Aromatic L-amino acid decarboxylase
Aromatic L amino acid decarboxylase (DOPA decarboxylase) | |||||||||
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KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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DOPA decarboxylase (aromatic L-amino acid decarboxylase) | |||||||
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Chr. 7 p11 | |||||||
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Aromatic L-amino acid decarboxylase (AADC or AAAD), also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme (EC 4.1.1.28), located in region 7p12.2-p12.1.
Mechanism
The enzyme uses pyridoxal phosphate (PLP), the active form of vitamin B6, as a cofactor. PLP is essential to the mechanism of decarboxylation in AADC. In the active enzyme, PLP is bound to lysine-303 of AADC as a Schiff base. Upon substrate binding, Lys-303 is displaced by the substrate's amine. This positions the carboxylate of the substrate within the active site such that decarboxylation is favored. Decarboxylation of the substrate produces a quinonoid intermediate, which is subsequently protonated to produce a Schiff base adduct of PLP and the decarboxylated product. Lys-303 can then regenerate the original Schiff base, releasing the product while retaining PLP.[2]
Probing this PLP-catalyzed decarboxylation, it has been discovered that there is a difference in concentration and pH dependence between substrates. DOPA is optimally decarboxylated at pH 6.7 and a PLP concentration of 0.125 mM, while the conditions for optimal 5-HTP decarboxylation were found to be pH 8.3 and 0.3 mM PLP.[3]
Structure
Aromatic L-amino acid decarboxylase is active as a
In PLP-deficient murine models, it has been observed that dopamine levels do not significantly deviate from PLP-supplemented specimens; however, the concentration of serotonin in the deficient brain model was significant. This variable effect of PLP-deficiency indicates possible isoforms of AADC with differential substrate specificity for DOPA and 5-HTP. Dialysis studies also suggest that the potential isoform responsible for DOPA decarboxylation has a greater binding affinity for PLP than that of 5-HTP decarboxylase.[3]
Regulation
AADC regulation, especially as it relates to L-DOPA decarboxylation, has been studied extensively. AADC has several conserved
Reactions
AADC catalyzes several different decarboxylation reactions:[9]
- L-DOPA to dopamine – a neurotransmitter
- neuromodulator
- L-Tyrosine to tyramine– a trace amine neuromodulator
- L-Histidine to histamine– a neurotransmitter
- L-Tryptophan to tryptamine– a trace amine neuromodulator
- 5-HTP to serotonin(5-hydroxytryptamine) – a neurotransmitter
However, some of these reactions do not seem to bear much or any biological significance. For example, histamine is biosynthesised strictly via the enzyme histidine decarboxylase in humans and other organisms.[10][11]
Clinical relevance
In normal
In humans, AADC is also the
Genetics
The
More than 50 mutations of DDC have been correlated with AADC deficiency[22] This condition is most prevalent in Asia, presumably due to the founder effect.[23]
Alternative splicing events and promoters have been observed that lead to various forms of the AADC enzyme. Unique usage of certain promoters leads to transcription of only the first exon to produce an extra-neuronal isoform, and splicing of exon 3 leads to a product devoid of enzymatic activity. Analyses via porcine specimens have elucidated two AADC isoforms – resulting from exclusion of exon 5 and exons 5 and 6 – that lack a portion of the decarboxylating domain.[19]
See also
- Aromatic L-amino acid decarboxylase inhibitor, a class of anti-Parkinson drugs
- Aromatic amino acids
- Histidine decarboxylase
References
- S2CID 19160912.
- PMID 24407024.
- ^ S2CID 22286973.
- PMID 22143761.
- S2CID 19636477.
- S2CID 205622115.
- PMID 19040557.
- S2CID 19823573.
- ^ "AADC". Human Metabolome database. Retrieved 17 February 2015.
- PMID 29973935.
- ISBN 9780470015902.
- PMID 19948186.
- PMID 15860375.
- PMID 24374199.
- S2CID 12374358.
- ^ "Patient registry".
- S2CID 20759513.
- S2CID 37950853.
- ^ S2CID 8292103.
- PMID 10578236.
- PMID 11992572.
- PMID 28100251.
- PMID 18567514.
External links
- Aromatic-L-Amino-Acid+Decarboxylases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)