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Biochemistry W10 Metabolism of Lipids I, Similar Mechanisms Introduce…

- - - - monoacylglycerol lipase (MGL)能夠將monoacylglycerol分解成一個脂肪酸鏈和甘油。
      - Hormone-sensitive lipase(HSL)因PKA的活化(PKA由cAMP活化)，而被磷酸化，進而將diacylglycerol分解成 two monoacylglycerol。
      - adipose triacylglycerol lipase (ATGL)需要CGI-58的活化才能將triacylglycerols 分解成diacylglycerol and monoacylglycerol。
        
        而CGI-58被perilipin固定在膜上，一旦perilipin被磷酸化(靠PKA的活化來影響)才能夠被釋放
      - Fatty acids經由serum albumin 白蛋白在血液中運送，並藉由fatty acid transporter運送至需要的細胞來進行氧化。
  - - - Glycerol kinase activates glycerol at the expense of ATP.And glycerol is activated by phosphorylation.
        
        L-glycerol 3-phosphate be oxidized by glycerol 3-phosphate dehydrogenase, then become dihydroxyacetone phosphate.
        (丟出來的H+由NDH+來接形成NADH)
        
        dihydroxyacetone phosphate(酮)become G-3-P(醛)
        by triode phosphate isomerase.
  - - - Intestinal lipase小腸酶degrade fats to fatty acid and other break-down products
        
        到達mucosa黏膜被吸收時，又重新組回去變成triacylglycerols.
        
        Triacylglycerols在mucosa裡 incorporated with cholesterol and apolipoprotein, 變成chylomicrons乳糜微粒
        (外有phospholipids, apolipoproteins and cholesterol
        內有triacylglycerols and cholesterol esters)
        
        乳糜微粒到達capillary後，capillary內的apoC-II脂蛋白原活化了lipoprotein lipase, 使triacylglycerols 分解成fatty acids and glycerol.
        
        Fatty acids are oxidized as fuel or reesterified for storage.
- - - - Become adult- adenylate,then fatty Acely- CoA synthetase make it synthesis fatty acryl-CoA.(釋出AMP)
    - - 因為CoA-SH太大，故先藉由carnitine acyltransferase1將S-CoA換成carnitine(過程在外膜)
        
        透過內膜上的transporter 進到Matrix，carnitine acyltransferase 2再將fatty acids上的carnitine換成CoA-SH
    - - Three Stages in Fatty Acid Oxidation Occurs in the Mitochondria
        
        Stage 2: 8 Acetyl CoA involves oxidation of acetyl-CoA into CO2 via citric acid cycle with concomitant generation NADH and FADH2.
        
        Stage 3: ETC generates ATP from NADH and FADH2 via the respiratory chain.
        
        Total ATP 見圖->
        
        Stages 1: β-Oxidation consists of oxidative conversion of two-carbon units into acetyl-CoA via β oxidation with concomitant generation of NADH and FADH2.
        
        Unsaturated fatty acid
        (contain cis double bonds which are NOT a substrate for enoyl-CoA hydratase)
        
        Monounsaturated
        
        Need isomerase(converts cis double bonds starting at carbon 3 to trans double bonds)
        
        形成saturated fatty acids 的β oxidation 的第一步驟完，故沒有FADH2的生成
        
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        Polyunsaturated 看圖‼️
        
        1. 把可以oxidation 的部分都完成後，遇到第一個不飽和鍵，使用Isomerase置換雙鍵位置，則可以再釋放出一個acetyl-CoA。
        
        2. 釋放完一個acetyl-CoA後再进行β oxidation 第一步驟。而後為了讓2個雙鍵變成一個雙鍵，由retuctase催化，從NADH+H+上把兩個氫分別加在C2,C5上，最後形成只剩C3,C4間有雙鍵。
        
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        (Results in 1 fewer FADH2 after isomerization, but 1 FADH2 is produced during the first step of the next cycle.)
        
        Odd-number fatty acid 看圖‼️
        
        Propionyl-CoA (3C compound) forms during final cycle of Propionyl-CoA (3-carbon compound) forms during final cycle of β oxidation of odd-numbered fatty acids.
        
        Carboxylation of Propionyl-CoA,biotin把HCO3-帶來，並藉由prpionyl -CoA carboxylase接上去
        
        D-Methylmalonyl-CoA變成L-Methylmalonyl-CoA by methylmalonyl-CoA epimerase
        
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        Saturated and even-number fatty acid看圖‼️
        
        Step 1:Dehydrogenation of Alkane to Alkene by acyl-CoA dehydrogenase (AD) on the inner-mitochondrial membrane(由FAD來接氫). Results in trans double bond, different from naturally occurring unsaturated fatty acids.
        
        Step2 : Hydration of Alkene by two isoforms of enoyl-CoA hydratase
        
        Step 3: Dehydrogenation of Alcohol by β-hydroxyacyl-CoA dehydrogenase(由NAD+接氫),
        
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        membrane-bound long-chain hydratase, part of trifunctional complex associated with inner-mitochondrial membrane.
        用在比較長鏈的碳上(12碳以上)
        
        soluble short-chain hydratase (crotonase) in the matrix 用在比較短鏈上(12碳以下)
        
        FAD & FMN
        
        注意接氫的方式
        
        總結：為了脫掉2c(C-O雙鍵和α碳)形成acetyl-CoA, β碳必須變成C-O雙鍵以繼續下次的脫碳。
        首先的脫氫是為了下步驟的β碳能接上OH(水和反應),使之有O。再來的脫氫是為了讓β碳變成雙鍵。最後則透過enzyme 將2c脫掉。
- - - - 主要的酮體有三種：國考必考‼️
        
        Acetoacetate
        
        D-β-hydroxybutyrate
        
        Acetone 丙酮
  - - - 2. Acetoacetyl-CoA再加入一個Acetyl-CoA和H2O(HMG-CoA催化)並釋放1個CoA-SH,形成HMG-CoA（6C)
        
        3. Degradation of HMG-CoA: 藉由HMG-CoA lyase 將HMG-CoA脫掉一個Acetyl-CoA形成Acetoacetate(4C) .This step is in order to remove CoA.
        
        透過acetoacetate decarboxylase將Acetoacetate脫掉一個CO2形成Acetone(3C).(不可逆反應)
        
        從HAND+H+拿2個氫接上Acetoacetate(打掉雙鍵)，形成D-β-hydroxybutyrate.(可逆反應)
        
        How ketone body be fuel? (生酮形成的逆反應)
        For example:
        
        先脫氫形成Acetoactate。
        
        succinylcholine-CoA給予CoA-SH給Acetoactate形成Acetoactyl-CoA。
        
        再給一個CoA-SH，最後切斷形成兩個Acetyl- CoA
        
        Acetoacetic acid and D-β-hydroxybutyric acid are exported as energy sources for the heart, skeletal muscle, kidneys and brain
- - - - How NADPH be produced
        
        in adipocytes
        
        PPP(G-6-P -> R-6-P)
        
        malic enzyme (maleate->pyruvate)
        
        in hepatocytes and mammary gland
        
        only PPP
  - - - 2. Malonyl CoA and acetyl CoA (or longer fatty acyl chain) are bound to FAS I and lose CoA.
        
        3. FASinvolves cycles of four enzyme-catalyzed steps:
        -condensation
        -reduction
        -dehydration
        -reduction
        
        Step 1:Condension
        —β-ketoacyl-ACP synthase(KS)使malonyl group 上的COO-釋出(釋出CO2)
        —MAT(malonyl/aceyl-CoA transferase)把acetyl group transfer to ACP(means malonyl group 的尾)
        
        Step 2: reduction
        β-ketoacyl-ACP reductase (KR) catalyzes NADPH+ H+加進acetoacetyl-ACP,使之還原(acetyl group 上C-O雙鍵被打掉)
        
        Step 3:Hydration
        β-hydroxyacyl-ACP dehydratase (DH) catalyzes OH group(from C3) and H(from C2),脫H2O,C2和C3間形成雙鍵。
        
        Step 4:Second reduction
        enoyl-ACP reductase (ER) catalyzes NADPH+H+加進C2和C3間，
        打掉C2和C3間的雙鍵。
        
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        Form trans-🔺2-butenoyl-ACP
        
        Form d-β-hydroxybutyryl-ACP
        
        Form acetoacetyl-ACP and CO2
        
        Two thiols must be charged with the correct acyl groups before the condensation reaction can begin.
        
        ・malonyl-CoA bound to thiol which from 4-phosphopantethine in ACP
        ・acetyl-CoA bound to thiol which from Cys in FAS (KS位)
        
        FAS 1
        (in vertebrates and fungi)
        
        Single polypeptide chain in vertebrates
        
        Leads to single product: palmitate 16:0
        
        C-15 and C-16 are from the acetyl-CoA used to prime the Rx
      - Reaction carboxylates acetyl-CoA, Catalyzed by acetyl-CoA carboxylase.
        (acetyl-CoA+CO2=malonyl-CoA)
        
        Reaction—Part 1:
        Biotin 透過Lys side chain和Biotin carrier protein(enzyme)結合。HCO3-(CO2)藉由enzyme的Biotin carboxylase結合上biotin(耗ATP)。
        
        Reaction—Part 2:
        Enzyme undergoes conformational change to carry carbamoyl to transcarboxylase site, and CO2 attaches to acetyl-CoA and leaves active site.
        (Form Malonyl-CoA)
- - - - Deliver to the fatty acid synthase