Degradation of acetylcholine: H20 ↓0 Choline Acetic acid AchE (CH)a N*-CH2-CH2-O-C-CH3 (CH)3 N+-CH2-CH2-OH CH3COOH ) AchE (H) Trp-86 Glu-334 His-447 600,000 Ach molecules/AchE/min Ser-203 turnover time of 150 microseconds Steps involved in the action of acetylcholinesterase: 1.Binding of substrate (Ach) 2.Formation of a transient intermediate(involving-OH on Serine 203,etc.) 3.Loss of choline and formation of acetylated enzyme 4.Deacylation of AchE (regeneration of enzyme)
+ CH3COOH AchE (CH3)3 N+–CH2–CH2 (CH3)3 N+–CH2–CH2–O–C–CH3 –OH O H2O (-) (H) AchE Trp-86 Glu-334 His-447 Ser-203 Degradation of acetylcholine: Steps involved in the action of acetylcholinesterase: 1. Binding of substrate (Ach) 2. Formation of a transient intermediate (involving -OH on Serine 203, etc.) 3. Loss of choline and formation of acetylated enzyme 4. Deacylation of AchE (regeneration of enzyme) 600,000 Ach molecules / AchE / min = turnover time of 150 microseconds Choline Acetic acid
Julius Axelrod (Nobel Laureate,1970) His discoveries concern the mechanisms which regulate the formation of norepinephrine in the nerve cells and the mechanisms which are involved in the inactivation of this important neurotransmitter. Synthesis of Catecholamines Tyrosine hydroxylase Phenylethanolamine- TH CH2 N-methyl transferase HC-COOH HO- HC-COOH Dopa decarboxylase NH2 NH2 Tyrosine DOPA (L-amino acid DD (L-AAD) decarboxylase) OH OH HO HO HO PNMT CH2 DBH HO- HO C出 HO- CH NHCHs Epinephrine Norepinephrine Dopamine H Adrenal medulla Dopamine B-hydroxylase
HO HO CH2 NHCH3 OH CH Epinephrine HO HO CH2 NH2 OH CH Norepinephrine HO HO CH2 NH2 CH2 Dopamine HO HO HC NH2 CH2 DOPA COOH HO HC NH2 CH2 Tyrosine COOH TH DD (L-AAD) PNMT DBH Adrenal medulla Synthesis of Catecholamines Tyrosine hydroxylase Dopa decarboxylase (L-amino acid decarboxylase) Dopamine -hydroxylase PhenylethanolamineN-methyl transferase 1 3 Julius Axelrod (Nobel Laureate, 1970) His discoveries concern the mechanisms which regulate the formation of norepinephrine in the nerve cells and the mechanisms which are involved in the inactivation of this important neurotransmitter
Regulation of Norepinephrine Synthesis and Metabolism: Na* Tyrosine Tyrosine Dopa. DDopamine R Signal (DA) DBH NE Uptake-1 ATP NE ) R DBH Post-synaptic Pre-synaptic +Ca2+ ATP NE ● NENE Ca2 Cellular messengers and effects COMT Diffusion, Normetanephrine(NMN) metabolism
Pre-synaptic Post-synaptic Ca2+ Na+ Tyrosine Cellular messengers and effects Diffusion, metabolism Tyrosine Dopa TH DD Dopamine (DA) NE DBH ATP Ca2+ NE DBH ATP NE NE COMT R R R NE (-) Signal Regulation of Norepinephrine Synthesis and Metabolism: Uptake-1 Normetanephrine (NMN)
Degradation of Catecholamines: OH OH HO CH HO CH HO PNMT DBH HO CH2 HO- HO CH2 Adrenal NHCH3 N Epinephrine medulla H Norepinephrin Dopamine MAO MAO MAO COMT OH HO CH HO CHgO HO- COOH LWOO HO- COOH HO- Dihydroxymandelic acid Dihydroxyphenylacetic acid Methoxytyrami (DOMA) (DOPAC) COMT MAO OH OH (-) Pargyline, Nialamide CH CH CHO CH HO HO CH2 HO. COOH NH2 Metanephrine Normetanephrine Homovanillic acid MAO MAO (NMN) (HVA) OH CHaO- CH HO- COOH 3-Methoxy-4-hydroxy- mandelic acid (VMA) COMT catechol-O-methyltransferase MAO monoamine oxidase *Diagnosis of pheochromocytoma
Degradation of Catecholamines: HO HO CH2 NHCH3 OH CH Epinephrine HO HO CH2 NH2 OH CH Norepinephrine HO HO CH2 NH2 CH2 Dopamine HO HO COOH OH CH Dihydroxymandelic acid (DOMA) HO CH3O COOH OH CH 3-Methoxy-4-hydroxymandelic acid (VMA)* CH3O HO CH2 NHCH3 OH CH Metanephrine HO CH2 NH2 OH CH Normetanephrine (NMN) CH3O HO HO COOH CH2 Dihydroxyphenylacetic acid (DOPAC) CH3O HO CH2 NH2 CH2 3-Methoxytyramine CH3O HO COOH CH2 Homovanillic acid (HVA) COMT COMT COMT COMT COMT MAO MAO MAO MAO MAO MAO PNMT DBH Adrenal medulla COMT = catecholO-methyltransferase MAO = monoamine oxidase *Diagnosis of pheochromocytoma ( - ) Pargyline, Nialamide