42 - neurotransmitter synthesis
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- Synthesis of phenylalanine-derived neurotransmitters
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Phenylalanine --> tyrosine by phenylalanine hydroxylase (defective enzyme in PKU); tyrosine --> DOPA by tyrosine hydroxylase
- Both reactions use BH4 (tetrahydrobiopterin). Synthesis of DOPA is therefore inhibited by deficits in biopterin synthesis or dihydrobiopterin reductase.
DOPA then decarboxylated (by DOPA decarboxylase)--> dopamine, which requires PLP (vitamin B6).
Dopamine hydroxylated --> norepinephrine; requires molecular O2, vitamin C (ascorbic acid) and copper.
Norepinephrine methylated --> epinephrine, using SAM as a methyl donor. - Catechoamine inactivation
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- Methylation = catechol O-methyltransferase (COMT) uses SAM as a methyl donor.
- Oxidation = monoamine oxidase (MAO) removes the NH4+ to form an aldehyde, aldehyde oxidases then --> acid
- Norepi is inactivated by conversion to vanillymandelic acid, which is then excreted. Epi has a similar inactivation pathway.
- Dopamine is converted to homovanillic acid. - Serotonin synthesis
- Tryptophan --> 5-hydroxytryptophan by trp hydroxylase (requires O2, BH4) --> serotonin by DOPA decarboxylase (generates amine from animo acid, requires PLP)
- Serotonin inactivation
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oxidation by monoamine oxidase, removal of NH3 --> aldehyde, then oxidation to carboxyl group using NAD+ --> NADH
(Unlike catecholamines there is no methylation of the ring hydroxyl group. - Melatonin synthesis
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Acetylation of serotonin --> methylation of ring hydroxyl --> melatonin
- SAM = methyl donor
- occurs in pineal gland. - GABA and histidine synthesis
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** AA decarboxylases **
glutamate --> GABA
histidine --> histamine
- both involve PLP-catalyzed decarboxylations
- Astroglial cells use NH4+ to synthesize glutamine, which is substrate for neuronal synthesis of GABA and glutamate
- Glutamate also transports excess NH4+ from brain into blood
- Inactivation of histamine via two pathways: 1) brain = methylation, MAO oxidase (MAO-B); 2) periphery = deamination, oxidation --> products of both excreted - Melanin synthesis
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Tyrosine --> DOPA quinone catalyzed by tyrosinase
- Cu-dependent enzyme
- UVB light = inc tyrosinase activity in melanocytes
Oxidized quinones polymerize to form melanins in the skin, eyes, and hair. - Thyroid hormone synthesis
- Tyrosine + I2 (iodide ions reduced and added to tyrosine ring) --> MIT and DIT; condensation = active T3 and T4 hormones
- NO synthesis
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Arginine --> NO by NOS
- NOS is a mixed function oxidase; utilizes O2 and NADPH. - NO signal transduction
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- Is made by endothelial cells; relaxes smooth muscle and dilates cardiac vessels.
- Activates guanylate cyclase pathway in smooth muscle cells
- Is cytotoxic, reacting with the Fe-S centers of ETC enzymes, inhibiting ATP production in nearby “parasites and tumor cellsâ€