TY  - JOUR
AU  - Szabó, Eszter
AU  - Wilk, Piotr
AU  - Nagy, Bálint
AU  - Zámbó, Zsófia Melinda
AU  - Bui, Dávid
AU  - Weichsel, Andrzej
AU  - Arjunan, Palaniappa
AU  - Törőcsik, Beáta
AU  - Hubert, Agnes
AU  - Furey, William
AU  - Montfort, William R
AU  - Jordan, Frank
AU  - Weiss, Manfred S
AU  - Ádám, Veronika
AU  - Ambrus, Attila
TI  - Underlying molecular alterations in human dihydrolipoamide dehydrogenase deficiency revealed by structural analyses of disease-causing enzyme variants
JF  - HUMAN MOLECULAR GENETICS
J2  - HUM MOL GENET
VL  - 28
PY  - 2019
IS  - 20
SP  - 3339
EP  - 3354
PG  - 16
SN  - 0964-6906
DO  - 10.1093/hmg/ddz177
UR  - https://m2.mtmt.hu/api/publication/30799456
ID  - 30799456
AB  - Human dihydrolipoamide dehydrogenase (hLADH, hE3) deficiency (OMIM# 246900) is an often prematurely lethal genetic disease usually caused by inactive or partially inactive hE3 variants. Here we report the crystal structure of wild-type hE3 at an unprecedented high resolution of 1.75 Å and the structures of six disease-causing hE3 variants at resolutions ranging from 1.44 to 2.34 Å. P453L proved to be the most deleterious substitution in structure as aberrations extensively compromised the active site. The most prevalent G194C-hE3 variant primarily exhibited structural alterations close to the substitution site, whereas the nearby cofactor-binding residues were left unperturbed. The G426E substitution mainly interfered with the local charge distribution introducing dynamics to the substitution site in the dimer interface; G194C and G426E both led to minor structural changes. The R460G, R447G, and I445M substitutions all perturbed a solvent accessible channel, the so-called H+/H2O channel, leading to the active site. Molecular pathomechanisms of enhanced reactive oxygen species (ROS) generation and impaired binding to multienzyme complexes were also addressed according to the structural data for the relevant mutations. In summary, we present here for the first time a comprehensive study that links three-dimensional structures of disease-causing hE3 variants to residual hLADH activities, altered capacities for ROS generation, compromised affinities for multienzyme complexes, and eventually clinical symptoms. Our results may serve as useful starting points for future therapeutic intervention approaches.
LA  - English
DB  - MTMT
ER  - 

TY  - JOUR
AU  - Sümegi, Balázs
AU  - Liposits, Zsolt
AU  - Inman, L
AU  - Paull, W K
AU  - Srere, P A
TI  - Electronmicroscopic study on the size of pyruvate dehydrogenase complex in situ
JF  - EUROPEAN JOURNAL OF BIOCHEMISTRY
J2  - EUR J BIOCHEM
VL  - 169
PY  - 1987
SP  - 223
EP  - 230
PG  - 8
SN  - 0014-2956
DO  - 10.1111/j.1432-1033.1987.tb13601.x
UR  - https://m2.mtmt.hu/api/publication/1060977
ID  - 1060977
N1  - Export Date: 27 January 2024
LA  - English
DB  - MTMT
ER  -