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

Authors
  • Korasick, David A1
  • Tanner, John J2
  • 1 Department of Biochemistry, University of Missouri, Columbia, MO, 65211, United States. , (United States)
  • 2 Department of Biochemistry, University of Missouri, Columbia, MO, 65211, United States; Department of Chemistry, University of Missouri, Columbia, MO, 65211, United States. Electronic address: [email protected] , (United States)
Type
Published Article
Journal
Biochimie
Publication Date
Apr 01, 2021
Volume
183
Pages
49–54
Identifiers
DOI: 10.1016/j.biochi.2020.09.016
PMID: 32956737
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

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