上游充通大学 SHANGHAI JIAO TONG UNIVERSITY Chapter 10: Regulatory Strategies 调控策略 2015年11月10日 1B三S
2015年11月10日 Chapter 10: Regulatory Strategies 调控策略
上游充通大兽 生物体内一直发生的大量生化过程 SHANGHAI JIAO TONG UNIVERSITY 中心体 内质网 线粒体 高尔基体 体 钮胞核 核仁 Like motor traffic,metabolic pathways flow more efficiently when regulated by signals. 如同机动车交通，用信号调节代谢途径流动效率更高 The activity of enzymes often must be regulated so that they function at the proper time and place. 调节酶活性：经常性/必需。 以便在合适的时间和地点发挥作用。“时空
Like motor traffic, metabolic pathways flow more efficiently when regulated by signals. 如同机动车交通，用信号调节代谢途径流动效率更高 生物体内一直发生的大量生化过程 The activity of enzymes often must be regulated so that they function at the proper time and place. 调节酶活性：经常性 /必需。 以便在合适的时间和地点发挥作用。“时空
Regulation of Enzyme Activity:Five principal ways 五种酶主要的酶活性调节方式 1.Allosteric Control 变构控制，别构控制 2.Multiple Forms of Enzymes:Isozymes,or isoenzymes 同功酶 3.Reversible Covalent Modification. 可逆共价修饰 4.Proteolytic Activation. 蛋白酶活化 5.Controlling the Amount of Enzyme Present 控制酶量
五种酶主要的酶活性调节方式 Regulation of Enzyme Activity: Five principal ways 1. Allosteric Control 变构控制，别构控制 2. Multiple Forms of Enzymes： Isozymes, or isoenzymes 同功酶 3. Reversible Covalent Modification. 可逆共价修饰 4. Proteolytic Activation. 蛋白酶活化 5. Controlling the Amount of Enzyme Present. 控制酶量
1.Allosteric Control 变构控制，别构控制 ·Allosteric proteins contain distinct regulatory sites(调控位点) and multiple functional sites.变构蛋白质含有独特的调节位点 和多个活性位点。 The binding of small signal molecules at regulatory sites is a significant means of controlling the activity.信号小分子与调节 位点的结合是控制这些酶蛋白活性的主要手段。 Substrate Active site Enzyme Distorted active site 别构抑制 有变构控制能力的蛋白质 也是信息转导分子： Allosteric site 能够将信号分子或同一酶 Allosteric- (a)Allosteric inhibition inhibitor 蛋白活性位点的信息传递 Distorted Substrate active site Active site 给蛋白质，调节酶蛋白活 别构激活 性。 Allosteric site Allosteric activator (b)Allosteric activation
1. Allosteric Control 变构控制，别构控制 • Allosteric proteins contain distinct regulatory sites (调控位点) and multiple functional sites. 变构蛋白质含有独特的调节位点 和多个活性位点。 • The binding of small signal molecules at regulatory sites is a significant means of controlling the activity. 信号小分子与调节 位点的结合是控制这些酶蛋白活性的主要手段。 有变构控制能力的蛋白质 也是信息转导分子： 能够将信号分子或同一酶 蛋白活性位点的信息传递 给蛋白质，调节酶蛋白活 性。 别构抑制 别构激活
上游充通大兽 SHANGHAI JIAO TONG UNIVERSITY Allosteric proteins show the property of cooperativity 协同性)：activity at one functional site affects the activity at others. Substrate Inactive form Active form stabilized of enzyme by a substrate molecule Proteins displaying allosteric control are thus information transducers(传感器)：their activity can be modified in response to signal molecules or to information shared among active sites
• Allosteric proteins show the property of cooperativity ( 协同性): activity at one functional site affects the activity at others. Proteins displaying allosteric control are thus information transducers (传感器): their activity can be modified in response to signal molecules or to information shared among active sites
Aspartate Transcarbamoylase (ATCase) 天冬氨酸氨基甲酰转移酶 Allosterically Inhibited by the End Product of Its Pathway 被途径的终产物所别构抑制 催化嘧啶 NH2 NH. +Pi 合成的第 oP032- N C00 一步 Carbamoyl Aspartate N-Carbamoylaspartate phosphate 氨基羧酸磷酸 天冬氨酸 N-氨羧基天冬氨酸 NH2 HO Figure 10.1 ATCase reaction OH Cytidine triphosphate(CTP) 如何精确调节这个酶，使之合成细胞所需量的CTP?
Aspartate Transcarbamoylase （ATCase） 天冬氨酸-氨基甲酰转移酶 Figure 10.1 ATCase reaction Allosterically Inhibited by the End Product of Its Pathway 被途径的终产物所别构抑制 氨基羧酸磷酸 天冬氨酸 N-氨羧基天冬氨酸 催化嘧啶 合成的第 一步 如何精确调节这个酶，使之合成细胞所需量的CTP？
CTP inhibits ATCase John Gerharti和Arthur Pardee.发现ATCase受CTP抑制 CTP是嘧啶合成途径的最终产物。 CTP浓度高，则酶催化活性降低。 0.5 1.0 [CTP],mM Figure 10.2 CTP inhibits ATCase.Cytidine triphosphate,an end product of the pyrimidine synthesis pathway,inhibits aspartate transcarbamoylase despite having little structural similarity to reactants or products
CTP inhibits ATCase Figure 10.2 CTP inhibits ATCase. Cytidine triphosphate, an end product of the pyrimidine synthesis pathway, inhibits aspartate transcarbamoylase despite having little structural similarity to reactants or products. John Gerhart和Arthur Pardee发现ATCase受CTP抑制 • CTP是嘧啶合成途径的最终产物。 • CTP浓度高，则酶催化活性降低
Feedback inhibition反馈抑制 ATCase CTP The inhibition of ATCase by CTP is an example of feedback inhibition( 馈抑制)，the inhibition of an enzyme by the end product of the pathway. CTP是嘧啶合成途径的最终产物，它所形成的抑制为反馈抑制。 Feedback inhibition by CTP ensures that N-carbamoylaspartate and subsequent intermediates in the pathway are not needlessly formed when pyrimidines are abundant. •该途径使CTP合成处于足量时，不再形成过量的反应产物及其后 的中间体
The inhibition of ATCase by CTP is an example of feedback inhibition (反 馈抑制), the inhibition of an enzyme by the end product of the pathway. Feedback inhibition by CTP ensures that N-carbamoylaspartate and subsequent intermediates in the pathway are not needlessly formed when pyrimidines are abundant. Feedback inhibition 反馈抑制 •该途径使CTP合成处于足量时，不再形成过量的反应产物及其后 的中间体。 • CTP是嘧啶合成途径的最终产物，它所形成的抑制为反馈抑制
Allosteric inhibition别构抑制 Because CTP is structurally quite different from the substrates of the reaction.Thus CTP must bind to a site distinct from the active site where substrate binds. Such sites are called allosteric or regulatory sites(调控位点) CTP is an example of an allosteric inhibitor(别构抑制剂)， NH2 0P032 Carbamoyl Aspartate N-Carbamoylaspartate HO OH phosphate Cytidine triphosphate(CTP) CTP与底物及产物的结构相似性很低，因此CTP的结合位点肯定 不是活性位点。 这种位点叫变构位点或调节位点。CTP是别构抑制剂
Because CTP is structurally quite different from the substrates of the reaction. Thus CTP must bind to a site distinct from the active site where substrate binds. Such sites are called allosteric or regulatory sites（调控位点）. CTP is an example of an allosteric inhibitor (别构抑制剂). substrates inhibitor Allosteric inhibition 别构抑制 CTP与底物及产物的结构相似性很低，因此CTP的结合位点肯定 不是活性位点。 这种位点叫变构位点或调节位点。CTP是别构抑制剂
Allosterically Regulated Enzymes Do Not Follow Michaelis- Menten Kinetics变构调节酶不遵循米氏动力学 产物形成速度对底物Asp浓 度作图呈$型曲线，表明一 个活性位点结合底物能够 增加这个酶蛋白分子其它 sigmoidal (S型的) 位点的活性。因此这个酶 是正协同酶 10 20 30 40 [Aspartate],mM Figure 10.3 ATCase displays sigmoidal kinetics.A plot of product formation as a function of substrate concentration produces a Sigmoidal curve because the binding of substrate to one active site increases the activity at the other active sites.Thus, the enzyme shows cooperativity
Allosterically Regulated Enzymes Do Not Follow MichaelisMenten Kinetics 变构调节酶不遵循米氏动力学 Figure 10.3 ATCase displays sigmoidal kinetics. A plot of product formation as a function of substrate concentration produces a Sigmoidal curve because the binding of substrate to one active site increases the activity at the other active sites. Thus, the enzyme shows cooperativity. 产物形成速度对底物Asp浓 度作图呈S型曲线，表明一 个活性位点结合底物能够 增加这个酶蛋白分子其它 位点的活性。因此这个酶 是正协同酶 sigmoidal （S型的）