DDC

Official Full Name

dopa decarboxylase

Organism

Homo sapiens

GeneID

1644

Background

The encoded protein catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine. Defects in this gene are the cause of aromatic L-amino-acid decarboxylase deficiency (AADCD). AADCD deficiency is an inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2011]

Synonyms

AADC;

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Detailed Information

Dopa decarboxylase (DDC) is a critical enzyme involved in the metabolism of neurotransmitters, particularly dopamine and serotonin.

Gene Structure and expression of DDC

DDC belongs to the a-family of aminotransferases (Fold-TypeI), in particular to the subgroup II of a-decarboxylases to which also glutamate decarboxylase and histidine decarboxylase belong. Their chemistry and reaction mechanism bases on the chemical features of the coenzyme: pyridoxal 50 -phosphate(PLP). Moreover, they share common features, such as similar active site architectures and conserved essential amino acidic residues. The resolution of the structure of histidine decarboxylase in the presence of the inhibitor histidine methyl ester revealed an active site conformation similar to that of DDC in the complex with carbi Dopa except for one residue, i.e. Ser-354, of histidine decarboxylase replaced by glycine in the same position in DDC. Interestingly, the S354G variant of histidine decarboxylase presents a decreased activity towards histidine and an increased activity towards L -Dopa. In addition, both decarboxylases possess a mobile loop considered essential for catalysis containing a tyrosine residue (Tyr-332 in DDC and Tyr-334 in histidine decarboxylase) playing a critical role in catalytic activity. DDC is widespread in mammals, insects and plants. In mammals, the enzyme is found in neuronal and non-neuronal tissues. While its presence in neuronal cells is in line with its activity in neuromodulators synthesis, it is more difficult to explain its abundance in other tissues, for example the kidney, where the enzyme is highly expressed. Finally, in plants there exist two forms of substrate-specific DDC: a tyrosine decarboxylase

Regulation of DDC

Dopa decarboxylase, an enzyme involved in the synthesis of the neurotransmitter dopamine, catalyses the formation of functional dopamine through decarboxylation of a precursor tyrosine derivative. In addition, it participates in the synthesis of trace amine compounds suggested to act as modulators of central neurotransmission. The dopa decarboxylase gene (dopa gene) maps to chromosome 7p12.1–p12.3 and contains 15 exons spanning over 85 kb. The DDC and ADHD in Irish population expression of the gene is controlled by two promoters located between positions −106 and −38 relative to the transcription initiation site. Expression in nerve and glial cells requires a CNS specific activator located between nucleotides −59 and −83 which bind to the transcription factor Elf1 in a tissue-specific manner. Mutations in the coding or promoter regions of this gene could alter either the function or the quantity of the enzyme and therefore lead to the production of abnormal levels of dopamine. Thus, the dopa decarboxylase gene may be considered as a candidate gene for ADHD susceptibility.

Figure 1. Schematic representation of the proposed mechanism concerning the relationship between viral infection, DDC, and PI3K/AKT pathway.

References:

Bredberg, J., & Lindström, L. (2019). The role of Dopa decarboxylase in Parkinson's disease. Journal of Parkinson's Disease, 9(2), 203-215.
Bertoldi M. Mammalian Dopa decarboxylase: structure, catalytic activity and inhibition. Arch Biochem Biophys. 2014;546:1-7. doi:10.1016/j.abb.2013.12.020
Hawi Z, Foley D, Kirley A, McCarron M, Fitzgerald M, Gill M. Dopa decarboxylase gene polymorphisms and attention deficit hyperactivity disorder (ADHD): no evidence for association in the Irish population. Mol Psychiatry. 2001;6(4):420-424. doi:10.1038/sj.mp.4000903

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