PMID- 29594200
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200930
IS  - 2405-5808 (Electronic)
IS  - 2405-5808 (Linking)
VI  - 2
DP  - 2015 Jul
TI  - Structural alterations by five disease-causing mutations in the low-pH 
      conformation of human dihydrolipoamide dehydrogenase (hLADH) analyzed by 
      molecular dynamics - Implications in functional loss and modulation of reactive 
      oxygen species generation by pathogenic hLADH forms.
PG  - 50-56
LID - 10.1016/j.bbrep.2015.04.006 [doi]
AB  - Human dihydrolipoamide dehydrogenase (hLADH) is a flavoenzyme component (E3) of 
      the human alpha-ketoglutarate dehydrogenase complex (alpha-KGDHc) and few other 
      dehydrogenase complexes. Pathogenic mutations of hLADH cause severe metabolic 
      diseases (atypical forms of E3 deficiency) that often escalate to cardiological 
      or neurological presentations and even premature death; the pathologies are 
      generally accompanied by lactic acidosis. hLADH presents a distinct conformation 
      under acidosis (pH 5.5-6.8) with lower physiological activity and the capacity of 
      generating reactive oxygen species (ROS). It has been shown by our laboratory 
      that selected pathogenic mutations, besides lowering the physiological activity 
      of hLADH, significantly stimulate ROS generation by hLADH, especially at lower 
      pH, which might play a role in the pathogenesis of E3-deficiency in respective 
      cases. Previously, we generated by molecular dynamics (MD) simulation the low-pH 
      hLADH structure and analyzed the structural changes induced in this structure by 
      eight of the pathogenic mutations of hLADH. In the absence of high resolution 
      mutant structures these pieces of information are crucial for the mechanistic 
      investigation of the molecular pathogeneses of the hLADH protein. In the present 
      work we analyzed by molecular dynamics simulation the structural changes induced 
      in the low-pH conformation of hLADH by five pathogenic mutations of hLADH; the 
      structures of these disease-causing mutants of hLADH have never been examined 
      before.
FAU - Ambrus, Attila
AU  - Ambrus A
AD  - Department of Medical Biochemistry, MTA-SE Laboratory for Neurobiochemistry, 
      Semmelweis University, 37-47 Tuzolto Street, Budapest 1094, Hungary.
FAU - Mizsei, Reka
AU  - Mizsei R
AD  - Department of Medical Biochemistry, MTA-SE Laboratory for Neurobiochemistry, 
      Semmelweis University, 37-47 Tuzolto Street, Budapest 1094, Hungary.
FAU - Adam-Vizi, Vera
AU  - Adam-Vizi V
AD  - Department of Medical Biochemistry, MTA-SE Laboratory for Neurobiochemistry, 
      Semmelweis University, 37-47 Tuzolto Street, Budapest 1094, Hungary.
LA  - eng
PT  - Journal Article
DEP - 20150507
PL  - Netherlands
TA  - Biochem Biophys Rep
JT  - Biochemistry and biophysics reports
JID - 101660999
PMC - PMC5871931
OTO - NOTNLM
OT  - FAD, flavin adenine dinucleotide
OT  - LADH, (dihydro)lipoamide dehydrogenase
OT  - Lipoamide dehydrogenase
OT  - MD, molecular dynamics
OT  - Molecular dynamics
OT  - Mutation
OT  - NAD+/NADH, nicotinamide adenine dinucleotide (oxidized/reduced)
OT  - PDHc, pyruvate dehydrogenase complex
OT  - RMSD, root mean square deviation
OT  - ROS, reactive oxygen species
OT  - Reactive oxygen species
OT  - S.E.M., standard error of the mean
OT  - WT, wild-type
OT  - alpha-KGDHc, alpha-ketoglutarate dehydrogenase complex
EDAT- 2015/05/07 00:00
MHDA- 2015/05/07 00:01
PMCR- 2015/05/07
CRDT- 2018/03/30 06:00
PHST- 2015/02/11 00:00 [received]
PHST- 2015/04/25 00:00 [revised]
PHST- 2015/04/27 00:00 [accepted]
PHST- 2018/03/30 06:00 [entrez]
PHST- 2015/05/07 00:00 [pubmed]
PHST- 2015/05/07 00:01 [medline]
PHST- 2015/05/07 00:00 [pmc-release]
AID - S2405-5808(15)00019-9 [pii]
AID - 10.1016/j.bbrep.2015.04.006 [doi]
PST - epublish
SO  - Biochem Biophys Rep. 2015 May 7;2:50-56. doi: 10.1016/j.bbrep.2015.04.006. 
      eCollection 2015 Jul.