Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy.
Int J Mol Sci. 2021 Mar 19;22(6):3146. doi: 10.3390/ijms22063146.
Aromatic amino acid decarboxylase (AADC) deficiency is a rare, autosomal recessive neurometabolic disorder caused by mutations in the gene, leading to a deficit of AADC, a pyridoxal 5'-phosphate requiring enzyme that catalyzes the decarboxylation of L-Dopa and L-5-hydroxytryptophan in dopamine and serotonin, respectively. Although clinical and genetic studies have given the major contribution to the diagnosis and therapy of AADC deficiency, biochemical investigations have also helped the comprehension of this disorder at a molecular level. Here, we reported the steps leading to the elucidation of the functional and structural features of the enzyme that were useful to identify the different molecular defects caused by the mutations, either in homozygosis or in heterozygosis, associated with AADC deficiency. By revisiting the biochemical data available on the characterization of the pathogenic variants in the purified recombinant form, and interpreting them on the basis of the structure-function relationship of AADC, it was possible: (i) to define the enzymatic phenotype of patients harboring pathogenic mutations and at the same time to propose specific therapeutic managements, and (ii) to identify residues and/or regions of the enzyme relevant for catalysis and/or folding of AADC.
芳香族氨基酸脱羧酶（AADC）缺乏症是一种罕见的常染色体隐性神经代谢疾病，由 基因突变引起，导致 AADC 缺乏，AADC 是一种需要吡哆醛 5'-磷酸的酶，催化 L-多巴和 L-5-羟色氨酸分别脱羧为多巴胺和 5-羟色胺。虽然临床和遗传研究对 AADC 缺乏症的诊断和治疗做出了主要贡献，但生化研究也有助于从分子水平理解这种疾病。在这里，我们报告了阐明酶的功能和结构特征的步骤，这些步骤有助于鉴定由突变引起的不同分子缺陷，无论是纯合子还是杂合子，与 AADC 缺乏症有关。通过重新审视已发表的关于纯化重组形式的致病性变异的生化数据，并根据 AADC 的结构-功能关系对其进行解释，可以：（i）定义携带致病性突变的患者的酶表型，同时提出特定的治疗管理方案，（ii）确定与 AADC 的催化和/或折叠相关的酶的残基和/或区域。
