| AromaticL-amino acid decarboxylase (DOPA decarboxylase) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
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| Identifiers | |||||||||
| EC no. | 4.1.1.28 | ||||||||
| CAS no. | 9042-64-2 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDBPDBePDBsum | ||||||||
| Gene Ontology | AmiGO /QuickGO | ||||||||
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| DOPA decarboxylase (aromaticL-amino acid decarboxylase) | |||||||
|---|---|---|---|---|---|---|---|
 AromaticL-amino acid decarboxylase homodimer, Human | |||||||
| Identifiers | |||||||
| Symbol | DDC | ||||||
| NCBI gene | 1644 | ||||||
| HGNC | 2719 | ||||||
| OMIM | 107930 | ||||||
| RefSeq | NM_000790 | ||||||
| UniProt | P20711 | ||||||
| Other data | |||||||
| EC number | 4.1.1.28 | ||||||
| Locus | Chr. 7p11 | ||||||
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AromaticL-amino acid decarboxylase (AADC orAAAD), also known asDOPA decarboxylase (DDC),tryptophan decarboxylase, and5-hydroxytryptophan decarboxylase, is alyaseenzyme (EC4.1.1.28), located in region 7p12.2-p12.1.
The enzyme usespyridoxal phosphate (PLP), the active form ofvitamin B6, as acofactor. PLP is essential to the mechanism of decarboxylation in AADC. In the active enzyme, PLP is bound tolysine-303 of AADC as aSchiff base. Upon substrate binding, Lys-303 is displaced by the substrate'samine. This positions thecarboxylate 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 andpH dependence between substrates.DOPA is optimally decarboxylated at pH 6.7 and a PLP concentration of 0.125 mM, while the conditions for optimal5-HTP decarboxylation were found to be pH 8.3 and 0.3 mM PLP.[3]
AromaticL-amino acid decarboxylase is active as ahomodimer. Before addition of thepyridoxal phosphate cofactor, the apoenzyme exists in an open conformation. Upon cofactor binding, a large structural transformation occurs as the subunits pull closer and close the active site. This conformational change results in the active, closed holoenzyeme.[4]
In PLP-deficientmurine 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 possibleisoforms 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]
AADC regulation, especially as it relates toL-DOPA decarboxylation, has been studied extensively. AADC has several conservedprotein kinase A (PKA) andprotein kinase G recognition sites, with residues S220, S336, S359, T320, and S429 all as potential phosphate acceptors.In vitro studies have confirmed PKA and PKG can both phosphorylate AADC, causing a significant increase in activity.[5][6] In addition,dopamine receptor antagonists have been shown to increase AADC activity in rodent models, while activation of somedopamine receptors suppresses AADC activity.[7] Such receptor-mediated regulation is biphasic, with an initial short term activation followed by long term activation. The short term activation is thought to proceed throughkinase activation and subsequent phosphorylation of AADC, while the sensitivity of long term activation to protein translation inhibitors suggests regulation ofmRNA transcription.[8]
AADC catalyzes several differentdecarboxylation reactions:[9]
However, some of these reactions do not seem to bear much or any biological significance. For example, histamine is biosynthesised strictly via the enzymehistidine decarboxylase in humans and other organisms.[10][11]
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In normaldopamine andserotonin (5-HT) neurotransmitter synthesis, AADC is not therate-limiting step in either reaction. However, AADC becomes the rate-limiting step of dopamine synthesis in patients treated withL-DOPA (such as inParkinson's disease), and the rate-limiting step of serotonin synthesis in people treated with5-HTP (such as in milddepression ordysthymia).[citation needed] AADC is inhibited bycarbidopa outside of theblood brain barrier to inhibit the premature conversion ofL-DOPA todopamine in the treatment ofParkinson's.
In humans, AADC is also therate-limiting enzyme in the formation oftrace amines.AromaticL-amino acid decarboxylase deficiency is associated with various symptoms as severe developmental delay,oculogyric crises and autonomic dysfunction. The molecular and clinical spectrum of AAAC deficiency is heterogeneous. The first case of AADC deficiency was described in twin brothers 1990. Patients can be treated withdopamine agonists,MAO inhibitors, andpyridoxine (vitamin B6).[15] Clinical phenotype and response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype–phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercialInternational Working Group on Neurotransmitter Related Disorders (iNTD).[16]
Immunohistochemical studies have revealed that AADC is expressed in variousneuronal cell types such asserotonergic andcatecholaminergic neurons. Neurons that express AADC but are not considered classicalmonoaminergic cell neurons are termed D cells. Cells that areimmunoreactive for AADC have also been found in the humanbrainstem. These cells includemelanin-pigmented cells that are typically designated as catecholaminergic and may also be serotonergic. Significant localization of dopaminergic cells that are also immunoreactive for AADC is reported in thesubstantia nigra,ventral tegmental area, and themesencephalic reticular formation. Unlike previous reports on animal models, nonaminergic (D cells) are unlikely to be observed in the human brain.[17]
Thegene encoding the enzyme is referred to asDDC is located onchromosome 7 in humans.[18] It consists of 15exons encoding a protein of 480amino acids.[19]Single nucleotide polymorphisms and other gene variations have been investigated in relation toneuropsychiatric disorders, for example, a one-base pair deletion at 601 and a four-base pair deletion at 722–725 inexon 1 in relation tobipolar disorder[20] andautism. No direct correlation between gene variation and autism was found.[21]
More than 50 mutations ofDDC have been correlated with AADC deficiency.[22] This condition is most prevalent in Asia, presumably due to thefounder effect.[23]
Alternative splicing events andpromoters 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-neuronalisoform, and splicing of exon 3 leads to a product devoid of enzymatic activity. Analyses viaporcine 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]
