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Functional Assessment of Urinary Neuro-biogenic Amines—A COMPREHENSIVE GUIDE 

55

Synthesis and Metabolism:

Phenylalanine

DopamineSO

4

HVA

Tyrosine

DOPAC

3-MT

L-DOPA

Dopamine

PAH

TH

COMT

COMT

CYPD2

D H

SULT1A3

AADC

MAO-A/B

ALDH

MAO-A/B

ALDH

AADC

AADC

Dopamine is synthesized in the CNS,

in the adrenal glands, and in various pe-

ripheral organs. The biosynthesis of do-

pamine begins with the hydroxylation of

tyrosine by tyrosine hydroxylase (TH)

to form the precursor 3,4-dihydroxy-

phenylalanine (L-DOPA). Tyrosine hy-

droxylation is normally tightly regulat-

ed, and requires tetrahydrobiopterin and

iron co-factors. Tyrosine hydroxylase is

located in dopamine and norepineph-

rine neurons in various brain areas. In

the periphery, TH is found in the adre-

nal medulla and in sympathetic ganglia

(nerve clusters). Animal studies indicate

that selenium-deficient diets increase

the activity of tyrosine hydroxylase two-

fold. Selenium deficiency also decreased

the expression of glutathione peroxidase

and glutathione reductase; decreased ex-

pression of these enzymes may increase

intracellular oxidative stress. TH en-

zyme function may be downregulated

by oxidative stress, nitrosative stress and

thiolation (reactions with sulfur amino

acids). Single nucleotide polymorphisms

(SNPs) in the genes coding for tyrosine

hydroxylase have been associated with

altered stress responses, blood pressure,

heart rate and norepinephrine secretion.

Dopamine, norepinephrine, and

epinephrine are all feedback inhibitors

of tyrosine hydroxylase (TH), which

synthesizes 3,4-dihydroxyphenylalanine

(L-DOPA). L-DOPA is then de-car-

boxyated by aromatic amino acid de-

carboxylase (AADC). Excess manga-

nese may interfere with catechoamine

metabolism in the adrenal glands; it also

decreases tetrahydrobiopterin levels. In

vitro studies indicate that exposure to

high levels of manganese decreases do-

pamine metabolite levels.

Aromatic amino acid decarboxylase

(AADC) activity is dependent on do-

pamine levels, but not specific to dopa-

mine. AADC requires pyridoxal phos-

phate (vitamin B6) as a cofactor. The

enzyme also metabolizes tyrosine, tryp-

tophan and histidine as well. Increased

dopamine levels increase AADC activ-

ity, which may then affect other neu-

rotransmitter levels. Once synthesized,

dopamine is sequestered into synaptic

vesicles by the vesicular monoamine

transporter (VMAT2). Storing dopa-

mine inside vesicles prevents oxidative

stress to the cytosol of neurons. Vesicle

storage may be disrupted by reserpine,

amphetamines, or similar compounds.

Mutations or SNPs in VMAT2 may also

affect the ability of cell to sequester

neurotransmitters. Animal and in vitro

studies have also demonstrated dopa-

mine synthesis from cytochrome P450

enzymes (CYP450). In this pathway,

tyrosine is first converted to tyramine,

which is then hydroxylated by CYPD2

enzymes. This pathway may be used in

the CNS and the peripheral nervous

system to synthesize dopamine, research

continues in this area.