生物化学_Fatty Acid Catabolism

Fatty Acid Catabolism

基础
- 图
mobilize动员 fatty acid from food and adipose tissue
- Hormones Trigger the Release of Fatty Acids from Adipose Tissue
  从脂肪组织动员
  - 总结就是一串激活, 然后3/2/1的lipase把fatty acid 拆下来扔到血里
  - hormone → receptors → adenylyl cyclase → cAMP → protein kinase A → triacylglycerol lipase
  - Fatty acids are released from adipocytes
  - hormone messengers
    - adrenaline/epinephrine 肾上腺素
    - glucagon 胰高血糖素
    - adrenocorticotropic hormone(ACTH)促肾上腺皮质激素
  - These signal molecules bind to receptors on membrane of adipose cells and lead to the activation of adenylyl cyclase 腺苷酸环化酶, which forms cAMP from ATP.
  - cAMP activates protein kinase A, which phosphorylates and activates a triacylglycerol lipase that hydrolyzes a fatty acid from C-1 or C-3 of triacylglycerols.
  - Subsequent actions of diacylglycerol lipase and monoacylglycerol lipase yield fatty acids and glycerol.
  - The cell then releases the fatty acids into the blood, where they are bound to serum albumin血清白蛋白
  - Serum albumin transports free fatty acids to sites of utilization.
  - 图
- Degradation of Dietary Triacylglycerols Occurs Primarily in the Duodenum
  从小肠吸收
  - 拆开
    - The pancreatic duct胰管 secretes digestive fluids into the duodenum
    - Hydrolysis of triacylglycerols by pancreatic and intestinal lipases.
    - Pancreatic lipases cleave fatty acids at the C-1 and C-3 positions
    - Intestinal lipases cleave fatty acids at C-2 in monoacyl glycerols
    - 图
  - 吸收后组装
    - Fatty acids and monoacylglycerols are absorbed through the intestinal wall and assembled into lipoprotein termed chylomicrons乳糜微粒
oxidize fatty acid
- 偶数碳,饱和 β-oxidation
  最主要,最常见
  - 总览
    - 整体上是通过β-oxidation重复切下来acetyl-CoA
  - Coenzyme A Activates Fatty Acids for Degradation
    准备
    - cozenzyme A
    - β-oxidation之前需要COO-的尾巴变成CO-SCoA
    - formation of a thiol ester bond硫醇酯键 between the fatty acid and the thiol group of coenzyme A
    - 酶 - acyl-CoA synthetase, also called acyl-CoA ligase or fatty acid thiokinase
    - Net of two ATP equivalents are consumed to activate one fatty acid to thioester
    - 位置
      - For long-chain fatty acids,this reaction normally occurs at the outer mitochondrial membrane in higher eukaryotes before entry of the fatty acid into the mitochondrion, may also occur at the surface of the endoplasmic reticulum.
      - Short/medium-length fatty acids undergo this activating reaction in the mitochondria.
  - Carnitine肉毒碱 Carries Long Fatty Acyl groups Across the Inner Mitochondrial Membrane
    运输到线粒体基质
    - Short-chain fatty acids
      - transported into the matrix as free acids and form the acyl-CoA derivatives there
    - Long-chain fatty acyl-CoA derivatives
      - cannot be transported into the matrix directly, which must first be converted to acylcarnitine derivatives
      - The formation of acylcarnitines and their transport across the inner mitochondrial membrane.
      - 酶 - carnitine acyltransferases on both the inner and outer mitochondrial membranes
      - 酶 - translocase that shuttles O-acylcarnitines酰基肉碱 across the inner membrane.
  - β-Oxidation Involves a Repeated Sequence of Four Reactions
    循环氧化
    - 单次β-Oxidation
      - 图
      - 前三步的策略是氧化双键,上OH,然后变成C=O,与TCA里succinate to oxaloacetate 一样
      - 每一轮循环+FADH +NADH +Acetyl-CoA -H2O -2 carbon of fatty acid
      - 酶
        
        step1 - Acyl-CoA Dehydrogenases (CAD)
        
        very long-chain CAD (VLCAD)
        membrane-bound homodimer of 67-kD subunits
        
        long-chain CAD (LCAD)
        soluble homotetramers of 40- to 45-kD subunits
        
        medium-chain CAD (MCAD)
        soluble homotetramers of 40- to 45-kD subunits
        
        short-chain CAD (SCAD)
        soluble homotetramers of 40- to 45-kD subunits
        
        step2 - Enoyl-CoA hydratase (ECH)
        
        step3 - L-Hydroxyacyl-CoA dehydrogenase (HAD)
        
        step4 - Ketoacyl-CoA thiolase 硫解酶 (KT)
        
        酶的选择
        
        VLCAD与ECH,HAD,KT的complex是在膜上的, 同时有游离的CAD,ECH,HAD,KT
    - 产物去向
      - Equations for the Complete Oxidation of Palmitoyl-CoA to CO2 and H2O
      - FADH2
        
        进入电子传递链, 产生1.5ATP
      - Acety-CoA
        
        further metabolized in the TCA cycle
        
        used as a substrate in lipid or amino acid biosynthesis
        
        ketone bodies
        
        Acety-CoA → acetone, acetoacetate, and beta-hydroxybutyrate
        
        这三个合称ketone bodies
        
        The process is known as ketogenesis生酮作用, most happens in liver mitochondria matrix
        
        ketone bodies are important sources of fuel and energy for many tissues, including brain, heart, and skeletal muscle
        
        Ketone bodies are easily transportable
        在循环系统中移动时候比脂肪方便,不需要其他东西帮助
        
        Reconversion of ketone bodies to acetyl-CoA in the mitochondria of many tissues (other than liver)
        
        在其他组织中转回Acetyl-CoA释放能量
      - H2O
        
        Acetyl-CoA可以产出大量水
        
        鲸鱼和骆驼都分解脂肪来补充水
      - 理论ATP产出
        
        Complete oxidation of palmitoyl-CoA yields a total of 108 ATP, 减去刚开始激活的2 ATP, 净产出106 ATP
- 奇数碳,饱和 β-oxidation
  - Fatty acids with odd numbers of carbonatoms are rare in mammals but common in plants and marine organisms.
  - Humans and animals metabolize odd-carbon fatty acids via the marine海洋 β-oxidation pathway.
  - The final product of beta-oxidation in this case is the three-carbon propionyl-CoA instead of acetyl-CoA.
  - propionyl-CoA后续
    - succinyl-CoA
      - Three specialized enzymes then carry out the reactionsthat convert propionyl-CoA to succinyl-CoA, a TCA cycle intermediate
      - succinyl-CoA 可以在TCA里跑, 但是这样不算完全氧化
      - succinyl-CoA 完全氧化
        
        Net Oxidation of Succinyl-CoA Requires Conversion to Acetyl-CoA
        
        Succinyl-CoA → malate → pyruvate → 乙酰CoA → 进入TCA完全氧化成CO2
    - amino acid catabolism
      - Because propionyl-CoA is a degradation product of methionine, valine, and isoleucine, this sequence of reactions is also important in amino acid catabolism.
- 不饱和 β-oxidation
  - 以oleoyl-CoA(右侧)举例
  - three beta-oxidation cycles produce threemolecules of acetyl-CoA and leave cis-D3-dodecenoyl十二烯酰基-CoA
    先来三个正常β循环, 然后碰到了双键
  - Rearrangement of enoyl-CoA isomerase gives the trans-D2 species, which then proceeds normally through thebeta-oxidation pathway
    enoyl-CoA isomerase 异构酶把cis变成trans, 然后从β-oxidation第二步接上正常流程
- Peroxisomal β-oxidation
  - Peroxisomal β-Oxidation Requires FAD-Dependent Acyl-CoA Oxidase
  - Plant beta-Oxidation does not occur significantly in mitochondria, most beta-oxidation occurs in peroxisomes过氧化物酶
  - While, in animal, although beta-oxidation in mitochondria is the principal pathway of fatty acid catabolism, several other minor pathways play important roles in fat catabolism, for example, peroxisomes and glyoxysomes乙醛酸循环体,carry out beta-oxidation processes
  - Electrons captured as FADH2 are used to produce the hydrogen peroxide过氧化氢 required for degradative processes in peroxisomes and thus are not available for eventual generation of ATP
    - 与此同时线粒体中的FADH2可以进入电子传递链产生ATP
- 有支链 α-oxidation
  - 图
  - In phytanic acid, the methyl group at C-3 will block beta-oxidation.
  - Branched-chain fatty acids are oxidized by alpha-oxidation, as shown for phytanic acid.
  - The product of the phytanic acid oxidase,pristanic acid, is a suitable substrate for normal beta-oxidation.
  - Isobutyryl-CoA 异丁酰辅酶A and propionyl-CoA can both be converted to succinyl-CoA, which can enter the TCA cycle.
- 加速 ω-oxidation
  - 氧化另一边, 让脂肪酸可以从两头进行β-oxidation
  - omega-Oxidation of Fatty Acids Yields Small Amounts of Dicarboxylic Acids
  - In the endoplasmic reticulum of eukaryotic cells, the oxidation of the terminal carbon of a normal fatty acid
  - Dicarboxylic acids can be formed by oxidation of the omega carbon of fatty acids in a cytochrome P-450–dependent reaction—a mono oxygenase enzyme that requires NADPH as a coenzyme and uses O2 as a substrate
  - Either end can forman ester linkage to CoA and be subjected to β-oxidation, producing a variety of smaller dicarboxylic acids.