3.1: Glycolysis
3.1.1:糖酵解的十个步骤
- 前五步消耗2个ATP。后五步生成4个ATP。
3.1.2
Recall that ATP has a free energy of hydrolysis that is intermediate between the free energies of hydrolysis of other phosphate-carrying molecules in cells, and describe why.
Explain the concept of coupling and how coupling is constrained in cells.
Describe the difference between anaerobic厌氧 and aerobic好氧 pathways of glucose catabolism葡萄糖分解代谢.
Recall the steps of lactate and ethanol fermentation发酵.
3.2: Unique features of glycolysis in red blood cells
3.2.1
Explain why red blood cells rely on glycolysis for the production of ATP.
Describe the specialized functions of glycolysis products and intermediates in red blood cells.
Identify branch points in glycolysis that contribute to red blood cell function.
3.2.2
Describe the relationship between hemoglobin oxygenation氧合血红蛋白 and its conformational state构象状态.
Explain how cooperativity impacts hemoglobin's 血红蛋白affinity for oxygen.
Identify the effect of pH and 2,3 bisphosophoglycerate on hemoglobin's affinity for oxygen.
Relate physiological states to the regulation of hemoglobin affinity血红蛋白亲和力.
3.3: Bacterial energetics细菌的能量
3.3.1 E. coli 在低氧条件下的酵解通路
3.3.2
Differentiate between aerobic respiration, fermentation酵解, and anaerobic respiration无氧呼吸.
Recall different possible final electron acceptors used by anaerobes, and their relative energetic potential.
Discuss the importance of denitrifying bacteria.
Explain the steps of denitrification脱氮反应, and how they contribute to ATP production.
3.3.3 综述了人体内的细菌
3.4: The citric acid cycle 三羧酸循环
3.4.1 the major energetic pathways in aerobic organisms，产生ATP
上面粉色的是Electron donating过程，对应的是将营养物质自己消化，下面绿色的是Electron accepting过程，对应的是获得电子为自己所用，供能的过程。
其中的Glycolysis 发生于cytoplasm。而oxidative decarboxylation of pyruvate 和 citric acid cycle 发生于mitochondria线粒体
3.4.2 Pyruvate转换为Acetyl-CoA
- Pyruvate在Pyruvate Dehydrogenase Complex酶（丙酮酸脱氢酶复合体 ，PDH）作用下转换为Acetyl-CoA的过程，这一过程是在Mitochondria中实现的，是oxidative decarboxylation反应
在PDH作用下，oxidative decarboxylation共分为四步进行：1) Decarboxylation
- Oxidation 3) Transfer 4) Regeneration
指的是重新生成Lipoamide以用于第二步Oxidation
在高产物、高能量状态、Acetyl CoA、NADH存在状态下会抑制PDH，而在高reactants、低能量状态、Pyruvate、NAD+、ADP状态下会激活PDH。
其具体的反应机理如下图所示：
PDK通过在PDH的辅酶E1上加入磷酸基团使其失活，而PDP可以使得失活的PDH重新激活。
3.4.3 Citric Acid Cycle
- Enzymes of the Citric Acid Cycle
- Pyruvate Dehydrogenase
- Citrate synthase
- Aconitase
- Aconitase
- Isocitrate dehydrogenase
- Oxalosuccinate dehydrogenase
- α-‐ketoglutarate dehydrogenase
- Succinyl Co-‐A synthetase
- Succinic dehydrogenase
- Fumarase
- Malate dehydrogenase
The first role of the cycle is to produce reduced electron donors, NADH and FADH2. The reduced electron donors are used for the production of ATP via oxidative phosphorylation.
The second role of the citric acid cycle is to produce precursors for the biosynthesis of fatty acids and amino acids.
- The anaplerotic reactions regenerate citric acid cycle intermediates that are depleted by other metabolic pathways.
3.4.4 Glyoxylate cycle乙醛酸循环
如图1所示，在动物中，Acetyl-CoA是不能转换为Glucose的，因为Acetyl-CoA是不能转换为Pyruvate的，但Archea古细菌、Bacteria细菌、Protists原生生物、Plants植物、Fungi真菌可以通过Glyoxylate cycle将Acetyl-CoA转换为Glucose。其通路在图10 的基础之上又增加了一部分，如图11所示：
而在真核植物细胞和原核细菌中，Glyoxylate cycle又有所区别，先说真核植物细胞。
Succinate由Glyoxysome经过Cytosol细胞液进入线粒体中。植物细胞通常经过光合作用生成葡萄糖，但是当光合作用削弱的时候，便通过Glyoxylate cycle生成葡萄糖，比如发芽的种子中。
细菌中的Glyoxylate cycle又与植物不同，因为其没有细胞器，所以尽可能最大化利用其细胞通路。
3.4.5 人体巨噬细胞的免疫反应
- 巨噬细胞是人体的第一道防线，它的作用一是胞吞，二是释放cytokines以生成Inflammation
- 巨噬细胞在LPS诱导炎症反应的时候Irg1的表达会增强，那么Irg1发挥了什么作用呢？
- 这是因为Irg1的高表达会产生Itaconic acid，Itaconic acid会抑制细菌中的Isocitrate lyase (ICL)，如图11所示，从而抑制细菌中的Glyoxylate cycle，从而起到杀菌的作用。所以潜在的抗菌药物可以是ICL和MS抑制剂。
3.5 Electron transport 电子转移
3.5.1
Recall the subcellular localization of oxidative phosphorylation.
Explain how the chemiosmotic theory links the exergonic transfer of electrons to ATP synthesis.
Identify the major universal electron acceptors and donors used by cells.
3.5.2
Relate reduction potential还原电势 to the spontaneity of redox reactions氧化还原反应 and ΔG.
Recall the structure and function of the major electron carriers in the ETC (such as ubiquinone and the cytochromes).
Understand how to dissect the order of events in the electron transport chain using both theory and experiments.
3.5.3
Recall the key components and overall organization of the electron transport chain.
Explain how two electrons are transferred from ubiquinol (QH2) to two molecules of cytochrome c.
Recall the net reaction of electron transport.
3.5.4 Review the Q cycle
3.6: ATP synthesis
3.6.1
Relate the energetics of the electron transport chain with the energetics of the electrochemical gradient that powers ATP synthesis.
Explain the concept of coupling between the electrochemical gradient and electron transport.
Recall experiments that support coupling between the proton motive force and ATP synthesis.
3.6.2 ATP synthase合成酶
3.6.3 ATP synthase的机制以及怎样利用proton motive force
Explain how ATP synthase catalyzes the highly endergonic synthesis of ATP.
Relate the conformations of the ATP synthase β subunits to the binding of ATP, ADP and inorganic phosphate.
Recall how the proton motive force is harnessed to transport the products and reactants of ATP synthesis.
3.6.4 the mechanism that couples c-ring rotation to the proton motive force
3.7: Regulation of glycolysis糖酵解 in liver cells
- 参见图1的糖酵解位置
3.7.1 ATCase酶的Allosteric regulation变构调节
CTP浓度升高，会抑制ATCase酶的活性
ATCase酶有T和R两个状态。当无底物时，处于非激活的T状态；当有底物结合时处于激活的R状态。T和R两种状态的变化是通过结构变化调节的。CTP是ATCase酶的Inhibitor，使其处于T状态；ATP是Activator，使其处于R状态。
the conformation of each monomer of the enzyme is connected. If one monomer switches to the R state, they all do. The binding of a substrate to a monomer favors the R state of that monomer, and thus the whole protein
the conformation of each monomer of the enzyme is independent, but the conformation of a monomer is totally dependent on substrate binding. When upbound, the monomer is in the T state, and switches to the R state upon substrate binding. The R state of one monomer favors a swith to binding and the R state in other monomers.
3.7.2 Homeostasis&Forms of metabolic regulation
Homeostasis
Homeostasis 内稳态is the process of returning metabolism to steady state after a perturbation, by changing metabolic fluxes.细胞会处于Homeostasis但非 equilibrium，因为完全的平衡会导致细胞死亡。
Substrate-limited reactions
意思是该反应受限于底物。在此反应下物质接近于均衡状态，底物快速转换为产物。
Enzyme-limited reactions（Rate-limiting reactions）
意思是该反应主要受限于酶。在此反应下物质远非均衡状态。只有在酶被effectors激活之后反应才会发生，酶在此像是一个开关阀。
Forms of metabolic regulation
Allosteric regulation: Allosteric regulators usually reflect
cell metabolic state。Fast regulation (a few milliseconds)Reversible covalent modification：IE - phosphorylation。Slower than allosteric (a few seconds)
Transcriptional regulation：Slowest form of regulation 。Change in expression of enzymes
3.7.3 PFK-1和PFK-2调控liver中的glycolysis过程
Phosphofructokinase-1 (PFK-1)参与Glycolysis的过程
- ATP是PFK-1的inhibitor;AMP是PFK-1的Activator。当ATP/AMP 高时，Glycolysis下调，ATP合成下调；当ATP/AMP 低时，Glycolysis上调，ATP合成上调。
ADP既非抑制剂也非激活剂
Liver regulation of PFK-1
- Fructose 2,6-bisphosphate (F-2,6-BP) activates PFK-1
- Phosphofructokinase 2 (PFK-2)的作用
- 高血糖时调高PFK-2以调高Glycolysis糖酵解
- 低血糖时激活FBPase-2以抑制Glycolysis糖酵解
- 低血糖时激活FBPase-2的原理图
3.7.4 糖酵解通路中上游的Hexokinase酶和下游的Pyruvate Kinase发挥的作用
Hexokinase酶
-
在肌肉细胞中，高血糖浓度下，Hexokinase受到抑制，糖酵解被抑制。使得葡萄糖留在血液中
图22 Hexokinase酶在肌肉细胞中发挥的作用。When blood glucose is high, glucose 6-phosphate accumulates in the muscle due to downstream inhibition of PFK-1. This leads to an inhibition of the upstream enzyme Hexokinase, and ultimately glucose remains in the blood . -
在肝脏细胞中，高血糖浓度下，糖酵解同样会被抑制，但是却可以利用Glucokinase使得葡萄糖被合成为Lipids和Glycogen。这解释了为什么吃甜食会发胖。
图23 肝脏细胞将葡萄糖被合成为Lipids和Glycogen Glucose-6-phosphate在其他通路中也会被转换
Pyruvate Kinase
PK-L和PK-M
3.8: Regulation of blood sugar by the liver
3.8.1 Gluconeogenesis糖异生
Gluconeogenesis糖异生可看做Glycolysis糖酵解的反过程。其中有如图26所示的三个Enzyme-limited reactions，其余都是Substrate-limited reactions。
第一个不可逆过程Pyruvate→PEP
第二个不可逆过程Fructose 1,6-BP→Fructose 6-P
第三个不可逆过程Fructose 6-P→Glucose
3.8.2 The reciprocal regulation相互调节 of glycolysis and gluconeogenesis in the liver contributes to the control of glucose metabolism.
低血糖时导致Gluconeogenesis糖异生
对照图20和21看。低血糖促使胰高血糖素分泌，激活PKA，PKA使得PFK-2磷酸化让它失活，而使得FBPase-2激活，由F2,6BP生成F6P。由图32所知。F2,6BP的减少激活FBPase-1而失活PFK-1，从而使得F1,6BP转换为F6P，更进一步促进了Gluconeogenesis糖异生
高血糖时导致Glycolysis
高血糖时分泌insulin,促使Phospho-protein phosphatase激活PFK-2，将F6P转换为F2,6BP。由图32所知，F2,6BP增多抑制了FBPase-1而激活了PFK-1，从而使得F6P转换为F1,6BP，更进一步促进了糖酵解
glycolysis and gluconeogenesis相互调节
3.8.3 血糖高或者低时对糖原Glycogen的调控
低血糖时将糖原分解为葡萄糖
低血糖分泌Glucagon, 从而磷酸化glycogen phosphorylase，从而将Glycogen分解为Glucose 1P，释放Glucose
低血糖时糖原合成受抑制
低血糖分泌Glucagon, 从而使得glycogen synthase磷酸化而失活，从而使得Glucose 1P合成为Glycogen受到抑制
高血糖时糖原合成受促进
高血糖分泌insulin，从而促进Protein kinases磷酸化GSK而使其失活，而GSK本来是使得glycogen synthase失活的，由于GSK失活，使得glycogen synthase被激活，促进了glycogen合成。
3.8.4 肝脏细胞中血糖高或者低时PP1对糖原Glycogen的调控
高血糖时PP1激活Glycogen synthase从而促进Glycogen合成；同时使得Glycogen phosphorylase失活，从而抑制糖原分解
低血糖时分泌Glucagon, PP1被PKA抑制，从而获得相反的反应。
3.8.5.1 糖尿病的种类
百分之九十的都是二型糖尿病
Hyperglycemia高血糖症的含义： comes from two root words: “hyper” meaning excessive, and “glycemia” meaning presence of glucose in the blood.
3.8.5.2 环境和遗传因素怎样导致的一型糖尿病
3.8.5.3 一型糖尿病的症状
3.8.5.4 一型糖尿病的治疗
3.8.6 二型糖尿病的治疗
一型糖尿病是不能正常分泌胰岛素，二型糖尿病是胰岛素能正常分泌，但不能被机体响应。
