An Updated View on the Molecular Pathomechanisms of Human Dihydrolipoamide Dehydrogenase Deficiency in Light of Novel Crystallographic Evidence

Attila Ambrus

doi:10.1007/s11064-019-02766-9

Abstract

Dihydrolipoamide dehydrogenase (LADH, E3) deficiency is a rare (autosomal, recessive) genetic disorder generally presenting with an onset in the neonatal age and early death; the highest carrier rate has been found among Ashkenazi Jews. Acute clinical episodes usually involve severe metabolic decompensation and lactate acidosis that result in neurological, cardiological, and/or hepatological manifestations. Clinical severity is due to the fact that LADH is a common E3 subunit to the alpha-ketoglutarate, pyruvate, alpha-ketoadipate, and branched-chain alpha-keto acid dehydrogenase complexes, and is also a constituent in the glycine cleavage system, thus a loss in LADH function adversely affects multiple key metabolic routes. However, the severe clinical pictures frequently still do not parallel the LADH activity loss, which implies the involvement of auxiliary biochemical mechanisms; enhanced reactive oxygen species generation as well as affinity loss for multienzyme complexes proved to be key auxiliary exacerbating pathomechanisms. This review provides an overview and an up-to-date molecular insight into the pathomechanisms of this disease in light of the structural conclusions drawn from the first crystal structure of a disease-causing hE3 variant determined recently in our laboratory.

Highlights

E3 Deficiency—the Disease, Enzyme, and Affected Multienzyme Complex Functions (Dihydro)lipoamide dehydrogenase (LADH, E3; gene: dld) deficiency is an often prematurely lethal rare autosomal recessive genetic disorder [1]; the highest carrier rate (1:94-1:110, G194C-hE3, h for human) has been found among Ashkenazi Jews with a disease frequency of 1:35,000–1:48,000 [2, 3]
High-resolution crystal structures have very recently been determined in our laboratory for the P453L- (PDB ID: 6I4Z), G194C- (PDB ID: 6I4P), R460G- (PDB IDs: 6I4R and 6HG8), R447G- (PDB ID: 6I4S), I445M- (PDB ID: 6I4T), and G426E-hE3 (PDB ID: 6I4U) disease-causing variants and for hE3 at the hitherto highest 1.75 Å resolution (PDB ID: 6I4Q), the thorough and comparative analysis of these structures is still in progress
This channel is solvent accessible, leads to the active site and it is the continuation of the lipoic acid (LA)-binding substrate channel (Fig. 1); the H+/H2O channel appears to have catalytic roles in LADH function and perhaps Reactive oxygen species (ROS) generation by hE3 [61]

Summary

Introduction

E3 Deficiency—the Disease, Enzyme, and Affected Multienzyme Complex Functions (Dihydro)lipoamide dehydrogenase (LADH, E3; gene: dld) deficiency is an often prematurely lethal rare autosomal recessive genetic disorder [1]; the highest carrier rate (1:94-1:110, G194C-hE3, h for human) has been found among Ashkenazi Jews with a disease frequency of 1:35,000–1:48,000 [2, 3]. Recent results suggest that the missing clues could be (i) enhanced reactive oxygen species (ROS) production by various pathogenic hE3 mutants [20, 23, 24], in acidosis [24], (ii) liberation of selected hE3 variants from the E3-tethering multienzyme complexes [25,26,27,28,29], and (iii) ROS generation by the E1–E2 subcomplex of the hKGDHc (when E3 is scarce) [20], principally in the course of acidosis [30].

Results

Conclusion