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matabolism of lipids(分解）, glycerol kinase, glycerl-3-phosphate…
matabolism of lipids(分解）
脂肪運輸
Transported
in the Blood as Chylomicrons乳糜微粒
Apolipoprotein : 載脂蛋白(C-II很重要)
Hormones Trigger Mobilization of Stored Triacylglycerols激素觸發儲存的三酸甘油脂
Lipases are activated by hormones glucagon and epinepherine.脂肪酶會被升糖素和腎上腺素活化
step1:激素附著在脂肪細胞膜上
step2:刺激腺苷酸環化酶，使G-protein製造c-AMP進一步活化 PKA，PKA 在此時有兩種用途
step3:PKA 使 HSL 磷酸化
step4:PKA使脂質滴表面的Perilipin磷酸化
step5:使 CGI-58 從 Perilipin 分離
step6:ATGL 使三酸甘油脂轉變成二酸甘油脂
step7:HSL 使二酸甘油質轉變成單酸甘油脂
step8:MGL 會讓最後一個單酸甘油脂「換頭」後成為三個一樣的脂肪酸
step9:進入血液(透過 serum albumin)中後可藉由酵素(Fatty acid transporter)進入 ß oxidation, 檸檬酸循環以及呼吸鏈
脂肪分解
Glycerol from Fats Enters Glycolysis脂肪（甘油）進入醣解作用
:warning:
Allows limited anaerobic catabolism of fats
Glycerol kinase activates glycerol at the expense ofATP
甘油激酶(Glycerolkinase)消耗ATP活化甘油
Subsequent reactions recover more than enough ATP to cover this cost.
steps
Glycerol Is Oxidized to the Glycolytic Intermediate Dihydroxyacetonephosphate
Glycerol Is Activated by Phosphorylation磷酸化
DHAP Continues Through Glycolysis
Transport or Attachment to Phospholipids Requires Conversion to Fatty Acyl-CoA
磷脂的運輸或附著需要轉化為 Fatty Acyl-CoA
steps
脂肪酸必須先和ATP 反應，轉變為活化的中間產物
才能與其他酵素做更近一步的代謝，這是脂肪酸整個分解過程中唯一需要ATP提供能量的步驟
ATP脫去兩個PPi後會和脂肪酸結合fatty acyl adenylate
coA在fatty acyl-coA synthetase(硫激酶＝thiokinase，存在粒線體膜上）的催化下，coA上有SH基（很強的未共用電子對）把AMP取代釋放出去，形成中產物 fatty acyl-coA
Fatty Acid Transport into Mitochondria
脂肪酸的運輸
Fatty acids are transported to other tissues for fuel through the blood.脂肪酸藉由血液運輸（白蛋白）
:star:β oxidation of fatty acids occurs in mitochondria.
ß oxidation 發生在粒線體中
stage1:consists of oxidative conversion of two-carbon units into acyl coA via oxidation with concomitant generation of NADH and FADH2
每次藉由β-oxidation 分解 2個碳產生acyl-coA和 NADH及 FADH2
stage2:involves oxidation of acetyl-CoA into CO2 via citric acid cycle with concomitant generation NADH and FADH2.
藉由檸檬酸循環將acetyl-CoA轉換成二氧化碳 且伴隨產生NADH和FADH2
stage 3:generates ATP from NADH and FADH2 via the respiratory chain經過呼吸鏈 ， 從 NADH和FADH2中產生ATP
Small (< 12 carbons) fatty acids
diffuse freely across mitochondrial membranes.
Larger fatty acids (most free fatty acids)大多數是游離脂肪酸
steps
fatty acyl-coA 透過carnitine acyltransferase I 催化，和粒線體 外膜上的 carnitine 結合 形成 fatty acyl-carnitine 進入膜間腔。 (fatty acyl-CoA 也可以直接通過粒線體外膜， 再轉換成 fatty acyl-carnitine，因為外膜不具有選擇性)
fatty acyl-carnitine 進入膜間腔，利用 fatty acyl-carnitine/ carnitine transporter 可以再進 入粒線體基質 (matrix) 中
粒線體內膜上的 carnitine acyltransferase II 會再將 fatty acyl- carnitine 轉回 fatty acylCoA，轉回來的 carnitine 會再送回 膜間腔
transported via acyl-carnitine/carnitine酰基肉鹼/肉鹼轉運蛋白) transporter.
不飽和脂肪酸的氧化(可與右側對比）Oxidation of Unsaturated Fatty Acids
自然存在的不飽和脂肪酸有順式雙鍵:
不是 enoyl-CoA hydratase 的反應物
Naturally occurring unsaturated fatty acids containcis double bonds.(對比beta氧化第二步驟
Two additional enzymes are required.
異構酶:將碳 3 上的雙鍵變成反式。isomerase: converts cis double bonds starting at carbon 3 to trans double bonds
Monounsaturated fatty acids require
還原酶:還原不在碳 3 處的雙鍵。
reductase: reduces cis double bonds not at carbon 3
Polyunsaturated fatty acids require both enzymes.
steps
先進行 β-oxidation 直到遇到雙鍵
利用異構酶將順式雙鍵轉換成為反式雙鍵
再繼續進行 β-oxidation
因為少了「烷烴脫氫製造烯烴」
的步驟所以少製造一個 FADH2
利用”還原酶“跟 NADPH(能量來源)去補平一個雙鍵。
再利用異構酶將雙鍵轉換到 C2 跟C3 之間。
繼續進行 β-oxidation。
glycerol kinase
glycerol
L-glycerol3-phosphate
ATP
ADP
glycerl-3-phosphate dehydrogenase
L-glycerol3-phosphate
Dihydroxyacetone phosphate
NAD+
NADH + H+
β氧化步驟
Dehydrogenation of Alkane to Alkene烷烴“脫氫”製造烯烴
Catalyzed by isoforms of acyl-CoA dehydrogenase (AD乙醯輔酶Ａ) on the inner-mitochondrial membrane粒線體內膜
Results in trans double bond, different from naturally occurring unsaturated fatty acids產生反式雙鍵
FADH2 氧化成 FAD 出來的電子經由電子傳遞黃素蛋白 ETF 進入電子傳遞鏈。
Dehydrogenation of Alcohol
羥基“脫氫”
（NAD+接變NADH＋Ｈ＋出去）
Catalyzed by β-hydroxyacyl-CoA dehydrogenase利用 β-hydroxyacyl-CoA dehydrogenase 催化。
The enzyme uses NAD cofactor as the hydride acceptor
NAD 為 H 的受體形成 NADH，透過 NADH dehydrogenase 再將電子傳入電子傳遞鏈。
只有L-form的L-isomers of hydroxyacyl CoA act as substrates
Hydration of Alkene
烯烴“水合”
:star:Catalyzed by two isoforms of “enoyl-CoA hydratase:”
利用 enoyl-CoA hydratase 的兩個同功型(isoforms)催化
soluble short-chain hydratase (crotonase)可溶性短鏈水合酶(巴豆酸酶 crotonase)
membrane-bound long-chain hydratase, part of trifunctional complex與膜結合的長鏈水合酶，三功能複合物的一部分
Water adds across the double bond yielding alcohol on β carbon其中 OH 插在 β 碳上，H 插在 α 碳上，將雙鍵變回單鍵。
Transfer of Fatty Acid Chain and Release of Acetyl-CoA
轉移脂肪酸鏈和釋放乙醯輔酶 A
Catalyzed by acyl-CoA acetyltransferase (thiolase) via covalent mechanism
利用 acyl-CoA acetyltransferase (thiolase 硫解酶)通過共價機制催化。
Active-site thiolate acts as a nucleophile and releases acetyl-CoA.
活性位上的硫醇鹽(thiolate)當作親核試劑並釋放出乙醯輔酶 A。
The carbonyl carbon in β-ketoacyl-CoA is electrophilic.
β-ketoacyl-CoA 中的羰基的 C 是親電的
Terminal sulfur in CoA-SH acts as a nucleophile and picks up the fatty acid chain from the enzyme.
CoA-SH 的 S 當作親核試劑與脂肪酸結合
Oxidation of Odd-Numbered Fatty Acids奇數碳脂肪酸的氧化
大多食用攝取的脂肪酸是偶數Most dietary fatty acids are even-numbered.
奇數碳脂肪酸的 β-oxidation 會形成一個丙醯輔酶 A(Propionyl-CoA)
Propionyl-CoA (3-carbon compound) forms during
final cycle of oxidation of odd-numbered fatty acids.
steps
用 propionyl-CoA carboxylase 催化，
跟 biotin、HCO3-跟 ATP 反應，在中間的碳上加入 COO-。
用 methylmalonyl-CoA epimerase 製造 L-methylmalonyl- CoA。(D 變成 L)
用 methylmalonyl-CoA mutase 跟維生素 B12 製造出 succinyl- CoA。
Ketone Bodies酮體
Formation of Ketone Bodies: Degradation of HMG-CoA
In order to traffic to other tissues, CoA must be removed. Acetone, acetoacetate, and β-hydroxybutyrate can then travel through the blood.
Acetone is removed as a gas
acetoacetate and β-hydroxybutyrate
can traffic to the brain for use in energy production 心臟、腎臟 ，腦或是骨骼肌的能量來源（間單說就是到了製造能量的地方就會被變回乙醯輔酶Ａ
當乙醯輔酶 A進入檸檬酸循環所需的 OAA 被用盡時，乙醯輔酶A就會被轉變為酮體 Entry of acetyl-CoA into citric acid cycle requires oxaloacetate.
When oxaloacetate is depleted acetyl-coA is converted into ketone bodies
(frees coenzyme A for continued oxidation)
三大酮體
acetone丙酮(唯一的氣體，臭味來源)
Acetoacetate乙醯乙酸酯
β- hydroxybutyrate.β-羥基丁酸
酮體的形成可以使輔酶 A 被釋放出來以繼續進行 β oxidation
Formation of Ketone Bodies: Generating Free CoA
steps
酮體的形成第一步是 β oxidation 最後一步反過來: 硫解酶(thiolase)把兩個乙醯輔酶 A 合成，放出一個CoA，形成乙醯乙醯輔酶 A (Acetoacetyl-CoA)
The first step is reverse of the last step in the oxidation: thiolase reaction joins two acetate units.
羥甲基戊二酸單醯輔酶 A 合成酶(HMG-CoA synthase)會將一個乙醯輔酶 A 和乙醯乙醯輔酶A 合成為羥甲基戊二酸單醯輔酶 A (HMG-CoA)，過程中一樣釋放出一個coA。
A third acetyl-CoA is incorporated in the second step
形成HMG-coA的過程中會有兩個從三個乙醯輔酶中釋放出來在肝臟進行
Together, two CoA are freed from three acetyl- CoA.
triose phosphate isomerase
Dihydroxyacetone phosphate
D-Glyceraldehyde3-phosphate
FADH2
每次反應都產生一個乙醯輔酶A並使鏈縮短兩個C，
產生出來的乙醯輔酶 A 會進入 CAC 繼續反應。
Each Round Produces an Acetyl-CoA and Shortens the Chain by Two Carbons
最後一次出來兩個acetyl coA，十六碳的脂肪酸只要切七刀
NADP+
NADH + H+
此反應製造的 ATP 足以應付過程所需消耗的能量
:star:
:star:
fatty acids游離脂肪酸的分解，運送，黏附都需要接上coA
fatty acyl-coA
:star:Fats are degraded into fatty acids and glycerol in the cytoplasm of adipocytes
脂肪會在脂肪細胞的細胞質降解為脂肪酸和甘油
:star:Acyl-Carnitine/Carnitine Transport
一次檸檬酸循環可以產三個NADH和一個FADH2所以八個脂肪酸產生24/8
類似與比較：Analogous to succinate dehydrogenase reaction in the citric acid cycle
跟 CAC 中的 succinate 利用 succinate dehydrogenase產生 fumarate 類似
類似與比較： Analogous to fumarase reaction in the citric acid cycle
跟 CAC 的 Fumarate 水合反應產生 malate 類似:相同的立體特異性(stereospecificity)。
類似與比較：Analogous to malate dehydrogenase reaction in the citric acid cycle跟 CAC 的 malate 脫氫產生 oxaloacetate 類似。
在（催化劑）時把acetyl-CoA加進來，產物把兩碳與剛加入的acetyl-coA放出去
總反應是碳-碳鍵的硫解 The net reaction is thiolysis of the carbon-carbon bond.
alpha betaC之間變成雙鍵
打掉雙鍵，OH接上beta碳
alpha與beta切一刀
+
alpha
beta
因為催化素又加上來ace-coA
切掉coA
前三步驟跟「只有一個雙鍵的脂肪酸的反應途徑」一樣。
為了保持能量的完整 所以要補回來，再做一輪上述步驟停在第一產物
beta oxidation*3 脫掉3acetyl -coA
enoyl-coA isomerase
beta oxidation脫掉acetyl coA (二三碳雙鍵切斷後，3 to 1 / 4 to 2 / 5 to 3 再跑一次氧化後停在第一產物
＝
aceyl-coA dehydrogenase 脫氫
enoyl-coA hydratase 水合
beta- hydroxyacyl-coA dehydrogenase脫氫NAD+接
(thiolase)coA-SH接上來
beta 氧化比較
2.4-dienoyl-coA reductase還原酶(2.4加氫，變成3與4可形成雙鍵）有NADPH ＋ H+參與
enoyl -coA isomerase
5 acetyl-coA
beta oxidation
生成
Succinyl-CoA 可進入 CAC 反應。
:star:
Isomerization to Succinyl-CoA＝＝>CAC
:star:
酮體的形成在肝臟中進行
:star:
要在血液中移動，需要去除 HMG-CoA 中的 CoA
