Aromatic Amino Acid Decarboxylase Deficiency: The Added Value of Biochemistry

Abstract

Aromatic amino acid decarboxylase (AADC) deficiency is a rare, autosomal recessive neurometabolic disorder caused by mutations in the DDC 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.

Keywords: AADC deficiency; aromatic amino acid decarboxylase; dopa decarboxylase; pathogenic variants; pyridoxal 5′-phophate; rare disease.

Figure 1

Main physiological reactions of Dopa decarboxylase (DDC). Decarboxylation of L-Dopa and L-5-HTP catalyzed by DDC.

Figure 2

Pictet–Spengler reaction of pyridoxal 5′-phosphate (PLP). Scheme of the condensation reaction between PLP and L-Dopa generating the Pictet–Spengler adduct.

Figure 3

DDC structural features and active site architecture. (A) Ribbons represent the DDC monomeric and dimeric units. The N-terminal, large, and C-terminal domains are colored in blue, gray, and magenta, respectively. (B) Active site of unliganded holo-DDC or (C) in complex with the inhibitor carbidopa. PLP molecules are represented as green sticks, the PLP binding residues are represented as cyan sticks. The residues in the proper position to interact with the carbidopa catechol ring are highlighted. Image was rendered by PyMol software (Schrödinger).

Figure 4

Structural regions involved in the apo-to-holo transition of DDC. Global conformational change accompanying the transition from the apo to the holo form of DDC. The N-terminal, large, and C-terminal domains are colored blue, gray, and magenta, respectively. The two monomers are distinguished by dark and light colors. The PLP molecules are represented as green sticks and loops 1, 2, and 3 are highlighted in yellow, orange, and cyan, respectively. Image was rendered by PyMol software (Schrödinger).