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CATECHOLAMINE-RELATED MOLECULES & DISORDERS 1

Molecules Disorders
Aldehyde dehydrogenases
Aldehyde reductases
Carbinolamine dehydratase (PCBD)
Catechol-O-methyltransferase
Copper transporting ATPase 1
Dihydropteridine reductase (DHPR)
Dopamine
Dopamine -hydroxylase
Dopamine receptor D3
Dopamine receptor D4
Dopamine transporter
Epinephrine
G7 protein
GTP-cyclohydrolase 1 (CGH1)
L-aromatic amino acid decarboxylase
Monoamine oxidase: A; B
Neurofibromin
Norepinephrine
Norepinephrine transporter
Phenolsulfotransferase
Phenylalanine hydroxylase (PKU)
RET oncogene
SLC6A2 (Norepinephrine tranporter)
Tyrosinase
Tyrosine hydroxylase
Vesicular amine transporter 1; 2
Albinism
Autonomic
  Hyperactivity
  Hypotension
Brunner syndrome
Dystonia
Menkes
Neonatal hypotonia & seizures
Occipital horn syndrome
Phenyketonuria
  DHPR
  GCH
  PCBD
  PKU
Pheochromocytoma
  Multiple Endocrine Neoplasia
  Neurofibromatosis
  von Hippel-Lindau


ENZYMES & DISEASES

Enzyme or Protein Biochemistry Syndromes
Phenylalanine hydroxylase L-phenylalanine to L-tyrosine Phenylketonuria
Tyrosine hydroxylase L-tyrosine to L-DOPA L-DOPA responsive
  dystonia
L-aromatic amino acid
  decarboxylase
L-DOPA to dopamine;
5OH-tryptophan to serotonin
Neonatal seizures;
Hypotonia; Infantile death
Dopamine -hydroxylase Dopamine to Norepinephrine Orthostatic Hypotension
Monoamine oxidase-A Norepinephrine to
  dihydroxyphenylglycol
With aldehyde reductase
Brunner syndrome
  Retardation: Mild
  Impulsive behavior
Monoamine oxidase-B Norepinephrine to
  dihydroxyphenylglycol
With aldehyde reductase
? asymptomatic
Linkage:
  Norrie syndrome
Catechol-O-
  Methyltransferase
Degradation of dopamine,
epinephrine and norepinephrine
? asymptomatic
Linkage:
  Velo-cardio-facial &
  DeGeorge syndrome
Copper-transporting
  ATPase 1
ATP to ADP
Reduced DβH activity
Menkes
Occipital horn
SMAX3
GTP-cyclohydrolase 1 Biopterin H4 synthesis: Step 1
  GTP to D-erythro-7,8-
    dihydroneopterin (PO4)3
L-DOPA responsive
  dystonia
Hyperphenylalaninemia:
  Severe
Dihydropteridine reductase Biopterin H2 to
  Biopterin H4
Phenyketonuria:
  Atypical
Carbinolamine dehydratase 4a-OH-Biopterin H4 to
  Biopterin H2
Phenyketonuria:
  Mild
Tyrosinase Tyrosine to Dopaquinone Albinism
Phenolsulfotransferase Catecholamine inactivator
  by sulfoconjugation
?
Norepinephrine transporter
  (SLC6A2 )
Removes NE from
  synaptic cleft
Orthostatic Intolerance
Dopamine receptor D2 Neuroleptic receptor Myoclonus dystonia (DYT11)
Polymorphism:
  Risk of Dopamine dystonia
Dopamine receptor D3 Iodosulpride Mouse knockout:
Hyperactivity
Dopamine receptor D4 Clozapine: High affinity Autonomic hyperactivity
Dopamine transporter . ?
Vesicular amine transporter 1
  (SLC18A1 )
Adrenal chromaffin granules ?
Vesicular amine transporter 2
  (SLC18A2 )
Accumulates cytosolic monoamines
  into Brain synaptic vesicles
Site of action of
 reserpine and tetrabenazine
Aldehyde dehydrogenases Dopamine inactivation
  with MAO
?
Neurofibromin Tumor suppressor Pheochromocytoma
Neurofibromatosis
G7 protein Tumor suppressor Pheochromocytoma
Von Hippel-Lindau
RET tyrosine-protein
  kinase receptor
Oncogene Pheochromocytoma
Multiple endocrine
  neoplasia 2



PHARMACOLOGY

Dopamine

Transmitter metabolism
Precursors: Tyrosine
  (a) L-dihydroxyphenylalanine (L-DOPA)
  (b) dopamine
Synthesizing enzymes: (a) Tyrosine hydroxylase,
(b) L-aromatic amino acid decarboxylase (DOPA decarboxylase)
Metabolizing enzymes: MAO and COMT
Metabolites: 3,4-Dihydroxyphenylacetic acid (DOPAC)
Homovanillic acid (HVA)


Dopamine Receptors
Receptor
subtypes
AgonistsAntagonistsSecond messengerDisorders
D1 SKF 38393
Dihydrexiedine
Sch 23390
SKF83566
SCH39166
Positive: cAMP
G-protein
Stimulate adenylyl cyclase
Mouse knockout
  Hyperactivity
  Diastolic hypertension
D2 (+)PHNO
Bromocriptine
(s)-Sulpiride
Raclopride
Domperidone
Haloperidol
Positive: gK+
G-protein
Inhibit adenylyl cyclase
Myoclonus-Dystonia
Anti-psychotic drugs
D3 7-OH-DPAT
PD128907
BP897
Nafadotride Positive: Ion channel Mouse knockout
  Hyperactivity
D4 . L745870
L741742
U101387
Positive: Ion channel Autonomic dysfunction
D5 . . Positive: cAMP
G-protein
Focal dystonia
Blepharospasm


Noradrenaline (NA) & Adrenaline (A)

Transmitter Metabolism
Precursors: L-Tyrosine
  (a) → L-DOPA
  (b) → Dopamine
  (c) → Noradrenaline
  (d) → Adrenaline
Synthesizing enzymes: (a) Tyrosine hydroxylase,
(b) L-aromatic amino acid decarboxylase,
(c) Dopamine -hydroxylase,
(d) Phenylethanolamine-N-methyl transferase
Metabolizing enzymes:MAO and COMT
Metabolites: Vanillylmandelic acid (VMA) and
3-methoxy-4-hydroxyphenylglycol (MHPG)


Adrenoceptors
Receptor
subtypes
Transmitter AgonistsAntagonistsSecond messenger
α(1A)
α(1C)
NA > A A61603 KMD3213
(+)-niguldipine
5-methyluradipil
Ca++: Influx into cell
α(1B) NA = A . Spiroperone
AH1111OA
Chloroethylclonidine
PI & Ca++; G-protein
α(1D) NA = A . BMY7378 PI & Ca++; G-protein
α(2A) A > NA Oxymetazoline . (-ve)cAMP,
(down)gCa++,
(down)gK+; G-protein
α(2B) A > NA . Prazosin
ARC 239
(-ve)cAMP,
(down)gCa++; G-protein
α(2C) A > NA . Prazosin
ARC 239
(-ve)cAMP; G-protein
β(1) NA > A Xamoterol,
RO363
Atenolol
CGP20712A
Betaxolol
(+ve)cAMP; G-protein
β(2) A > NA Procaterol
Zinterol
ICI118551 (+ve)cAMP; G-protein
β(3) NA > A BRL37344 Bupranolol
SR59230A
(+ve)cAMP; G-protein

NB: (+ve) indicates increase; (-ve) indicates decrease.




Tetrahydrobiopterin (Biopterin H4) is an essential cofactor for 3 aromatic amino acid monooxygenases (hydroxylases): phenylalanine, tyrosine, and tryptophan hydroxylases. The enzyme nitric oxide synthase also has an absolute requirement for tetrahydrobiopterin, for the oxidation of arginine to nitric oxide. Animals can synthesize tetrahydrobiopterin in vivo from GTP through several enzymatic reactions. The conversion of GTP to D-erythro-7,8-dihydroneopterin triphosphate is the first step in tetrahydrobiopterin biosynthesis, and GTP cyclohydrolase I catalyzes this reaction. This step is thought to be rate-limiting in the pathway.


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References
1. J. Neurochem 1996;67:1781-1790

5/9/2016