What is the biochemical pathway for dopamine synthesis from tyrosine?

Dopamine Synthesis from Tyrosine: Biochemical Pathway

The synthesis of dopamine from tyrosine occurs through a two-step enzymatic process involving tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC), with TH serving as the rate-limiting enzyme in this critical neurotransmitter pathway. 1

Biochemical Pathway Diagram

Tyrosine
   |
   | Tyrosine Hydroxylase (TH)
   | (Rate-limiting step)
   | + O₂, Tetrahydrobiopterin (BH₄)
   ↓
L-DOPA (L-3,4-dihydroxyphenylalanine)
   |
   | Aromatic L-amino acid Decarboxylase (AADC)
   | + Pyridoxal phosphate (Vitamin B6)
   ↓
Dopamine

Detailed Explanation of the Pathway

Step 1: Tyrosine to L-DOPA

• Enzyme: Tyrosine Hydroxylase (TH)
• Reaction: Hydroxylation of tyrosine at the 3-position of the phenol ring
• Cofactors required:
  • Tetrahydrobiopterin (BH₄) as electron donor
  • Molecular oxygen (O₂)
  • Iron (Fe²⁺) at the enzyme's active site
• Regulation: This is the rate-limiting step in dopamine synthesis and is highly regulated through:
  • Phosphorylation by multiple kinases at four different serine residues 1
  • Feedback inhibition by dopamine and other catecholamines 1
  • Protein-protein interactions with pathway enzymes 1

Step 2: L-DOPA to Dopamine

• Enzyme: Aromatic L-amino acid Decarboxylase (AADC)
• Reaction: Decarboxylation of L-DOPA
• Cofactor required: Pyridoxal phosphate (vitamin B6)
• Note: This enzyme is less regulated than TH and can also convert 5-hydroxytryptophan to serotonin 2

Regulation of Dopamine Synthesis

• Feedback inhibition: Dopamine binds to TH competitively with tetrahydrobiopterin and interacts with the regulatory domain 1
• Phosphorylation: Multiple kinases can phosphorylate TH at four different serine residues, generally increasing its activity 1
• Protein interactions: TH activity is modulated by interactions with:
  • Other enzymes in the same pathway
  • Tetrahydrobiopterin pathway enzymes
  • Structural proteins acting as chaperones
  • The vesicular monoamine transporter 1

Clinical Significance

• Parkinson's Disease: Characterized by decreased TH activity, TH synthesis, and TH mRNA in the striatum 3
• Gene Therapy Approaches: TH is a primary target for gene therapy in Parkinson's disease 3
• α-Synuclein Effects: The main component of Lewy bodies regulates dopamine production through interaction with TH 3

Cooperative Synthesis in Non-Dopaminergic Neurons

Interestingly, some neurons express only one of the two enzymes required for dopamine synthesis:

• "Monoenzymatic" neurons containing either TH or AADC can cooperate to produce dopamine 4
• TH-containing neurons convert tyrosine to L-DOPA, which is released and taken up by AADC-containing neurons to complete dopamine synthesis 4
• This cooperative synthesis serves as an adaptive mechanism to compensate for functional insufficiency of dopaminergic neurons 4

This biochemical pathway is fundamental to understanding neurological disorders involving dopamine dysregulation and developing targeted therapeutic approaches.