Journal of Inherited Metabolic Disease

, Volume 34, Issue 6, pp 1213–1224 | Cite as

Molecular insights into the pathogenicity of variants associated with the aromatic amino acid decarboxylase deficiency

  • Riccardo Montioli
  • Barbara Cellini
  • Carla Borri Voltattorni
Original Article


Dopa decarboxylase (DDC or AADC) is a pyridoxal 5’-phosphate (PLP)-dependent enzyme that catalyzes the decarboxylation of L-aromatic amino acids into the corresponding aromatic amines. AADC deficiency is an inborn error of neurotransmitters biosynthesis with an autosomal recessive inheritance. About 30 pathogenic mutations have been identified, but the enzymatic phenotypes causing AADC deficiency are unknown, and the therapeutic management is challenging. Here, we report biochemical and bioinformatic analyses of the human wild-type DDC and the pathogenic variants G102S, F309L, S147R and A275T whose mutations concern amino acid residues at or near the active site. We found that the mutations cause, even if to different extents, a decreased PLP binding affinity (in the range 1.4-170-fold), an altered state of the bound coenzyme and of its microenvironment, and a reduced catalytic efficiency (in the range 17-930-fold). Moreover, as compared to wild-type, the external aldimines formed by the variants with L-aromatic amino acids exhibit different spectroscopic features, do not protect against limited proteolysis, and lead to the formation, in addition to aromatic amines, of cyclic-substrate adducts. This suggests that these external Schiff bases are not properly oriented and anchored, i.e., in a conformation not completely productive for decarboxylation. The external aldimines that the variants form with D-Dopa also appear not to be correctly located at their active site, as suggested by the rate constants of PLP-L-Dopa adduct production higher than that of the wild-type. The possible therapeutic implications of the data are discussed in the light of the molecular defects of the pathogenic variants.


Melatonin Pathogenic Variant Molecular Defect Carbidopa A275T Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Pyridoxal 5’-phosphate


Dopa decarboxylase




2,4,6-trinitrobenzene-1-sulfonic acid



This work was supported by grants from M.I.U.R. (Prin 2007) to (C.B.V.). The skilful technical assistance of Silvia Bianconi is acknowledged.

Supplementary material

10545_2011_9340_Fig9_ESM.jpg (140 kb)
Figure 1SM

Superimposition of the structure of wild type (gray) and (A) G102S, (B) F309L, (C) S147R and (D) A275T mutants (purple), obtained by an in silico energy minimization analysis. In each case the mutated residue and the PLP molecule are represented as yellow and green sticks respectively. H-bonds as dotted line, phosphorus, oxygen and nitrogen atoms are colored orange, red and blue, respectively. In panel B the residues belonging to the hydrophobic and the polar cavity are represented as blue and red sticks respectively. Picture was created by means Pymol software (DeLano Scientific) (JPEG 139 kb)

10545_2011_9340_MOESM1_ESM.tif (21.4 mb)
High resolution image file (TIFF 21906 kb)


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Copyright information

© SSIEM and Springer 2011

Authors and Affiliations

  • Riccardo Montioli
    • 1
  • Barbara Cellini
    • 1
  • Carla Borri Voltattorni
    • 1
  1. 1.Dipartimento di Scienze della Vita e della Riproduzione, Sezione di Chimica Biologica, Facoltà di Medicina e ChirurgiaUniversità degli Studi di VeronaVeronaItaly

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