The complete nucleotide structure of the human DDC gene has been determined from tissues of neural and non-neural origin (Sumi-Ichinose et al., 1992; Ichinose et al., 1992). The full DDC cDNA sequence has been cloned from human cells, such as pheochromocytoma (Ichinose et al., 1989), liver (Ichinose et al., 1992), hepatoma cells (Scherer et al., 1992), placenta (Siaterli et al., 2003), peripheral leukocytes (Kokkinou et al., 2009b), as well as from several human cell lines, such as, U937 macrophage cells (Kokkinou et al., 2009a), SH-SY5Y, HTB-14 and HeLa cells (Chalatsa et al., 2011).

The human DDC gene exists as a single-copy in the haploid genome. It is composed of 15 exons and 14 introns, spanning for more than 85 kbs (Sumi-Ichinose et al., 1992). The size of the exons was found to range from 20 to 406 bps (Sumi-Ichinose et al., 1992), whereas the size of the introns ranged from 927 to 24077 bps (Sumi-Ichinose et al., 1992; Yu et al., 2006). The DDC gene is located in close proximity to the epidermal growth factor (EGF) gene (Craig et al., 1992).

Alternative splicing events are responsible for the production of two distinct DDC mRNAs, termed neural and non-neural, which differ in their 5 untranslated region (UTR). The neural-type transcript includes exon N1 (83 bps) that is located 17.8 kbs upstream of exon two. The non-neural type DDC mRNA bears exon L1 (200 bps), which is located 4.2 kbs upstream to the location of exon N1. The second exon contains the translation start site and is located 22 kbs downstream from the non-neural (L1) exon (Ichinose et al., 1992). The transcription of the gene starts at position -111 (Sumi-Ichinose et al., 1992).
It has been reported that the two alternative DDC transcripts share identical coding regions and that their production is a result of alternative splicing and alternative promoter usage (Ichinose et al., 1992; Sumi-Ichinose et al., 1995). Neural and non-neural promoters have been identified 5 to the flanking region of the respective exon 1 (Le Van Thai et al., 1993; Sumi-Ichinose et al., 1995; Chatelin et al., 2001; Dugast-Darzacq et al., 2004). The generation of the two alternative DDC mRNAs is not a mutually exclusive and tissue-specific event as previously thought (Siaterli et al., 2003; Vassilacopoulou et al., 2004; Kokkinou et al., 2009a; Kokkinou et al., 2009b; Chalatsa et al., 2011).
An alternative splicing event has been described within the coding region of DDC mRNA, leading to the formation of a shorter transcript lacking exon 3 (OMalley et al., 1995; Chang et al., 1996). It must be noted that the above authors did not specify the nature, neural or non-neural, of this shorter transcript. Recent evidence have revealed the neural nature of this alternative transcript in humans (Kokkinou et al., 2009a; Kokkinou et al., 2009b; Chalatsa et al., 2011).
A novel DDC mRNA coding region splice-variant, resulting in the formation of a truncated DDC mRNA has been also identified. This human DDC mRNA (1.8 kbs), termed as Alt-DDC, lacks exons 10-15 of the full-length transcript, but includes an alternative exon 10 (Vassilacopoulou et al., 2004). The Alt-DDC exon 10 (358 bps) was found within intron 9 of the DDC gene. Although Alt-DDC mRNA was detected in human placenta, high expression levels of this alternative transcript were found in human kidney (Vassilacopoulou et al., 2004).
The notion that transcription of the human DDC gene leads to the production of multiple mRNA isoforms, which are expressed in a non-mutually exclusive and tissue-specific manner, underlines the complexity of the expression patterns of this gene (table 1).

None has been identified yet.

Although, it was initially suggested that the DDC gene encoded for a single protein product (Sumi-Ichinose et al., 1992), evidence that demonstrated the expression of additional DDC protein isoforms in humans, argue against it (OMalley et al., 1995; Chang et al., 1996; Vassilacopoulou et al., 2004).

The DDC enzyme (EC 4.1.1.28) was initially purified and characterized from pig kidney (Christenson et al., 1970) as well as from the insects Calliphora vicina (Fragoulis and Sekeris, 1975) and Ceratitis capitata (Mappouras and Fragoulis, 1988; Bossinakou and Fragoulis, 1996). DDC is a homodimer of 100-110 kDa, with a subunit molecular mass of 50-55 kDa (Voltattorni et al., 1979; Mappouras et al., 1990; Bossinakou and Fragoulis, 1996). The full-length protein molecule consists of 480 amino acids (Ichinose et al., 1989). DDC is a pyridoxal-5-phosphate (PLP)-dependent enzyme possessing a single binding-site for PLP per subunit (Voltattorni et al., 1982; Ichinose et al., 1989; Burkhard et al., 2001).
Expression of the DDC gene, in humans, results in the production of additional protein isoforms (OMalley et al., 1995; Chang et al., 1996; Vassilacopoulou et al., 2004). OMalley et al. (1995) identified of a new DDC protein isoform (OMalley et al., 1995). The truncated DDC protein isoform (Mr; 50 kDa) consists of 442 amino acid residues (DDC442). This isoform was found to be inactive towards the decarboxylation of both L-Dopa to Dopamine and 5-Hydroxytryptophan (5-HTP) to serotonin (OMalley et al., 1995). As mentioned above, the translation of Alt-DDC mRNA resulted in the synthesis of a truncated 338 amino acid long polypeptide, termed as Alt-DDC (Mr; 37 kDa). This isoform was identical to the full-length DDC protein up to amino acid residue 315. The remaining 23 amino acids of the C-terminal sequence are encoded by the alternative DDC exon 10 and are not incorporated in the full-length DDC protein sequence (Vassilacopoulou et al., 2004).
Although previous data had suggested that DDC was a rather unregulated molecule, several findings have indicated that DDC activity can be modulated by many factors, such as D1, DA receptor antagonists (Rossetti et al., 1990), a2-adrenergic receptor antagonists (Rossetti et al., 1989), D1, D2 receptor antagonists (Zhu et al., 1992; Hadjiconstantinou et al., 1993), DA receptor agonists (Zhu et al., 1993), PK-A and PK-C mediated pathways (Young et al., 1993; Young et al., 1994) and by endogenous inhibitors isolated from human serum (Vassiliou et al., 2005) and placenta (Vassiliou et al., 2009).

DDC has been detected throughout the length of the gastrointestinal tract (Eisenhofer et al., 1997) and in blood plasma (Boomsma et al., 1986). DDC is expressed in normal human kidney and placenta (Mappouras et al., 1990; Siaterli et al., 2003). DDC expression was observed in normal peripheral leukocytes and T-lymphocytes (Kokkinou et al., 2009b). Furthermore, DDC is expressed in the human cancer cell lines U937 (Kokkinou et al., 2009a), SH-SY5Y, HeLa and HTB-14 (Chalatsa et al., 2011). Interestingly, the expression of the alternative DDC isoform (Alt-DDC) was also demonstrated in peripheral leukocytes (Kokkinou et al., 2009b), U937 (Kokkinou et al., 2009a), SH-SY5Y and HeLa cell lines (Chalatsa et al., 2011).
In the central nervous system, increased DDC enzymatic activity is detected in the hypothalamus, epiphysis, striatum, locus ceruleus, olfactory bulb and retina (Park et al., 1986). Elevated enzymatic DDC activity is also detected in peripheral organs such as liver, pancreas, kidney, lungs, spleen, stomach, salivary glands, as well as in the endothelial cells of blood vessels (Lovenberg et al., 1962; Rahman et al., 1981; Lindström and Sehlin, 1983).

DDC was considered to be a cytosolic molecule (Lovenberg et al., 1962; Sims et al., 1973). Nevertheless, additional experimental findings have demonstrated that a population of enzymatically active DDC molecules is associated with the cellular membrane fraction in the mammalian CNS (Poulikakos et al., 2001). Membrane-associated, enzymatically active DDC subpopulations were detected in the highly hydrophobic fractions of normal human leukocytes and U937 cancer cells (Kokkinou et al., 2009a; Kokkinou et al., 2009b).

In terms of substrate specificity, the DDC molecule purified from insects demonstrated a remarkably high affinity towards the decarboxylation of L-Dopa to dopamine (Fragoulis and Sekeris, 1975; Mappouras and Fragoulis, 1988; Bossinakou and Fragoulis, 1996). However, work by Mappouras et al. (1990) in the normal human kidney has suggested that the enzyme is capable of also decarboxylating L-5-Hydroxytryptophan to serotonin, although the decarboxylation activity towards L-5-Hydroxytryptophan was found to be considerably lower than the one observed for L-Dopa (Mappouras et al., 1990). Since DDC expression results in the production of multiple protein isoforms, it is conceivable that these different protein molecules could be responsible for the decarboxylation of other aromatic L-amino acids.

Comparison of the amino acid sequence of DDC from different species, suggested that the enzyme is an evolutionarily conserved molecule. The amino acid sequence around the coenzyme binding lysine is also evolutionarily conserved (Bossa et al., 1977; Ichinose et al., 1989). The conserved amino acids are residues 267-317, which surround the PLP-binding site (Ichinose et al., 1989), as well as, the extended regions of amino acids 64-155 and 182-204, which according to Maras et al. (1991) are important for the enzymes catalytic function (Maras et al., 1991). Table 2 shows the percentage of human DDC amino acid identity to other species (Maras et al., 1991; Mantzouridis et al., 1997).

Such mutations have not been identified so far.

Aromatic L-amino acid decarboxylase (AADC) deficiency, a rare autosomaly-recessive inherited defect, is associated with mutations of the DDC gene. This disorder leads to profound modifications in the homeostasis of central and peripheral nervous system (Hyland et al., 1992). In their majority, such mutations are missense and are listed above (table 3). Other mutations of the human DDC gene that are related to AADC-deficiency are also included (Fiumara et al., 2002; Chang et al., 2004; Pons et al., 2004; Tay et al., 2007; Lee et al., 2009).