Impact of missense mutations in the ALDH7A1 gene on enzyme structure and catalytic function

Abstract

Certain mutations in the ALDH7A1 gene cause pyridoxine-dependent epilepsy (PDE), an autosomal recessive metabolic disease characterized by seizures, and in some cases, intellectual disability. The mutational spectrum of PDE is vast and includes over 70 missense mutations. This review summarizes the current state of biochemical and biophysical research on the impact of PDE missense mutations on the structure and catalytic activity of ALDH7A1. Paradoxically, some mutations that target active site residues have a relatively modest impact on structure and function, while those remote from the active site can have profound effects. For example, missense mutations targeting remote residues in oligomer interfaces tend to strongly impact catalytic function by inhibiting formation of the active tetramer. These results shows that it remains very difficult to predict the impact of missense mutations, even when the structure of the wild-type enzyme is known. Additional biophysical analyses of many more disease-causing mutations are needed to develop the rules for predicting the impact of genetic mutations on enzyme structure and catalytic function.

Keywords: ALDH7A1; Aldehyde dehydrogenase; Inherited metabolic disease; Missense mutations; Protein oligomerization; Pyridoxine-dependent epilepsy.

Fig. 1.

Reactions and protein fold of ALDH7A1. (A) The reaction catalyzed by ALDH7A1 (top) and the reaction of P6C with PLP (bottom). (B) The fold of ALDH7A1, with the domains colored red (NAD⁺-binding), blue (catalytic), and green (oligomerization). NAD⁺ and AA are shown in magenta and cyan sticks, respectively. The gray spheres mark the residues affected by pathogenic missense mutations (Table 1). (C) Missense mutations affecting active site residues mapped onto the protein structure (gold spheres).

Fig. 2.

Pathogenic missense mutations affecting residues in the oligomeric interfaces of ALDH7A1. (A) The fold of ALDH7A1, with the domains colored red (NAD⁺-binding), blue (catalytic), and green (oligomerization). NAD⁺ and AA are shown in magenta and cyan sticks, respectively. The pink spheres indicate residues in the dimer interface targeted by pathogenic missense mutations. (B) Two views of the ALDH7A1 dimer. The red spheres indicate dimer interface residues that are targeted by pathogenic missense mutations. (C) The purple spheres indicate residues in the tetramer interface that are targeted by pathogenic missense mutations. (D) Tetramer of ALDH7A1. The red spheres indicate tetramer interface residues that are targeted by pathogenic missense mutations.