Transcript β-甲基戊二醯輔酶A(HMG-CoA)

Chapter 21
Lipid Metabolism
Lipid metabolism allows polar bear to
thrive in arctic climates and endure
months of hibernation
脂質代謝使得北極熊得以存活在極寒氣候中,
1
並可冬眠長達數個月之久
Outline
21.1 Lipids Are Involved in the Generation and
Storage of Energy 脂質參與能量的產生與儲存
21.2 Catabolism of Lipids 脂質的分解代謝
21.3 The Energy Yield from the Oxidation of Fatty
Acid 脂肪酸氧化反應產生的能量
21.4 Catabolism of Unsaturated Fatty Acids and
Odd-Carbon Fatty Acid
不飽和脂肪酸及奇數碳脂肪之分解代謝
21.5 Ketone Bodies 酮體
21.6 Fatty Acids Biosynthesis 脂肪酸的合成
21.7 Synthesis of Acylglycerols and Compound
Lipid 醯化甘油與複合脂質的合成
21.8 Cholesterol Biosynthesis 膽固醇的合成
2
Typical Naturally Occurring
Unsaturated Fatty Acids
Table 8.2
Typical Naturally Occurirng Unsaturated Fatty Acids
Acid
Number of
Degree of
Carbon Atoms
Unsaturation
Formula
Melting Point
(oC)
Palmitoleic
棕櫚油酸; 十六烯酸
16
16:1-∆9
CH3(CH2)5CH=CH(CH2)7CO2H
-0.5
Oleic
油酸;十八烯酸
18
18:1-∆9
CH3(CH2)7CH=CH(CH2)7CO2H
16
Linoleic
亞麻油酸
18
18:2-∆9,12
CH3(CH2)4CH=CH (CH2) CH=CH(CH2)7CO2H
-5
Linolenic
次亞麻油酸
18
18:3-∆9,12,15
CH3(CH2CH=CH)3(CH2)7CO2H
-11
Arachidonic
花生四烯酸
20
20:4-∆5,8,11,14
CH3(CH2)4(CH=CH(CH2)4(CH2)2CO2H
-50
Table 8-2, p.186
Triacylglycerols (triglyceride)三酸甘油酯
•Do not occur as components of membranes
•Accumulate in the adipose tissue 脂肪組織 (fat cell)
•They serve as concentrated stores of metabolic energy
脂質所潛藏的能量存於三酸甘油酯的
脂肪鏈中
熱量過多時
 脂肪酸會被合成且儲存於脂肪細胞
能量需求大時
 脂肪酸會被代謝分解而釋出能量
Fig. 8-2a, p.187
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• Catabolism proceeds of lipids脂質的代謝作用
– Beginning with carboxyl group 由羧基開始
– Converting long-chain fatty acyl group to
acetyl-coA 將長鏈脂肪酸基團轉換成乙醯輔酶A
– Subsequently oxidized in the TCA cycle 進一步在
檸檬酸循環中被氧化
• The synthesis of fatty acids 脂肪酸的合成
– Begin with acetyl-CoA 由乙醯輔酶A開始
– After which carbon atoms are added to the
growing hydrocarbon chain 接著碳原子會被加入
增長的碳氫鏈中,通常一次會增加兩個碳
•Lipid synthesis and catabolism of lipids occur
simultaneously, but in different parts of the cell 脂
質的合成與代謝分解可以同時進行但其作用在細胞的不同
部位
– Synthesis take place in the cytosol, while
catabolism take place in the mitochondrion
合成→細胞質 代謝→粒線體
– NADPH is the donor of high-energy electrons in
lipid synthesis, whereas FAD and NAD+ are
electron acceptors in lipid catabolism
合成→NADPH為高能量電子提供者
代謝→FAD 及 NAD+為電子接受者
– Different activating ligands are used利用不同活性配
位子
•Coenzyme A is used in catabolism
•Acyl carrier protein (ACP) is used in anabolism
代謝→輔酶A 合成→醯基載體蛋白
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Catabolism of Lipids
脂質之分解代謝
Catabolism of Lipids
脂質之分解代謝
• The chief source of energy in the catabolism of lipid 脂
質代謝產生的能量主要來自:
– The oxidation of fatty acid 脂肪酸的氧化
• Sterols are not catabolized as a source of energy 固醇類的
脂質代謝不會被當作能量來源
• Fatty acids as part of their covalently bonded structure
以下二者都有脂肪酸的共價鍵鍵結
– Triacylglycerols 三酸甘油酯是脂質化學能的主要儲存形式
• The main storage form of the chemical energy of lipid
– Phosphoacylglycerols 磷酸甘油酯則為生物膜重要的成分
• Important components of biological membranes
• Fatty acid can be hydrolyzed by脂肪酸及其分子其餘部
分之間的鍵結是可以被水解的
– lipase (triacylglycerols)水解三酸甘油酯的是脂肪酶
– phospholipase (phosphoacylglycerols)水解磷酸甘油脂的
是磷脂酶
(phospholipid)
FIGURE 21.1 The release of fatty acids for future use.
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Fig. 21-1, p.608
Catabolism of Lipids
脂質之分解代謝
• Different phospholipases can be distinguished
on the basis of the site at which they hydrolyze
phospholipids不同磷脂酶依其水解不同磷脂質的位置
而有所區別
•Phospholipase A2磷脂酶A2
– Widely distributed in nature
•Phospholipase D磷脂酶D
– Occur in spider venom蜘蛛毒液
– Responsible for the tissue
damage 造成組織受傷
Phospholipase A2
FIGURE 21.2 Several phospolipases
hydrolyze phosphoacylglycerols
•Snake venom 蛇毒
– Also contain phospholipase
– The lipid product of hydrolysis
act to lyse red blood cells,
preventing clot formation 脂質
的水解產物可溶解紅血球,阻止血
液凝固
Catabolism of Lipids
脂質之分解代謝
•The release of fatty acids from triacylglycerols in
adipocytes is controlled by hormones 脂肪細胞中的
三酸甘油酯釋放出脂肪酸的過程會受到荷爾蒙的調控
– Hormone binds to a receptor on the plasma
membrane of the adipocyte荷爾蒙會結合到脂肪細胞之細
胞膜上的受體
•The main hormone -- epinephrine腎上腺素
– Activates adenylate cyclase 會活化腺核啟酸環化酶
•production of active protein kinase A (cAMPdependent protein kinase) 導致活化態蛋白質激酶A
(cAMP依賴型蛋白質激酶) 的產生
– Protein kinase phosphorylates triacylglycerols
lipase 蛋白質激酶會磷酸化三酸甘油酯脂肪酶
– Cleaves the fatty acids from the glycerol
backbone 從甘油骨架上切出脂肪酸
Epinephrine
腎上腺素
受體
細胞膜
脂肪細胞
腺核苷酸環化酶
蛋白質激酶
(不活化態)
蛋白質激酶
(活化態)
三酸甘油酯
三酸甘油酯脂肪酸
(活化態)
脂肪酸
三酸甘油酯脂肪酸
(不活化態)
磷脂酶
二醯甘油
磷脂酶
二醯甘油
脂肪酸
在脂肪組織中，由三酸甘
油酯釋放出脂肪酸，需要
荷爾蒙的參與--腎上腺素
甘油單酯
甘油單酯脂肪酸
脂肪酸
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Fig. 21-3, p.609
Fatty-acid oxidation begins with activation of the molecule
脂肪酸的氧化作用開始於分子的活化
Fatty acid
兩個高能磷酸鍵水
解會提供脂肪酸活
化所需的能量
醯基腺啟酸
中間產物
輔酶A
醯基輔酶A合成酶
硫酯
活化的醯基
Acyl-CoA 醯基輔酶A
FIGURE 21.4 The formation of an acyl-CoA.
醯基輔酶A的形成
esterification take place in the cytosol 酯化反應發生在細胞質內
•The
•The rest reactions of fatty-acid oxidation occur in the
mitochondrial matrix 脂肪酸氧化作用的其餘反應則發生在粒線體基質內
 The activated fatty acids must transport into the mitochondrial
13
Fig. 21-4, p.609
matrix 活化態的脂肪酸必須送到粒線體基質,氧化反應才能進行
肉鹼在醯基轉移到粒線體基
質的過程中所扮演的角色
醯基輔酶A可以通過粒線體
外膜但無法通過內膜
mitochondria
醯基肉鹼
Transesterification
可以通過粒線體內膜 轉酯作用
Carnitine
palmitoyltransferase肉鹼
棕櫚醯基轉移酶(CPT-I):
Specificity for acyl
groups between 14 and
18 crbons
肉鹼醯基轉移酶
Carnitine palmitoyltransferase (CPT-II)
基質
肉鹼棕櫚醯基轉移酶
Acyl-CoA
β-氧化作用
Carnitine translocase肉鹼轉
位酶 Specific carnitine/acylcarnitine
transporter轉運者
Oxidative cleavage takes place at
the (carboxyl end) b-carbon of the
14
acyl group esterified to CoA
Fig. 21-5, p.610
The role of carnitine in the transfer of acyl
groups to the mitochondrial matrix肉鹼在醯基轉移
到粒線體基質的過程中所扮演的角色
•The acyl-CoA cross the outer mitochondrial membrane
but not the inner membrane
醯基輔酶A可以通過粒線體外膜但無法通過內膜
•The acyl group is transferred to carnitine by
transesterfication – forms acyl-carnitine醯基肉鹼
醯基會經轉酯作用轉移給肉鹼，形成一種可以通過粒線體內膜的化合物
– Catalyzed by carnitine acyltransferase經由位於內膜上的肉鹼
醯基轉移酶所催化
•Carnitine palmitoyltransferase (CPT-I)肉鹼棕櫚醯基轉移酶
– Specificity for acyl groups 14 and 18 carbons
對於14到18個碳長鏈的醯基具有專一性
•The acylcarnitine pass through the inner membrane to
the matrix醯基肉鹼可以藉由一個被稱為肉鹼轉位酶的特殊肉鹼/醯基
肉鹼轉運者而通過粒線體內膜
– Via a specific carnitine/acylcarnitine transporter
•Called carnitine translocase
The role of carnitine in the transfer of acyl
groups to the mitochondrial matrix
•Transferred from carnitine to mitochondrial CoA-SH by
another transesterification
– Carnitine palmitoyltransferase (CPT-II)
•Located on the inner face of the membrane
一旦到達基質，肉鹼上的醯基會藉由另一個位在粒線體內膜上的第二個
肉鹼棕櫚醯基轉移酶經轉酯作用轉移給粒線體的輔酶A
• b-oxidation β-氧化作用
– The reaction successively cleaved two-carbon units from
fatty acid
– The b-carbon of acyl group esterified to CoA
在基質中，會有一連串重複的反應從羧基端開始每次切掉兩個碳單元。
因為此種氧化切割是發生在與輔酶A酯化的醯基之β-碳原子上，因而這個
過程被稱為β-氧化作用。而原始脂肪酸的β-碳原子會變成下一輪分解反
應的羧基碳。整個循環需要四個反應步驟。
醯基輔酶A
硫醇酶
較原本分子少兩個
碳的醯基輔酶A
由FAD依賴型醯基輔
酶A脫氫酶所催化
氧化
b-oxidation
β-酮醯輔酶A
α,β-不飽和醯基輔酶A
氧化反應
β-羥醯輔酶A脫氫酶
水合
羥醯輔酶A水合酶
β-羥醯輔酶A
飽和脂肪酸的β-氧化作用包含有四個酵素催化反應的循環。
The b-oxidation of saturated fatty acids involves a cycle
of four enzyme-catalyzed reactions
17
Fig. 21-6, p.611
The b-oxidation of saturated fatty acids
1. Oxidation
Acyl-CoA
FAD
FADH2
Acyl-CoA dehydrogenase
2. Hydration
b-enoyl-CoA
H 2O
Enoyl-CoA hydratase
b-enoyl-CoA (trans)
b-hydroxyacyl-CoA
3. Oxidation
b-hydroxyacyl-CoA
4. Cleavage
b-ketoacyl-CoA
NAD+
NADH+H+
b-hydroxylacyl-CoA
dehydrogenase
CoA-SH
b-ketoacyl-CoA
Acetyl-CoA
Thiolase
Fatty acyl-CoA
An even number of fatty acids undergoes successive round
of the b-oxidation cycle  the product is acetyl-CoA
偶數碳原子脂肪酸進行完整的β-氧化循環後的產物為β-乙醯輔酶A
FIGURE 21.7 Stearic acid (18 carbons) gives rise to nine 2-carbon units
after eight cycles of b-oxidation
硬脂酸(十八碳)經過八次氧化作用的循環之後會產生9個二碳單元。
從右邊的羧基端開始，經過八次β-氧化作用移除掉8個連續的二碳單
元之後，第九個二碳單元仍會以酯鍵結在輔酶A上
Fig. 21-7, p.612
Even number of carbon atoms undergoes successive
rounds of b-oxidation cycle偶數碳原子脂肪酸進行完整的β-氧化循環
– The product is acetyl-CoA產物為β-乙醯輔酶A
The number of molecules of acetyl-CoA produced is equal
to half of the number of carbons atoms in the original fatty
acid所產生的乙醯輔酶A的分子數會等於原始脂肪酸其碳原子數目的一半
– 18-carbon stearic acid molecule
– Nine 2-carbon acetyl units
– Requires eight cycles of b-oxidation
– The acetyl-CoA enters the citric acid cycle乙醯輔酶A會進入檸
檬酸循環
– Take place in the mitochondria matrix
• Also occur in other site
– Peroxisome and glyoxysome
•Hypolipidemic 降血脂的藥
– Drugs are used in an attempt to control obesity 控制肥胖症
• By stimulating b-oxidation in peroxisome
20
The Energy Yield from the Oxidation of
Fatty Acid脂肪酸氧化反應產生的能量
•The oxidation of acetyl-CoA formed by b-oxidation
of fatty acids can also produce ATP
– The reoxidation of NADH and FADH2 produced by the
b-oxidation of the fatty acid to acetyl-CoA脂肪酸氧化成乙
醯輔酶A時所產生之NADH與FADH2，可以再進行氧化作用
– ATP production from the acetyl-CoA through the citric
acid cycle and oxidative phosphorylation乙醯輔酶A經由
檸檬酸循環與氧化磷酸化作用所產生的ATP
– Stearic acid (18C) as an example
•Eight cycles of b-oxidation
– One mole of stearic acid to nine mole of acetyl-CoA
– 8 mole of FAD are reduced to FADH2
– 8 mole of NAD+ are reduced to NADH
O
ll
CH3(CH2)16C−S−CoA + 8FAD + 8NAD+ + 8H2O + 8 CoA-SH→
O
ll
9CH3−C−S−CoA + 8FADH2 + 8NADH +8H+
Table 21.1 The Balance Sheet for Oxidation of One Molecule
of Stearic Acid
Reaction
NADH
FADH2
1 Stearic acid  Stearyl-CoA (activation step)
2 Stearyl-CoA  9 acetyl-Co A (8 cycles of b-oxidation)
3
9 acetyl-CoA  18CO2 (citric acid cycle);
GDT  GTP (9 molecule)
4 Reoxidation of NADH from b-oxidation cycle
5 Reoxidation of NADH from citric acid cycle
ATP
-2
+8
+8
+27
+9
+9
-8
+20
-27
+67.5
6 Reoxidation of FADH2 from b-oxidation cycle
-8
+12
7 Reoxidation of FADH2 from citric acid cycle
-9
+13.5
0
0
+120
具有相同的碳原子數目，脂質氧化所產生的ATP產量還是比糖類高；
O 因脂質除了羧基之外，均由碳氫構成，以較高還原態存在的
ll
CH3(CH2)16C−S−CoA + 26 O2 + 122 ADP + 122 Pi 
18 CO2+ 17 H2O + 122 ATP + CoA-SH
Metabolic water代謝水
A source of water for organisms
that live in the desert.
有氧代謝反應常見的現象，
22
可做為沙漠生物的水份來源
Catabolism of Unsaturated Fatty Acids
and Odd-Carbon Fatty Acid
不飽和脂肪酸及奇數碳脂肪之分解代謝
•Odd numbered fatty acids also undergo the boxidation process奇數碳原子的脂肪酸也會進行β-氧化作用
最後一個循環
的β-氧化作用
會產生一分子
的丙醯輔酶A
丙醯輔酶A羧化酶
propionyl-S-CoA
carboxylase
Requires Vitamin B12
(Co (III))
進行結構重排
甲基丙二醯輔酶A
琥珀醯輔酶A
進入檸檬酸循環
The oxidation of a fatty acid containing an odd
number of carbon atoms
The conversion of a monounsaturated fatty acid to
acetyl-CoA requires a cis-trans isomerization單元不飽和
脂肪酸轉變成乙醯輔酶A需要順式-反式異構化作用
(β-氧化作用產生的不飽和脂肪酸其雙鍵是反式排列，而自然界存在的脂
肪酸其雙鍵多是順式排列)
– Successive rounds of b-oxidation of oleic acid (18:1) as
an example 以油酸經完全的β-氧化作用為例,其在第九和第十個
碳之間有一個順式雙鍵
•Three round of b-oxidation 經過三次的b-氧化
•12-carbon unsaturated fatty acid with a cis double bond
(3:4)產生一個十二碳的不飽和脂肪酸，其第三與第四個碳之間
會有一個順式雙鍵
•A cis-trans isomerase produced a trans bouble bond (2:3)順
式-反式異構酶將第三和第四個碳之間的順式雙鍵轉變成第二和
第三個碳之間的反式雙鍵,此後的代謝與飽和脂肪酸相同
24
反式-△2-十二碳烯醯輔酶A
油醯輔酶A
β-氧化作用
(三次循環)
4
烯醯輔酶A水合酶
3
順式-△3-十二碳烯醯輔酶A
烯醯輔酶A異構酶
β-氧化作用延續
3
2
反式-△2-十二碳烯醯輔酶A
FIGURE 21.9 b-oxidation of unsaturated fatty acids
25
Fig. 21-9a, p.616
• b-oxidation of polyunsaturated fatty
acids多元不飽和脂肪酸
– Linoleic acid (18:2) as an example
FIGURE 21.10 The oxidation pathway for polyunsaturated fatty acids,
illustrated for linoleic acid.
26
Fig. 21-10a, p.578
• Linolenic acid (18:3) with three double bonds
– The first double bond requires the isomerase
– The second one requires the reductase and
iosmerase
– The third requires the isomerase
• The oxidation of unsaturated fatty acids does not
generate as many ATPs as the fatty acid with the
same number of carbon
– Fewer FADH2 will be produced
不飽和脂肪酸的氧化，不像同碳數之飽和脂肪酸可以產生很
多的ATP，因為有雙鍵的存在，表示醯基輔酶脫氫酶的步驟是
被跳過的，所以會產生較少的FADH2
Ketone Bodies 酮體
• When an excess of acetyl-CoA arises from boxidation, ketone bodies are produced –
substance related to acetone.當β-氧化作用所產生之醯
基輔酶A過多時，會產生與丙酮相關的物質，此即為酮體
– Not enough oxaloacetate is available發生在當沒有足夠的
草醋酸可和大量的乙醯輔酶A反應，而將之帶入檸檬酸循環
• High intake of lipids and low intake of carbohydrate
攝入大量的脂質與少量醣類時會發生
• Also in starvation and diabetes 飢餓和糖尿病亦會產生
– Start with the condensation of two molecules of
acetyl-CoA to produce acetoacetyl-CoA
反應始於兩分子的乙醯輔酶A縮合產生乙醯基乙醯輔酶A
– Acetoacetate is produced from acetoacetyl-CoA
through the condensation with another acetyl-CoA
to form b-hydroxy-b-methylglutaryl-Co A (HMGCoA)乙醯乙酸由乙醯基乙醯輔酶A與另一個乙醯輔酶A經縮合作用形
成β-羥基-β-甲基戊二烯輔酶A(HMG-CoA)所產生
• HMG-CoA for cholesterol synthesis
Acetyl-CoA
硫醇酶
HMG-CoA lyase then release acetyl-CoA to
give acetoacetate
乙醯乙醯輔酶A HMG-CoA裂解酶會釋出乙醯輔酶A而產生乙醯乙酸
Acetoacetate can produce:乙醯乙酸可產生
Acetyl-CoA
HMG-輔酶A合成酶–
b-hydroxybutyrate 經由還原反應產生β-羥基丁
酸
• Catalyzed by b-hydroxybutyrate
dehydrogenase
β-羥基-β-甲基戊二
烯輔酶A
– Acetone 經自發性去羧作用產生丙酮
• The spontaneous decarboxylation of
acetoacetate
HMG-輔酶A裂解酶
乙醯乙酸
β-羥基丁酸脫氫酶
丙酮
β-羥基丁酸
FIGURE 21.11 The formation of ketone bodies,
29
Fig. 21-11, p.617
synthesized primarily in the liver.
因為乙醯乙酸與β-羥基丁酸是酸性的，高濃度存在時會破壞血液的緩
衝能力。當血液中的pH值降低時 (即酮酸中毒)，身體會將H+排放到尿
液中，而Na+、K+與水也會被排出體外，因而造成嚴重的脫水
•The excess of acetoacetate, and consequently of acetone, is
a pathological condition known as ketosis酮病 過多的乙醯乙
酸所形成的丙酮是造成酮病的病理條件
酮酸中毒
– Lowering of blood pH (ketoacidosis)
– Excreting H+ into the urine
– Excretion of Na+, K+ and water
– Cause diabetic coma糖尿病昏迷
• Synthesis of ketone bodies is liver mitochondria酮體合成的主要
位置為肝臟的粒線體
• In heart muscle and the renal cortex, acetoacetate is the
preferred source of energy
酮體是水溶性的，可在血液中運送。肝臟以外的器官會利用酮體，特別是乙
醯乙酸，在心肌與腎皮質中，乙醯乙酸是較為優先的能量來源
30
Fatty Acids Biosynthesis
脂肪酸的形成
通常合成和分解並不是彼此間完全相反的反應
• The anabolism of fatty acids is not simply a
reversal of the reactions of b-oxidation 脂肪酸的合
成並非單純的b-oxidation的逆反應
– Anabolic reaction in cytosol合成在細胞質進行
– Degradative reaction of b-oxidation reaction in
mitochondrial matrix β-氧化作用的分解反應是發生在
粒線體的基質內
• The first step in fatty acid biosynthesis is
transport of acetyl-CoA to cytosol
脂肪酸生合成的第一個步驟是將乙醯輔酶A運送到細胞質
內
乙醣
輔酶A
在細胞質的
糖解作用
丙酮酸 乙醯輔酶A 檸檬酸
檸檬酸
即可合成脂肪酸
乙醯輔酶A
丙酮酸
脂質
一些胺基酸
草醋酸
輔酶A
•Acetyl-CoA enters the
pathway for fatty acid
synthesis
•NADPH is required for
fatty acid anabolism
乙醯基團從粒線體到細胞質的運送
FIGURE 21.12 The transport of acetyl groups from the
mitochondrion to the cytosol.
32
Fig. 21-12, p.620
acetyl-CoA carboxylase乙醯輔酶A羧化酶
A key intermediate in fatty acid
biosynthesis是一種脂肪酸生合成的
關鍵性中間產物
乙醯輔酶A
丙二醯輔酶A
FIGURE 21.13 The formation of malonyl-CoA, catalyzed by acetyl-CoA carboxylase
在細胞質: 乙醯輔酶A會被化成羧化而產生丙二醯輔酶A (malonyl-CoA)
Acetyl-CoA carboxylase complex乙醯輔酶A羧化酶複合體
•Consists of three enzyme包含三種酵素
•Biotin carboxylase生物素羧化酶
•Catalyzed the transfer of carboxl group to biotin
•Biotin carrier protein 生物素攜帶蛋白質
•Carboxyl transferase 羧基轉移酶
•Require Mn2+
•Biotin生物素
•ATP
33
Fig. 21-13, p.620
•Acetyl-CoA carboxylase complex
–Biotin carboxylase生物素羧化酶
•Catalyzed the transfer of carboxl group to biotin
催化羧基傳遞給生物素的反應
•The activated “CO2” (from the bicarbonate ion HCO3-)
is covalently bond to biotin 活化態二氧化碳(羧基來自碳酸鹽離
子，HCO3-)是共價鍵結到生物素上
–Biotin carrier protein生物素攜帶蛋白質
•Biotin (whether carboxylated or not) is bound to the
biotin carrier protein by amide linkage to the e-amino
group of a lysine side chain.生物素(不論有無被羧化)會以醯
胺鍵鍵結到生物素攜帶蛋白之離胺酸側鏈的ε-胺基上
–Carboxyl transferase 羧基轉移酶
•The carboxylated biotin transfer the carboxyl group to
acetyl-CoA to produce malonyl-CoA 將羧基轉移給乙醯
輔酶A，而產生丙二醯輔酶A
•Malonyl-CoA strongly inhibits the carnitine
acyltransferase I on the outer face of the inner
mitochondrial membrane丙二醯輔酶A可很強抑制粒線體
外膜的醯基轉移酶的作用,避免再送回粒線體
生物素的羧化反應
Biotin
carboxylase
N-carboxybiotin
amide linkage
Biotin carrier protein
生物素的轉羧基反應
Acetyl-CoA
Nucleophilic attack
Carboxyl
transferase
Malonyl-CoA
丙二醯輔酶A
A mechanism for the acetyl-CoA carboxylase reaction
35
Fig. 21-14b, p.621
•The biosynthesis of fatty acids involves the
successive addition of two-carbon units to
the growing chain脂肪酸的合成就是依序地將二碳單元加
到正在增長的碳鏈上;丙二醯輔酶A之丙二醯基的三個碳原子中的兩個
，會在每次的生合成反應的循環中被加入正在增長的脂肪酸鏈上
– Required multienzyme complex located in
the cytosol – fatty acid synthase此反應需要一個
位於細胞質內而非任何膜上的多酵素複合體的參與，叫做脂肪酸合
成酶
– The anabolism of palmitate (16-carbon
saturated fatty acid)脂肪酸合成代謝的常見產物為棕
櫚酸鹽，是一種含16個碳的飽和脂肪酸
Acyl carrier protein (ACP)
醯基載體蛋白
β-酮醯基-S-ACP合成酶:以硫酯鍵鍵結
b-ketoacyl-S-ACP synthase
Thioester (ser)
Thioester (cys)
乙醯轉移酶
condensation
Acetoacetyl-ACP
Thioester bond
與輔酶A以硫酯鍵鍵結的丙
二醯基會轉移到ACP上並也
以硫酯鍵鍵結
37
Fig. 21-15a, p.583
From acetyl-ACP
From malonyl-ACP
Release CO2
β-酮醯基-ACP還原酶
β-羥丁醯ACP
β-羥丁醯ACP脫氫酶
丁烯醯ACP
butyryl-ACP plays the same
role as acetyl-CoA in the first
round
丁醯ACP
38
Fig. 21-15b, p.583
丁醯ACP所扮演的角色就如同乙醯
丁醯ACP
ACP在第一輪的循環中一樣
Butyryl-ACP
丙二醯基
malonyl-ACP
b-ketoacyl-ACP
In mammalian system, the process stops at C16
because the fatty-acid synthase does not produce
longer chains.
39
Fig. 21-15c, p.623
• In mammalian system, the process stops at C16
because the fatty-acid synthase does not produce
longer chains.在哺乳動物系統中，因為脂肪酸合成酶無
法產生更長的碳鏈，因而反應進行到C16時就會停止
• Fatty-acid synthase from different types of organism
have markedly different characteristics不同種類的生
物體其合成酶具有不同的特性
– In E. coli大腸桿菌
• The multienzyme system consists of an aggregate of
separate enzymes, including a separate ACP多重酵素系
統是由個別的酵素所聚合而成的，包括有一個獨立的ACP
– In eukaryotes真核生物的脂肪酸合成:
• Multienzyme complex一多重酵素複合體
– In yeast在酵母菌
» Multienzyme complex : a6b6 complex
– In mammalian哺乳動物
» Only one type of subunit, but is a dimer of this subunit
(miltifunctional enzyme)脂肪酸合成酶則只具有一種次單
元，而活化態的酵素則是由此次單元以二聚體的形式組成，
但每一個次單元都是一個可以催化反應進行的多功能酵素
• ACP as a “swinging arm”旋轉手臂,可在含有不同次
單元的酵素活性之間來回擺動
結構相似
醯基載體蛋白(ACP)的磷酸泛醯硫乙胺基團
輔酶A的磷酸泛醯硫乙胺基團
•Several additional reactions are required for the
elongation of fatty-acid chains and the
introduction of double bonds.脂肪酸鏈增長以及導
入雙鍵則需要許多額外的反應參與
•In mammals哺乳動物
–Two sites for the chain-lengthening reactions要製造出
比棕櫚酸鹽更長的脂肪酸時，此反應不需要細胞質內的脂肪酸合成酶
的參與，可利用:
•Mitochondrion粒線體
– Acetyl-CoA as intermediates (Not acetyl-ACP) 中間產物為
醯基輔酶A型(而不是醯基ACP型)
– The reverse of the catabolic reactions of fatty-acid 是脂肪
代謝反應的逆反應
•The endoplasmic reticulum (ER)內質網
– The source of additional carbon atoms is malonyl-CoA 主
要來源為丙二醯輔酶A
– There is no intermediates bound to ACP 不會有與ACP鍵結
的中間產物產生
•Reaction in which a double bond is introduced in
fatty acids mainly take place on the ER將雙鍵導入脂
肪酸的反應主要是發生在內質網內
–Catalyzed by a mixed function oxidase 由具混合性功能
的氧化酶所催化
•Required O2 and NAD(P)H
•Both NAD(P)H and fatty acid are oxidized, O2 is reduced
to water
–Mammals cannot introduce a double bond beyond
carbon atom 9 of the fatty-acid chain哺乳動物無法在
脂肪酸鏈的第九個碳(由羧基端數過來)之後加入雙鍵
•Linoleate [CH3-(CH2)4-CH=CH2-CH=CH-(CH2)7-COO- ],
with 2 double bond帶兩個雙鍵的亞麻油酸鹽
•Linolenate [CH3-(CH2)4-CH=CH2-CH=CH-CH2-CH=CH(CH2)4-COO- ], with 3 double bond帶三個雙鍵的亞麻脂酸鹽
•Must be included in the diets of mammals必須要外加入飲食
中
•They are essential fatty acids because they are precusors
of other lipids, including prostaglandins由於它們是前列腺素
等其他脂質的前驅物，所以它們是屬於必需脂肪酸
Table 21.2 A comparison of Fatty Acid Degradation and Biosynthesis
Degradation
1.
2.
3.
4.
5.
6.
7.
Product is acetyl-CoA
Malonyl-CoA is not involved; no requirement for biotin
Oxidative process; requires NAD+ and FAD and Produces ATP
Fatty acids form thioesters with CoA-SH
Starts at carboxyl end (CH3COO2-)
Occurs in the mitochondrial matrix, with no ordered aggregate of enzymes
b-Hydroxyacyl intermediates have the L configuration
Biosynthesis
1.
2.
3.
4.
5.
6.
7.
Precusor is acetyl-CoA
Malonyl-CoA is source of two-carbon units; biotin required
Reductive process; requires NADPH and ATP
Fatty acids form thioesters with acyl carrier proteins (ACP-SH)
Starts at methyl end (CH3CH2-)
Occurs in the cytosol, catalyzed by an ordered multienzyme complex
b-Hydroxyacyl intermediates have the D configuration
44
Table 21-2, p.626
Table 21.2
粒線體: b-oxidation作用的分解代
謝及一些碳鏈的加長
內質網:碳鏈加長及雙鍵導入
細胞質: 合成代謝及醯基
輔酶A的形成
the sites of various aspects of fatty-acid metabolism
46
Fig. 21-18, p.625
Synthesis of Acylglycerols and
Compound Lipid
醯化甘油與複合脂質的合成
• Other lipids, are derived from fatty acids and
metabolites of fatty acids, such as
acetoaccetyl-CoA包括三酸甘油酯、磷酸甘油酯與類固醇等
脂質，均來自脂肪酸及脂肪酸的代謝產物，例如乙醯乙酸輔酶A
• Free fatty acids do not occur in the cell, they
are normally found incorporated in
triacylglycerols and phosphoacylglycerols細胞內
的游離脂肪酸並不多，一般都併入三酸甘油酯及磷酸甘油酯之中
– The biosynthesis take place on the ER of liver
cells of fat cells (adipocytes)這兩類化合物的生合成主要
是發生在肝臟細胞或是脂肪細胞的內質網裡
Synthesis of Acylglycerols and
Compound Lipid
醯化甘油與複合脂質的合成
• Triacylglycerols三酸甘油酯
– The glycerol portion of lipid is derived from脂質的
甘油部分是由
• glycerol-3-phosphate (from glycolysis)甘油-3-磷酸
衍生(來自於糖解作用)
• In liver and kidney, glycerol released by
degradation of acylglycerols 肝臟與腎臟中,甘油的來
源是醯基甘油經分解所釋放出來的
– An acyl group of a fatty acid is transferred from
an acyl-CoA脂肪酸的醯基是由醯基輔酶A轉移而來
• The products are CoA-SH and lysophosphatidate此
反應的產物為輔酶A與溶磷脂酸(一種單醯基甘油磷酸)
• The acyl group is esterified at carbon 2 (C-2)
醯基被酯化在甘油的第二個碳上
而
Synthesis of Acylglycerols and
Compound Lipid
醯化甘油與複合脂質的合成
• Triacylglycerols
– Second acylation reaction第二次的醯化反應
• Producing a phosphatidate經由相同的酵素催化而
產生磷脂酸
– Occur in membrane and are precursors of other
phospholipids 磷脂酸是位在細胞膜上，也是其他磷脂
質的前驅物質
– Phosphate group is removed by hydrolysis,
producing a diacylglycerol 磷脂酸之磷酸基部分若
經水解去除會產生二醯甘油
– Third acyl group is from acyl-CoA當要加入第三個醯
基時其來源為醯基輔酶A而不是脂肪酸
醯基甘油的分解
糖解作用
甘油
磷脂酸
甘油-3-磷酸
醯基輔酶A
C-2
醯基輔酶A
溶磷脂酸
醯基輔酶A
Pathways for the biosynthesis of triacylglycerols.
三酸甘油脂
50
Fig. 21-19, p.627
Synthesis of Acylglycerols and Compound Lipid
醯化甘油與複合脂質的合成
Phosphoacylglycerol 磷酸甘油酯
• Base on phosphoatidates以磷脂酸為基礎
– With the phosphate group esterified to another
alsohol, such as ethanolamine磷酸基被另一個醇類酯化，
而通常是含氮的醇類如乙醇胺
– Requires nucleoside triphosphates, particularly
cystidine triphopsphate (CTP)磷脂酸轉換成磷脂質通常需
要有核啟三磷酸的存在，尤其是胞核啟三磷酸
• In bacteria 在細菌
– CTP react with phosphatidate to produce cytidine
diphosphate diacylglycerol (CDP diglyceride) CTP會和
磷脂酸反應而產生CDP 甘油二酯
胞核苷二磷酸二醯甘油
一種磷酸脂
磷脂醯絲胺酸
The biosynthesis of
phosphatidylethanolamine in bacteria
磷脂酸乙醇胺
52
Fig. 21-20, p.629
Synthesis of Acylglycerols and
Compound Lipid
醯化甘油與複合脂質的合成
•In eukaryotes 在真核細胞
– The removal by hydrolysis of the phosphate group of
the phosphatidate, producing a diacylglycerol水解移
除磷脂酸的磷酸根，產生二醯甘油
– ethanolamine phosphate with CTP to produce
pyrophosphate and cytidine diphosphate
ethanolamine 磷酸乙醇胺與CTP作用而產生焦磷酸 (PPi) 及胞
核苷二磷酸乙醇胺
CDP-ethanolamine + diacylglycerol phosphatidylethanolamine
CDP乙醇胺會與二醯甘油作用而產生磷脂醯乙醇胺
•In mammals
– Alcohol exchange from serine to ethanolamine allows
the interconversion of Phosphatidylethanolamine with
ohosphatidylserine藉由絲胺酸到乙醇胺的乙醇轉換，使得磷
脂醯乙醇胺與磷脂醯絲胺酸之間的互換得以進行
磷酸乙醇胺
CTP:磷酸乙醇
胺胞核苷醯
轉移酶
磷脂酸
二醯甘
油激酶
磷脂酸磷酸酶
CDP-乙醇胺
二醯甘油
磷脂醯乙醇胺
Production of phosphatidylethanolamine in 54
Fig. 21-20, p.590
eukaryotes.
磷脂醯乙醇胺
絲胺酸
內質網
粒線體
乙醇胺
The interconversion of phosphatidylethanolamine
and phosphatidylserine in mammals
55
Fig. 21-21, p.591
Sphingolipids 神經鞘脂質
• Structre basis: sphingosine結構基礎是神經鞘胺醇
– A long chain amine長鏈胺類
– The precusors are palmitoyl-CoA and serine,
which react to produce dihydrosphingosine其前驅
物是棕櫚醯輔酶A與絲胺酸，二者反應產生二氫神經鞘胺醇
– Fig 21-22; form N-acylsphingosine also called
ceramide神經鞘胺醇的胺基與另一個醯基輔酶A作用形成一
個醯胺鍵，所形成的產物為N-醯基神經鞘胺醇
• The parent compound of
– Sphingomyelin神經鞘磷脂
» Phosphorylchloline to the primary alcohol group
– Cerebrosides 腦苷脂
» Sugars such as glucose at the same site
– Gangliosides 神經節糖啟
» Attachment of oligosaccharides that contain a silaic acid
» Tay-Sachs disease泰薩氏症– hexosaminidase A is missing
and the catabolism is bloked
泰薩氏症是一種先天性脂質代謝異常
所造成的不幸結果。在這個疾病中，
神經節苷脂的代謝會被抑制，是因負
責水解來自神經節苷脂GM2的N-乙醯
半乳胺糖的酵素己醣胺酵素A有缺失
所導致的。
棕欄醯-S-輔酶A
絲胺酸
神經鞘胺醇
二氫神經鞘胺醇
一種腦醯胺
58
Fig. 21-22a, p.592
Cholesterol Biosynthesis
膽固醇的合成
•The precusor of chloresterol and steroids is the
acetyl group of acetyl-CoA其碳原子的前驅物為乙醯輔酶A
的乙醯基團
–The condensation of three acetyl group produces
mevalonate (6-C)三個乙醯基團先縮合產生含六個碳的二羥甲基
戊酸鹽
–Decarboxylation of mevalonate produces isoprene
unit (5-C)去羧化產生在脂質結構中常見的五元碳異戊二烯單元
–Six isoprene units condense to form squalene (30-C)
六個異戊二烯單元會縮合形成含30個碳原子的鯊烯
–Squalene is converted to cholesterol (27-C)鯊烯會被轉
化成含27個碳原子的膽固醇
–Squalene can also be converted to other steroid鯊烯
也可以被轉化成其他固醇類
Acetate
C2
Mevalonate
C6
[Isoprene]
C5
squalene
C30
cholesterol
C27
異戊二烯
二羥甲基戊酸
乙醯輔酶A
鯊烯
Outline of the biosynthesis of
cholesterol
膽固醇
60
Fig. 21-23, p.593
Two molecule of Acetyl-CoA
•This step is inhibited by high
levels of cholesterol
•Major control point
•Lovastatin (drug) as inhibitor to
lower blood cholesterols
將三個乙醯輔酶A的乙醯基變化成二羥甲基
戊酸鹽的轉化過程需要經過幾個步驟
HMG-CoA or
3-hydroxy-3-methylglutaryl-CoA
由兩分子的乙醯輔酶A來產生醯基乙醯
輔酶A，第三個乙醯輔酶A會與醯基輔
酶A縮合形成β-羥基-β-甲基戊二醯輔酶
A(HMG-CoA)
羥甲基戊二醯輔酶A會轉化成二
羥甲基戊酸鹽，並且是受到羥甲
基戊二醯輔酶A還原酶(HMG-CoA
還原酶)的催化
The biosynthesis of mevalonate
Mevalonate
二羥甲基戊酸鹽
61
Fig. 21-26, p.631
Transition-state analogue
(過度狀態類似物)
Lovastatin的代謝物
Lovastatin: 羥甲基戊二醯輔酶A合成酶的抑制劑
62
Fig. 21-27, p.633
decarboxylation
phosphorylation
dephosphorylation
15-C
The conversion of mevalonate to squalene
63
Fig. 21-27a, p.595
NADPH+O2
Complex cyclization reaction
Cholesterol is synthesized from squalene via lanosterol
64
Fig. 21-28a, p.596
Complex cyclization reaction
Cholesterol is synthesized from squalene via lanosterol
65
Fig. 21-28b, p.596
Cholesterol is synthesized from squalene via lanosterol
66
Fig. 21-28c, p.596
Cholesterol Is a Precusor of Other Steroids膽固
醇是其他類固醇的前驅物
Cholesterol can be converted to other steroids of
widely varying physiological function膽固醇被製造
出來之後，它可以被轉化成其他具有多種生理功能的類固
醇
–Occur in smooth ER平滑內質網是合成膽固醇及轉化成其
他類固醇的地方
•Most of the cholesterol is formed in liver, is
converted to bile acids, such as cholate and
glycocholate肝臟是哺乳動物形成膽固醇的主要位置，大
部分在肝臟中製造的膽固醇會被轉化成膽酸(bile acids)如
膽酸鹽及肝膽酸鹽
–Aid in the digestion of lipid droplets可藉由乳化脂肪油
滴並使得較容易與酵素作用，而有助消化作用
膽酸鹽
由膽固醇合成膽酸的過程
The synthesis of bile acids from cholesterol
膽醯輔酶A
甘胺膽酸鹽
68
Fig. 21-29, p.597
• Steroid hormones膽固醇也是重要類固醇荷爾蒙的前驅物
– Pregnenolne孕烯酮醇is formed from cholesterol
– Progesterone黃體激素is formed from Pregnenolne
• Sex hormone
• Precusor of testosterone睪固酮and estradiol雌二醇
– Cortisone皮質酮is an example of glucocorticoids
• Hormones plays role in carbohydrate metabolism
– Mineralocortocoids 礦物性皮質素
• Involved in the metabolism of electrolytes,
including metal ions and water 與礦物質和水電解質的
代謝有關
• Aldosterone 酫固酮
孕烯酮醇
黃體激素
皮質酮(一種糖皮質素)
睪固酮(主要的
雄性激素)
雌二醇(主要的
雌激素)
The synthesis of steroid hormones
from cholesterol
70
醛固醇(一種礦物性
Fig. 21-30, p.598
皮質素)
The role of cholesterol in Heart Disease膽固醇
在心臟疾病中所扮演的角色
•動脈粥狀硬化是動脈被大大小小的膽固醇斑塊沉積而堵塞
所造成，會導致心臟病
– 飲食與遺傳均會影響動脈粥狀硬化的發生
•大部分的膽固醇來源是屬於內生性(體內合成)而非飲食
•有數種脂蛋白會參與血液中脂質的運送,依其密度而分類
– 乳糜微粒
– 極低密度脂蛋白、
– 中密度脂蛋白、
– 低密度脂蛋白
– 高密度脂蛋白
當它們的蛋白質含量增加時，密度就會增加
乳糜微粒(chylomicrons)
極低密度脂蛋白(VLDL)
中密度脂蛋白(IDL)
低密度脂蛋白(LDL)
高密度脂蛋白(HDL)
72
Table 21-3, p.599
73
Fig. 21-31, p.599
• LDL顆粒是在細胞內被分解的。經由高度調控的胞
飲作用，具有LDL顆粒及其受體的細胞膜部分會進
入細胞內。當LDL在溶小體內被分解之後，受體會
再回到細胞表面
• LDL的蛋白質部分會被水解成胺基酸，膽固醇酯則
會被水解成膽固醇與脂肪酸。游離膽固醇可以直
接被利用做為細胞膜組成。
• 不需要用於細胞膜合成的膽固醇，其羥基會與脂
肪酸酯化結合，而以油酸酯或棕櫚油酸酯的形式
儲存。這些酯類的產生是由醯基輔酶A：膽固醇醯
基轉移酶 (ACAT) 所催化進行的，而游離膽固醇的
存在可以增加ACAT的酵素活性。
75
Fig. 21-32, p.600