Chapter 7 Metabolism of Lipids
脂肪,甘油 + 脂肪酸 (三酰甘油、甘油三脂 )
类脂,磷脂、糖脂、固醇类物质
?生物学功能:
o 良好的 能源 物质
o 生物膜 和 细胞质 的重要成分
o 固醇类物质是动物 激素 和 Vit D的前体
?代谢失调会导致疾病:
如:肥胖症、血管硬化、
结石、脂肪肝、酮尿
?脂类
I,Catalyzed hydrolysis of lipids
1,Hydrolyzed with lipase,
Hydrolyzate,glycerol + fatty acid
甘油三脂 ? 甘油二脂 ? 甘油单脂 ? 甘油
H2O R1COOH H2O R1COOH H2O R1COOH
2,Hydrolyzed with phospholipase:
包含:磷酸二脂酶、磷酸单脂酶。
产物:甘油二脂、磷酸、胆碱。
3,Hydrolysis of simple lipids,
简单脂类包括:胆固醇、乙酰胆碱等。
胆固醇
( 胆固醇脂酶 ) ? 胆固醇 + 脂肪酸
乙酰胆碱
( 胆碱脂酶 ) ? 胆碱 + 乙酰
I,Catalyzed hydrolysis of lipids
II,Catabolism of fat
1,Oxidation of Glycerol,
首先,(甘油磷酸激酶 + ATP) ? ?-?甘油
然后,(?甘油脱氢酶 + NAD+ ) ??二羟丙酮
<Fig.> 糖酵解
Change of energy:
o Activation of glycerol,-1 ATP
o?-甘油 ??二羟丙酮,1 NADH+ H+ 即 3 ATP
o?二羟丙酮彻底氧化,?PA,2 ATP,1 NADH+H+ 即 5 ATP
?乙酰 CoA,1 NADH+ H+ 即 3 ATP
?TCA Cycle,共 12 ATP
TOTAL,22 ATP
2,Catabolism of fatty acid,
?History:
??-oxidation theory (Knoop 1904)
?―activated‖ acetyl acid (Lehninger 1940S)
?―activated‖ acetyl acid is acetyl CoA (Lynen 1951)
II,Catabolism of fat
?Process,?-oxidation of saturated fatty acid
(Fig.)
?Acivation of fatty acid– fatty acyl-CoA
?Dehydrogenation (?-oxidation)
?Hydration
?Dehydrogenation (?-oxidation)
?Thiolysis \split
2,Catabolism of fatty acid
?Concept,?-oxidation
Oxidation of ?-C of fatty acid,which undergo 4
reactions,dehydrogenation,hydration,
dehydrogenation (again) and thiolysis \split in turn,
the fatty acid chain then reduce 2C and produce 1
acetyl CoA.
2,Catabolism of fatty acid
2,Catabolism of fatty acid
?Position, role of carnitine <肉 (毒 )碱 >
?-oxidation of fatty acid occurred in mitochondria,
while the activation of fatty acid is in cytosol.
Fatty acyl-CoA + carnitine ?fatty acyl-carnitine + CoA
(fatty acyl-CoA,carnitine fatty acyl transferase)
< Fatty acyl-carnitine can permeate membrane of mitochondria.>
(Fig.)
2,Catabolism of fatty acid
?Energy:
?Acivation of fatty acid -2 ATP
??-oxidation 1 FADH +1 NADH 5 ATP
?Oxidation per acetyl CoA 12 ATP
How many acetyl CoA will be produced per fatty acid?
?Cn/2 acetyl CoA and (Cn/2)-1 [FADH + NADH]
(It is suggested that n is even.)
2,Catabolism of fatty acid
?Energy,(Cont.)
ATP = 17 Cn/2 –7 ( n is even)
e.g,Palmitate(C16) yields 129 ATP when oxidized to CO2 and
H2O,
The energy efficiency is 129 × 7.3 / 2340 = 40.24%
Q,1分子三硬脂酸甘油脂彻底氧化产生多少 ATP?
?Odd-number fatty acids -- 1 propionyl CoA
(羧化 )?甲基丙二酸单酰 CoA?(变位 )?琥珀酰 CoA
<e.g,深海鱼油 >
3,Oxidation of unsaturated fatty acid
?Process, (be similar to saturated fatty acid)
Oxidation of unsaturated fatty acids requires two additional
enzymes,enoyl-CoA isomerase and 2,4 dienoyl-CoA
reductase.
含 1个不饱和双键的脂酸 (如油酸 )只需要烯脂酰 CoA异构酶,
含 2个不饱和双键的脂酸 (如亚油酸 )还需羟脂酰 CoA立体 (差
向 )异构酶,形成 L(+)-?-羟脂酰 -CoA 。
?Energy:
ATP = 17 Cn/2 – 7 – 2 Dn ( n is even)
3,Other oxidation of fatty acid
??-oxidation,(in seeds,liver and brain)
长链脂肪酸 (C13-C18)?(单氧化酶 )??-C氧化为羟基
?(脱氢、脱羧 )?少 1个 C的脂肪酸
??-oxidation,(in endoplasmic reticulum <ER> of liver)
脂肪酸 (C10-C11)?(烷基端 ?-C羧化 )?二羧酸 ?(两端
继续 ?-氧化 )
NB 此两种方式都有利于脂肪酸的降解,是辅助途径。
4,Metabolism of ketone bodies
?Concept,Acetone,acetoacetate and D-?-hydroxybutyrate
are formed in liver.
肝脏内脂肪酸氧化大量生成乙酰 CoA,但不能彻底氧化,生成
酮体是必然的结果。在正常情况下,酮体可迅速渗透到其它组织。
?Product:
acetyl CoA?acetoacetyl CoA? ?-羟 - ?-甲基戊二酰 CoA?(HMG-
CoA裂解 )?acetoacetate
?(reduction)?D-?-hydroxybutyrate
?(decarboxylation)?acetone
?Oxidation \ Utility,在 肝外氧化 (?),作为能源物质利用。
?Acetone随尿排出体外或由肺呼出。
?D-?-hydroxybutyrate?(可逆地氧化 )acetoacetate?(琥珀酰
CoA转硫酶 )或 (乙酰乙酸硫激酶 )?乙酰乙酰 CoA?(乙酰硫
解酶 )?2 乙酰 CoA?(TCA cycle)
肝外氧化 (?) ?relative enzyme system
4,Metabolism of ketone bodies
?Biological meaning:
?1,在需要动用脂肪时 (如饥饿 ),肌肉可以大量利用酮体以
节约糖,而肌肉对脂肪的利用有限。
血液中,[脂肪酸 ]不能太高 (? 5倍 ),而酮体此时可上升到 20倍。
酮体溶于水,便于运输、扩散到细胞中;脂肪酸则否。
?2,大脑不能利用脂肪酸,却能利用酮体。
饥饿时,大脑利用酮体可替代 25%的葡萄糖的量。
Q,哪些组织可利用酮体?
e.g.大脑、骨骼肌,肝脏, 红细胞 。
4,Metabolism of ketone bodies
III,Anabolism of fat
1,Biosynthesis of fatty acid,
?Pathways and Position,
?Synthesis by de novo
—in cytosol (of animals) or chloroplasts (of plants)
cf,catabolism in mitochondra
?Extension of C-chain
—in mitochondra or microsome
Where the corresponding enzyme system occur?
III,Anabolism of fat
1,Biosynthesis of fatty acid,de novo
?Process:
not the reverse of ?-oxidation of fatty acid
?Transfer of acetyl CoA— Citric acid-pyruvic acid shuttle
(The coenzyme of malatase is also NADP+.)
(Fig.)
?Synthesis of malonyl CoA— activation of acetyl CoA
?Synthesis of fatty acid— multi-enzyme complex
(Fig.)
?Process,(cont.)
?Synthesis of malonyl CoA— activation of acetyl CoA
Acetyl-CoA?(carboxylase\Biotin\CO2\Mn2+\ATP)
?malonyl CoA
(Fig.)
As a allosteric enzyme,acetyl-CoA carboxylase is the key
enzyme of fatty acid biosynthesis,Citric acid is the allosteric
activator,while anti-biotin protein <in egg white> is an
inhibitor,??
2,Biosynthesis of fatty acid
?Process,(cont.)
?Synthesis of fatty acid— multi-enzyme complex
(Fig.)
i.e,7 components of fatty acid synthase complex:
ACP,acyl carrier protein ACP-acyl transferase
ACP-malonyl transferase ?-ketoacyl-ACP synthase
?-ketoacyl-ACP reductase ?-hydroxyacyl-ACP dehydrase
enoyl-ACP reductase
2,Biosynthesis of fatty acid
?Process,(cont.)
?Condensation:acetyl-CoA + malonyl CoA (decarboxylation)
?Reduction,the ?-keto group is reduced to an alcohol.
?Dehydration,to create a double bond C=C
?Reduction,the double bond is reduced to form the corresponding
saturated fatty acyl group,
(Fig.)
4 reactions each step,C-chain lengthened by 2 carbons
2,Biosynthesis of fatty acid
?Process,(cont.)
?Synthesis of fatty acid
The overall process of palmitate synthesis de novo:
First:
7 Acetyl-CoA + 7 CO2 + 7 ATP ?7 malonyl CoA + 7 ADP + 7 Pi
Second:
Acetyl-CoA + 7 malonyl CoA + 14 (NADPH+H+) ?
Palmitate + 7 CO2 + 8 CoASH + 14 NADP+ + 6 H2O
Then:
8 Acetyl-CoA + 7 ATP + 14 (NADPH+H+) ?
Palmitate + 8 CoASH + 14 NADP+ + 7 ADP + 7 Pi + 6 H2O
2,Biosynthesis of fatty acid
?Process,(cont.)
?Synthesis of fatty acid – odd-number fatty acid
The first C-source \ precursor is propionyl-CoA instead of
acetyl-CoA in odd-number fatty acid biosynthesis de novo.
2,Biosynthesis of fatty acid
2,Biosynthesis of fatty acid
?Extension of C-chain
—in mitochondra or microsome
?in mitochondra,
是脂肪酸 ?-氧化的逆过程,使一些脂肪酸 (C16)延长,依次经历缩合、
还原、脱水、还原 (与从头合成相似 ),碳链延长 2C。
不同之处:缩合的底物是脂酰 CoA和乙酰 CoA。
?Microsome,
以丙二酰 CoA延长碳链,还原过程只需 NADPH+H+ 。
过程与线粒体合成系统相同。
—— 均无 以脂酰载体蛋白 (ACP)为核心的多酶复合体系
2,Biosynthesis of fatty acid
— unsaturated
?氧化脱氢途径
一般在脂肪酸的 C9,C10脱氢,由脂酰脱饱和酶催化。
??-氧化、脱水途径
首先在饱和脂肪酸的 ?-C氧化为羟酸,再 ?,?-碳 脱水形成双键。
(Fig.)
——NB:人体及高等动物不能合成亚油酸、亚麻酸,必须从食物中摄取。
?必需脂肪酸 。
3,Biosynthesis of Fat
脂肪由脂酰 CoA和 ?-?甘油形成:
?脂酰 CoA:脂肪酸与 CoASH结合而成。
??-?甘油:有两种来源
1,甘油 +ATP?(甘油激酶 )??-?甘油 +ADP
2,?二羟丙酮 ?(?-?甘油脱氢酶,NADH+H+)??-?甘油
?脂肪合成历程:
?-?甘油 +脂酰 CoA?(脂酰基?甘油转移酶 )??-?甘油二脂
(+H2O)?(磷脂酸磷酸酶 )?甘油二脂 ?
(脂酰基甘油二脂转移酶 )?脂肪酸
(Fig.)
比较 从头合成 ?-氧化
位置 细胞质 线粒体
运转载体 柠檬酸 肉毒碱
酰基载体 ACP CoA
电子供体、受体 NADPH+H+ NAD+,FAD
?-羟酰基 CoA立体异构型 D-型 L-型
对 CO2、柠檬酸的要求 YES NO
2C单位加上或断裂方式 丙二 (酸单 )酰 CoA 乙酰 CoA
酶 多酶复合体 较松散
能量转化 消耗 7ATP,14NADPH+H+ 放能 129ATP
反应历程 还原、脱水 氧化、加水
脂肪酸的从头合成与 ?-氧化的区别
IV,Metabolism of other lipids
?磷脂 (phospholipid)
—磷脂的分解前已述,产物为甘油、脂肪酸、磷酸、胆碱 (乙醇胺 )等。
—合成途径有三:
胆碱途径 ?磷脂酰胆碱 (卵磷脂 ) (Fig,p219)
磷脂酰乙醇胺途径 (以磷酸乙醇胺代替磷酸胆碱 )
磷脂酰丝氨酸合成途径 (略 )
?胆固醇 (cholesterol \ cholesterin)
(see also next page)
IV,Metabolism of other lipids
?胆固醇 (cholesterol \ cholesterin)
人和动物不食用胆固醇,体内的胆固醇含量并不降低,而且不断排出
胆固醇的多谢产物 (如粪固醇 )。 ?体内可合成胆固醇。
?同位素示踪实验 证明:可用小分子乙酸缩合而成胆固醇。
?POSITION,in endoplasmic reticulum of liver
?PROCESS,
(Fig.)
?TRANSFORMATION,?Biological importance
(Fig,7-9)