REGULATION OF ACETYL CoA PROCESSING BIOC 460 DR. TISCHLER LECTURE 37
OBJECTIVES 1.Regulation of processes in the formation of acetyl CoA: a) describe regulation of hormone-sensitive lipase by covalent modification b) mechanism by which activators or inhibitors of phospho- diesterase affect activity of hormone-sensitive lipase 2.Regulation of processes in the utilization of acetyl CoA: a)factors that induce (increase) or repress (decrease) synthesis of acetyl CoA carboxylase and FAS b)events associated with polymerization-depolymerization describe of acetyl CoA carboxylase c)events associated with covalent modification of acetyl CoA carboxylase d)induction of HMG CoA reductase through mRNA production in the presence of low cholesterol. e) events associated with covalent modification of HMG-CoA reductase 3.Drugs that inhibit HMG-CoA reductase to lower cholesterol
Mobilization of fats from triacylglycerols Regulated step – hormone sensitive lipase Specific for removing first fatty acid Phosphorylated “a” form is active Dephosphorylated “b” form is inactive LIPOLYSIS
Figure 1. Hormonal activation of triacylglycerol (hormone-sensitive) lipase. Hormone signals from epinephrine or glucagon promote mobilization of fatty acids (lipolysis) via production of cyclic AMP. Activated protein kinase A, phosphorylates HSL-b to the active HSL-a form. RECEPTORS ATP protein kinase A cell membrane Epinephrine Glucagon HORMONES cyclic AMP ATP ADP = activation - = inhibition Triacylglycerol Fatty acid + Diacylglycerol OP HSL-a protein phosphatase PiPi + Insulin - caffeine theophylline Phospho- diesterase AMP + Adenylyl cyclase (inactive form) HSL-b OH inactiveactive + + insulin
PHYSIOLOGICAL CONDITIONEFFECT High-carbohydrate, low-fat diet synthesis High-fat diet synthesis Fasting synthesis Table 1. Long-term control by induction or repression of acetyl CoA carboxylase and fatty acid synthase
acetyl CoA carboxylase polymeric malonyl CoA acetyl CoA ATP + HCO 3 - ADP + P i ACTIVE FORM citrate promotes polymerization acetyl CoA carboxylase (monomeric) LOW ACTIVITY OH Figure 2a. Regulation of acetyl CoA carboxylase by citrate and palmitoyl CoA via polymerization and depolymerization palmitoyl-CoA promotes depolymerization
acetyl CoA carboxylase polymeric malonyl CoA acetyl CoA ATP + HCO 3 - ADP + P i ACTIVE FORM citrate promotes polymerization acetyl CoA carboxylase (monomeric) LOW ACTIVITY OH Figure 2a. Regulation of acetyl CoA carboxylase by citrate and palmitoyl CoA via polymerization and depolymerization palmitoyl-CoA promotes depolymerization
INACTIVE FORM OPO 3 AMP PK (active) OPO 3 AMP PK (inactive) OH kin. kinase (active) OPO 3 kin. kinase (inactive) OH ATP ADP protein kinase A (cyclic AMP-activated) glucagon or epinephrine via cAMP ADP ATP ADP Figure 2b. Regulation of acetyl CoA carboxylase by glucagon, epinephrine and insulin acetyl CoA carboxylase (monomeric) LOW ACTIVITY OH
INACTIVE FORM OPO 3 AMP protein kinase (active) OPO 3 AMP protein kinase (inactive) OH kinase (active) OPO 3 kinase (inactive) OH ATP ADP protein kinase A (cyclic AMP-activated) glucagon or epinephrine via cAMP ADP ATP PiPi +insulin protein phosphatase ATP ADP PiPi protein phosphatase PiPi protein phosphatase acetyl CoA carboxylase (monomeric) LOW ACTIVITY OH Reversing the inactivation of acetyl CoA carboxylase
INACTIVE FORM OPO 3 AMP protein kinase (active) OPO 3 AMP protein kinase (inactive) OH kinase (active) OPO 3 kinase (inactive) OH ATP ADP protein kinase A (cyclic AMP-activated) glucagon or epinephrine via cAMP ADP ATP PiPi +insulin protein phosphatase ATP ADP PiPi protein phosphatase PiPi protein phosphatase acetyl CoA carboxylase (monomeric) LOW ACTIVITY OH Reversing the inactivation of acetyl CoA carboxylase
NUCLEUS ENDOPLASMIC RETICULUM High Cholesterol Figure 3. HMG CoA reductase is induced when intracellular cholesterol becomes too low while with high cholesterol SREBP is bound to the endoplasmic reticulum and is thus rendered ineffective NUCLEUS Low Cholesterol ENDOPLASMIC RETICULUM mRNA for HMG CoA Reductase synthesis of HMG CoA reductase = SREBP, sterol regulatory element binding protein
RK (active) OPO 3 RK (inactive) OH RKK(active) OPO 3 OH RKK (inactive) ATP ADP ATP HMG-CoA +2 NADPH +2 H + INACTIVE FORM OPO 3 HR ACTIVE FORM OH HR mevalonate + 2 NADP + + CoA ATP ADP via cAMP PKA + glucagon or epinephrine Figure 4. Inactivation of HMG CoA reductase by phosphorylation in response to glucagon or epinephrine
RK (active) OPO 3 RKK (active) OPO 3 ATP HMG-CoA +2 NADPH +2 H + ACTIVE FORM OH HR + mevalonate + 2 NADP + + CoA ATPADP ATP glucagon or epinephrine via cAMP PKA + RKK (inactive) OH PiPi PP insulin + RK (inactive) OH PP insulin PiPi INACTIVE FORM OPO 3 HR P i insulin PP + ADP Figure 4. Activation of HMG CoA reductase by dephosphorylation in response to insulin
RK (active) OPO 3 RKK (active) OPO 3 ATP HMG-CoA +2 NADPH +2 H + ACTIVE FORM OH HR + mevalonate + 2 NADP + + CoA ATPADP ATP glucagon or epinephrine via cAMP PKA + RKK (inactive) OH PiPi PP insulin + RK (inactive) OH PP insulin PiPi INACTIVE FORM OPO 3 HR P i insulin PP + ADP Figure 4. Activation of HMG CoA reductase by dephosphorylation in response to insulin