AADC deficiency is a rare genetic disease caused by mutations in the gene of aromatic amino acid decarboxylase, the pyridoxal 5′-phosphate dependent enzyme responsible for the synthesis of dopamine and serotonin. Here, following a biochemical approach together with an in silico bioinformatic analysis, we present a structural and functional characterization of 13 new variants of AADC. The amino acid substitutions are spread over the entire protein from the N-terminal (V60A), to its loop1 (H70Y and F77L), to the large domain (G96R) and its various motifs, i.e. loop2 (A110E), or a core β-barrel either on the surface (P210L, F251S and E283A) or in a more hydrophobic milieu (L222P, F237S and W267R) or loop3 (L353P), and to the C-terminal domain (R453C). Results show that the β-barrel variants exhibit a low solubility and those belonging to the surface tend to aggregate in their apo form, leading to the identification of a new enzymatic phenotype for AADC deficiency. Moreover, five variants of residues belonging to the large interface of AADC (V60A, G96R, A110E, L353P and R453C) are characterized by a decreased catalytic efficiency. The remaining ones (H70Y and F77L) present features typical of apo-to-holo impaired transition. Thus, defects in catalysis or in the acquirement of the correct holo structure are due not only to specific local domain effects but also to long-range effects at either the protein surface or the subunit interface. Altogether, the new characterized enzymatic phenotypes represent a further step in the elucidation of the molecular basis for the disease.

AADC缺乏症是一种罕见的遗传疾病，是由芳香族氨基酸脱羧酶（一种负责多巴胺和5-羟色胺合成的吡ido醛5'-磷酸依赖性酶）基因突变引起的。在这里，根据生物化学方法和计算机生物信息学分析，我们提出了13个AADC新变体的结构和功能表征。氨基酸取代分布在整个蛋白质上，从N端（V60A）到其loop1（H70Y和F77L），大域（G96R）及其各种基序，即loop2（A110E）或核心β -桶在表面（P210L，F251S和E283A）或更疏水的环境中（L222P，F237S和W267R）或loop3（L353P），以及C端结构域（R453C）。结果表明，β-桶形变体显示出低溶解度，并且那些属于表面的变体倾向于以其载脂蛋白形式聚集，从而导致了针对AADC缺乏症的新酶表型的鉴定。此外，属于AADC大界面的五个残基变体（V60A，G96R，A110E，L353P和R453C）的特征是催化效率降低。其余的（H70Y和F77L）具有典型的从载脂蛋白到全氧的过渡受损的特征。因此，催化或获得正确的完整结构的缺陷不仅是由于特定的局部结构域效应，而且还由于蛋白质表面或亚基界面处的远距离效应。共，