Tyrosine to Dopamine Conversion Pathway
The conversion of tyrosine to dopamine involves a two-step enzymatic process: first, tyrosine is converted to L-DOPA by tyrosine hydroxylase (TH), which is the rate-limiting step, and then L-DOPA is converted to dopamine by aromatic L-amino acid decarboxylase (AADC).
Step-by-Step Conversion Pathway
Tyrosine → L-DOPA (First Step)
- Enzyme: Tyrosine hydroxylase (TH)
- Cofactor required: Tetrahydrobiopterin (BH4)
- Process: Hydroxylation of tyrosine at the para position
- Rate-limiting step: This is the slowest and most tightly regulated step in catecholamine synthesis 1
- Regulation: TH activity is controlled by:
- End-product inhibition by dopamine
- Phosphorylation of serine residues (Ser19, Ser31, Ser40) in the N-terminus 1
- Iron content in the enzyme's catalytic domain
L-DOPA → Dopamine (Second Step)
- Enzyme: Aromatic L-amino acid decarboxylase (AADC), also called DOPA decarboxylase (DDC)
- Cofactor required: Pyridoxal phosphate (vitamin B6)
- Process: Decarboxylation of L-DOPA
Regulation of the Pathway
The conversion pathway is tightly regulated through several mechanisms:
- Feedback inhibition: Dopamine inhibits TH activity through binding to the enzyme's N-terminus, particularly involving the amino acid sequence Gly36-Arg37-Arg38 2
- Phosphorylation: Phosphorylation of serine residues in TH's N-terminus relieves catecholamine-mediated inhibition 1
- α-Synuclein interaction: α-Synuclein can partially enfold TH, potentially reducing dopamine synthesis, which may be relevant in Parkinson's disease pathophysiology 3
Clinical Significance
- Parkinson's disease: Results from degeneration of dopaminergic neurons with insufficient dopamine production. Treatment involves L-DOPA administration to bypass the rate-limiting TH step 3
- L-DOPA responsive dystonia: Can be caused by mutations in the TH gene, resulting in reduced enzyme activity and decreased dopamine synthesis 4
- Compensatory mechanisms: Non-dopaminergic neurons can express TH or AADC individually and cooperate to produce dopamine when dopaminergic neurons are insufficient 5
Transport Considerations
- L-DOPA can cross the blood-brain barrier via the L-type amino acid transporter 1 (LAT1), which is present on both the blood-brain barrier and blood-retinal barrier 6
- This transport mechanism explains why systemic L-DOPA administration is effective for treating both motor symptoms of Parkinson's disease and associated ocular symptoms 6
Diagram of the Pathway
Tyrosine
|
| Tyrosine Hydroxylase (TH)
| + Tetrahydrobiopterin (BH4)
| + O₂
V
L-DOPA (L-3,4-dihydroxyphenylalanine)
|
| Aromatic L-amino acid decarboxylase (AADC/DDC)
| + Pyridoxal phosphate (Vitamin B6)
V
DopamineThis pathway represents the initial steps in catecholamine synthesis, with dopamine serving as a precursor for norepinephrine and epinephrine in neurons that express the necessary additional enzymes.