数为：,47+108=108,脂肪酸激活时消耗,2,个,ATP,，则：,1082=106,过去的计算是：,57+1282=129,。,（五）不饱和脂肪酸的氧化,油酰,CoA,的氧化,Oxidation of a monounsaturated fatty acid.,Oleic acid,as oleoyl-CoA(,9,),is the example used here.Oxidation requires an additional enzyme,enoyl-CoA isomerase,to reposition the double bond,converting the cis isomer to a trans isomer,a normal intermediate in,oxidation.,-Oxidation of unsaturated fatty acids.In the case of oleoyl-CoA,three-oxidation cycles produce three molecules of acetyl-CoA and leave,cis,-,3,-dodecenoyl-CoA.Rearrangement of enoyl-CoA isomerase gives the,trans-,2,species,which then proceeds normally through the,-oxidation pathway.亚油酰,CoA,的氧化,Oxidation of a polyunsaturated fatty acid.,The example here is linoleic acid,as linoleoyl-CoA(,9,12,).Oxidation requires a second auxiliary enzyme in addition to enoyl-CoA isomerase:NADPH-dependent 2,4-dienoyl-CoA reductase.The combined action of these two enzymes converts a,trans,-,2,cis,-,4,-dienoyl-CoA intermediate to the,trans,-,2,-enoyl-CoA substrate necessary for oxidation.,The oxidation pathway for polyunsaturated fatty acids,illustrated for linoleic acid.Three cycles of,-oxidation on linoleoyl-CoA yield the,cis,-,3,cis,-,6,intermediate,which is converted to a,trans,-,2,cis6,intermediate.An additional round of oxidation gives,cis,-,4,enoyl-CoA,which is oxidized to the,trans,-,2,cis,-,4,species by acyl-CoA dehydrogenase.The subsequent action of 2,4-dienoyl-CoA reductase yields the,trans,-3 product,which is converted by enoyl-CoA isomerase to the,trans,-,2,form.Normal oxidation then produces five molecules of acetyl-CoA.,（六）奇数碳原子脂肪酸的氧化生成丙酰,-CoA,Oxidation of propionyl-CoA produced by oxidation of odd-number fatty acids.,The sequence involves the carboxylation of propionyl-CoA to D-methylmalonyl-CoA and conversion of the latter to succinyl-CoA.This conversion requires epimerization of D-to L-methylmalonyl-CoA,followed by a remarkable reaction in which substituents on adjacent carbon atoms exchange positions.,The conversion of propionyl-CoA(formed from,-oxidation of oddcarbon fatty acids)to succinyl-CoA is carried out by a trio of enzymes as shown.Succinyl-CoA can enter the TCA cycle or be converted to acetyl-CoA.,The methylmalonyl-CoA epimerase mechanism involves a resonancestabilized carbanion at the,-position.,甲基丙二酸单酰,-CoA,分子重排的机制,Hydrogen atom transfer from methylmalonyl-CoA yields a methylmalonyl-CoA radical that can undergo rearrangement to form a succinyl-CoA radical.Transfer of an H atom regenerates the coenzyme and yields succinyl-CoA.,A mechanism for the methylmalonyl-CoA mutase reaction.In the first step,Co,3+,is reduced to Co,2+,due to homolytic cleavage of the Co,3+,-C bond in cobalamin.,维生素,B,12,活化的机制,Formation of the active coenzyme 5,-deoxyadenosylcobalamin from inactive vitamin B,12,is initiated by the action of flavoprotein reductases.The resulting Co,+,species,dubbed a supernucleophile,attacks the 5,-carbon of ATP in an unusual adenosyl transfer.,（七）,-,氧化,The,oxidation of a branched-chain fatty acid(phytanic acid)in peroxisomes.,Phytanic acid has a methyl-substituted,carbon and therefore cannot undergo,oxidation.The combined action of the enzymes shown here removes the carboxyl carbon of phytanic acid,to produce pristanic acid,in which the,carbon is unsubstituted,allowing oxidation.Notice that,oxidation of pristanic acid releases propionyl-CoA,not acetyl-CoA.The details of the reaction that produces pristanal remain controversial.,Branched-chain fatty acids are oxidized by,-oxidation,as shown for phytanic acid.The product of the phytanic acid oxidase,pristanic acid,is a suitable substrate for normal,-oxidationIsobutyryl-CoA and propionyl-CoA can both be converted to succinyl-CoA,which can enter the TCA cycle.,（八）,-,氧化,The,oxidation of fatty acids in the endoplasmic reticulum.,This alternative to oxidation begins with oxidation of the carbon most distant from the,carbonthe,(omega)carbon.The substrate is usually a medium-chain fatty acid;shown here is lauric acid(laurate).This pathway is generally not the major route for oxidative catabolism of fatty acids.,Comparison of,oxidation in mitochondria and in peroxisomes and glyoxysomes.,The peroxisomal/glyoxysomal system differs from the mitochondrial system in two respects:(1)in the first oxidative step electrons pass directly to O,2,generating H,2,O,2,and(2)the NADH formed in the second oxidative step cannot be reoxidized in the peroxisome or glyoxysome,so reducing equivalents are exported to the cytosol,eventually entering mitochondria.The acetyl-CoA produced by peroxisomes and glyoxysomes is also exported;the acetate from glyoxysomes(organelles found only in germinating seeds)serves as a biosynthetic precursor.Acetyl-CoA produced in mitochondria is further oxidized in the citric acid cycle.,Triacylglycerols as glucose source in seeds.,Oxidation,is one stage in a pathway that converts stored triacylglycerols,to glucose in germinating seeds.,（九）酮体,Formation of ketone bodies from acetyl-CoA.,Healthy,well-nourished individuals produce ketone bodies at a relatively low rate.When acetyl-CoA accumulates(as in starvation or untreated diabetes,for example),thiolase catalyzes the condensation of two acetyl-CoA molecules to acetoacetyl-CoA,the parent compound of the three ketone bodies.The reactions of ketone body formation occur in the matrix of liver mitochondria.The six-carbon compound,-,hydroxy-,-,methylglutaryl-CoA(HMG-CoA)is also an intermediate of sterol biosynthesis,but the enzyme that forms HMG-CoA in that pathway is cytosolic.HMG-CoA lyase is present only in the mitochondrial matrix.,酮体的形成,3.,肝外组织使用酮体作为燃料,-,羟基丁酸和乙酰乙酸可转化为乙酰,-CoA,进入柠檬酸酸环。丙酮很少被利用，主要通过呼吸系统或随尿液排出体外。,D,-,-,Hydroxybutyrate as a fuel.,D-,-,Hydroxybutyrate,synthesized in the liver,passes into the blood and thus to other tissues,where it is converted in three steps to acetyl-CoA.It is first oxidized to acetoacetate,which is activated with coenzyme A donated from succinyl-CoA,then split by thiolase.The acetyl-CoA thus formed is used for energy production.,Conditions that promote gluconeogenesis(untreated diabetes,severely reduced food intake)slow the citric acid cycle(by drawing off oxaloacetate)and enhance the conversion of acetyl-CoA to acetoacetate.The released coenzyme A allows continued oxidation of fatty acids.,Ketone body formation and export from the liver,（十）脂肪酸代谢的调节,1.,脂肪酸进入线粒体的调控,肉碱酰基转移酶,受丙二酰,-CoA,的强烈抑制，丙二酰,-CoA,含量高有利于脂肪酸的合成。,2.,心脏中脂肪酸氧化的调节,心脏以脂肪酸的氧化为主要能源，若耗能减少，乙酰,-CoA,和,NADH,含量增高，抑制脂肪酸的氧化。,3.,激素对脂肪酸代谢的调节,肾上腺素和胰高血糖素使脂肪组织的,cAMP,含量增高，促进脂肪酸的氧化，抑制脂肪酸的合成。胰岛素促进脂肪酸的合成。,4.,根据机体代谢需要的调控,若软脂酰,-CoA,过量，会抑制脂肪酸的合成。柠檬酸过量促进脂肪酸的合成。,5.,长时间膳食的改变导致相关酶水平的调整,长时间食用低脂肪饲料的大鼠，乙酰,-CoA,羧化酶的活力会大幅度提高，可能是提高了基因转录的速度。,三、磷脂和甾醇的代谢,1.,膜结构脂类,:,磷脂和糖脂,2.,磷酸甘油酯是磷脂酸的衍生物,3.,磷脂的分解代谢,4.,鞘磷脂的分解代谢,5.,鞘糖脂的分解代谢,红细胞糖苷脂,广泛性神经节苷脂沉积症,婴儿型黑蒙性痴呆,6.,甾醇的转化,强的松龙,强的松,牛黄胆酸,异己醛,*,皮质铁氧还蛋白,*,Side-chain cleavage in the synthesis of steroid hormones.,Cytochrome P-450 acts as electron carrier in this mixedfunction oxidase system that oxidizes adjacent carbons.The process also requires the electron-transferring proteins adrenodoxin and adrenodoxin reductase.This system for cleaving side chains is found in mitochondria of the adrenal cortex,where active steroid production occurs.Pregnenolone is the precursor of all other steroid hormones.,基本要求,1.,熟悉脂质的消化、吸收和传送。,2.,掌握饱和脂肪酸的氧化途径。,（重点）,3.,熟悉不饱和脂肪酸的氧化途径。,（难点）,4.,掌握酮体的生成、利用和生物学意义。,（重点）,5.,熟悉磷脂、鞘脂类和甾醇的代谢。,6.,掌握脂肪酸代谢的调节。,（重点）,