Crystal structures of the disease-causing D444V mutant and the relevant wild type human dihydrolipoamide dehydrogenase

Eszter Szabo, Reka Mizsei, Piotr Wilk, Zsofia Zambo, B. Törőcsik, Manfred S. Weiss, V. Ádám-Vizi, A. Ambrus

Research output: Article

1 Citation (Scopus)

Abstract

We report the crystal structures of the human (dihydro)lipoamide dehydrogenase (hLADH, hE3) and its disease-causing homodimer interface mutant D444V-hE3 at 2.27 and 1.84 Å resolution, respectively. The wild type structure is a unique uncomplexed, unliganded hE3 structure with the true canonical sequence. Based on the structural information a novel molecular pathomechanism is proposed for the impaired catalytic activity and enhanced capacity for reactive oxygen species generation of the pathogenic mutant. The mechanistic model involves a previously much ignored solvent accessible channel leading to the active site that might be perturbed also by other disease-causing homodimer interface substitutions of this enzyme.

Original languageEnglish
Pages (from-to)214-220
Number of pages7
JournalFree Radical Biology and Medicine
Volume124
DOIs
Publication statusPublished - aug. 20 2018

Fingerprint

Dihydrolipoamide Dehydrogenase
Crystal structure
Reactive Oxygen Species
Catalyst activity
Catalytic Domain
Substitution reactions
Enzymes

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Crystal structures of the disease-causing D444V mutant and the relevant wild type human dihydrolipoamide dehydrogenase. / Szabo, Eszter; Mizsei, Reka; Wilk, Piotr; Zambo, Zsofia; Törőcsik, B.; Weiss, Manfred S.; Ádám-Vizi, V.; Ambrus, A.

In: Free Radical Biology and Medicine, Vol. 124, 20.08.2018, p. 214-220.

Research output: Article

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AU - Szabo, Eszter

AU - Mizsei, Reka

AU - Wilk, Piotr

AU - Zambo, Zsofia

AU - Törőcsik, B.

AU - Weiss, Manfred S.

AU - Ádám-Vizi, V.

AU - Ambrus, A.

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AB - We report the crystal structures of the human (dihydro)lipoamide dehydrogenase (hLADH, hE3) and its disease-causing homodimer interface mutant D444V-hE3 at 2.27 and 1.84 Å resolution, respectively. The wild type structure is a unique uncomplexed, unliganded hE3 structure with the true canonical sequence. Based on the structural information a novel molecular pathomechanism is proposed for the impaired catalytic activity and enhanced capacity for reactive oxygen species generation of the pathogenic mutant. The mechanistic model involves a previously much ignored solvent accessible channel leading to the active site that might be perturbed also by other disease-causing homodimer interface substitutions of this enzyme.

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