Figure 1.

Biochemical pathways involving dopamine, serotonin, epinephrine, norepinephrine, and the cofactor BH4

Legend Figure 1: Biochemical pathways (p. 66 above)

The monoamines consist of catecholamines (for instance dopamine, norepinephrine and epinephrine) and serotonin. The amines are synthesized throughout a complex multienzymatic pathway which converts, tryptophan and tyrosine into serotonin and dopamine respectively, through reactions catalysed by tryptophan hydroxylase (TPH, EC 1.14.16.4), tyrosine hydroxylase (TH, EC 1.14.16.2) and aromatic L-aminoacid decarboxylase (AADC, EC 4.1.1.28). This latter enzyme acts as a common converging decarboxylating system for active neurotransmitter biosynthesis. In the case of AADC deficiency, the dopamine precursor (L-dihydroxyphenylalanine, DOPA) is metabolized into 3-Orthomethyldihydroxy-phenylalanine (3-OMD) and vanillactic acid (VLA). Both TPH and TH require tetrahydrobiopterin (BH₄) as cofactor, while AADC needs vitamin B6 (pyridoxine). In noradrenergic neurons, dopamine is further converted by dopamine beta hydroxylase (DBH) into norepinephrine and epinephrine by phenylethanolamine N-methyltransferase (PNMT). Since BH₄ is crucial in serotonin and dopamine biosynthesis, a large subset of monoamine defects is to be referred to pterins build up and regeneration mostly presenting hyperphenylalaninemia as a characterizing hallmark. The biosynthesis and regeneration of BH4 is carried out by a complex system of enzymes starting from guanosine triphosphate cyclohydrolase 1 (GTPCH1), the rate limiting enzyme for BH4 biosynthesis, which is responsible for the hydrolysis of guanosine triphosphate into 7,8-dihydroneopterin triphosphate (H₂NP₃), thus releasing neopterin. H₂NP₃ is further metabolized into 6-pyruvoyltetrahydropterin (6-PTP) by 6-pyruvoyltetrahydropterin synthase (PTPS), the second critical enzyme for BH4 build up. 6-PTP is used to form BH₄ through sepiapterin (SPT) by a two step enzymatic pathway of aldose reductase (AR) and sepiapterin reductase (SR). BH4 is the basic cofactor of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) and once it links with this enzyme it is then released as tetrahydrobiopterin-4a-carbinolamine. Tetrahydrobiopterin-4a-carbinolamine is used to recycle BH₄ through the biosynthesis of quinonoid-dihydrobiopterin (qBH2) by pterin-4a-carbinolamin dehydratase (PCD) and dihydropteridin reductase (DHPR), which is also linked to folate metabolism via methylenetetrahydrofolate reductase (MTHFR) through an incompletely defined mechanism. This two step enzymatic regeneration (through PCD and DHPR) can be partly enzymatic partly not. BH4 is also related to nitric oxide (NO) metabolism through arginine, cytrulline and nicotinamide adenine dinucleotide phosphate (NADPH). This finding may explain the effect of BH4 in vasogenic control. The catabolism of the monoamine is then carried out by a two step pathway involving monoamine oxidase (MAO) and cathecol-O-methyltransferase (COMT) and major metabolites are represented by homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) and also vanillylmandelic acid (VMA). The three major end products are measured in the CSF reflecting overall dopaminergic, serotoninergic and noradrenergic activity. The process of monoamine neurotransmission requires, in summary, the biosynthesis of monoamines in the nerve terminal, their upload in the synaptic vesicles through the vesicular monoamine transporter (VMAT2) with the subsequent excytotic release, action at specific receptors in the postsynaptic interface and the termination of the effect either by degradation or by reuptake by dopamine transporter (DAT).