PMID- 30187773
OWN - NLM
STAT- MEDLINE
DCOM- 20200702
LR  - 20200702
IS  - 1557-7716 (Electronic)
IS  - 1523-0864 (Linking)
VI  - 30
IP  - 16
DP  - 2019 Jun 1
TI  - Redox-Driven Signaling: 2-Oxo Acid Dehydrogenase Complexes as Sensors and 
      Transmitters of Metabolic Imbalance.
PG  - 1911-1947
LID - 10.1089/ars.2017.7311 [doi]
AB  - SIGNIFICANCE: This article develops a holistic view on production of reactive 
      oxygen species (ROS) by 2-oxo acid dehydrogenase complexes. Recent Advances: 
      Catalytic and structural properties of the complexes and their components evolved 
      to minimize damaging effects of side reactions, including ROS generation, 
      simultaneously exploiting the reactions for homeostatic signaling. CRITICAL 
      ISSUES: Side reactions of the complexes, characterized in vitro, are analyzed in 
      view of protein interactions and conditions in vivo. Quantitative data support 
      prevalence of the forward 2-oxo acid oxidation over the backward NADH oxidation 
      in feeding physiologically significant ROS production by the complexes. Special 
      focus on interactions between the active sites within 2-oxo acid dehydrogenase 
      complexes highlights the central relevance of the complex-bound thiyl radicals in 
      regulation of and signaling by complex-generated ROS. The thiyl radicals arise 
      when dihydrolipoyl residues of the complexes regenerate FADH(2) from the flavin 
      semiquinone coproduced with superoxide anion radical in 1e(-) oxidation of 
      FADH(2) by molecular oxygen. FUTURE DIRECTIONS: Interaction of 2-oxo acid 
      dehydrogenase complexes with thioredoxins (TRXs), peroxiredoxins, and 
      glutaredoxins mediates scavenging of the thiyl radicals and ROS generated by the 
      complexes, underlying signaling of disproportional availability of 2-oxo acids, 
      CoA, and NAD(+) in key metabolic branch points through thiol/disulfide exchange 
      and medically important hypoxia-inducible factor, mammalian target of rapamycin 
      (mTOR), poly (ADP-ribose) polymerase, and sirtuins. High reactivity of the 
      coproduced ROS and thiyl radicals to iron/sulfur clusters and nitric oxide, 
      peroxynitrite reductase activity of peroxiredoxins and transnitrosylating 
      function of thioredoxin, implicate the side reactions of 2-oxo acid dehydrogenase 
      complexes in nitric oxide-dependent signaling and damage.
FAU - Bunik, Victoria I
AU  - Bunik VI
AD  - 1 Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State 
      University, Moscow, Russian Federation.
AD  - 2 Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State 
      University, Moscow, Russian Federation.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20181018
PL  - United States
TA  - Antioxid Redox Signal
JT  - Antioxidants & redox signaling
JID - 100888899
RN  - 0 (Keto Acids)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Reactive Nitrogen Species)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (TXN protein, human)
RN  - 52500-60-4 (Thioredoxins)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - EC 1.8.4.2 (Protein Disulfide Reductase (Glutathione))
RN  - S88TT14065 (Oxygen)
SB  - IM
EIN - Antioxid Redox Signal. 2019 Sep 20;31(9):671. PMID: 31361539
MH  - Catalysis
MH  - Energy Metabolism
MH  - Humans
MH  - Iron/metabolism
MH  - Keto Acids/*metabolism
MH  - Mixed Function Oxygenases/chemistry/*metabolism
MH  - Multienzyme Complexes/chemistry/*metabolism
MH  - *Oxidation-Reduction
MH  - Oxygen/chemistry/metabolism
MH  - Protein Disulfide Reductase (Glutathione)/metabolism
MH  - Reactive Nitrogen Species/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Structure-Activity Relationship
MH  - Substrate Specificity
MH  - Thioredoxins/metabolism
OTO - NOTNLM
OT  - 2-oxo acid dehydrogenase
OT  - cellular defense
OT  - lipoate
OT  - nitrosylation
OT  - peroxide
OT  - thioredoxin
EDAT- 2018/09/07 06:00
MHDA- 2020/07/03 06:00
CRDT- 2018/09/07 06:00
PHST- 2018/09/07 06:00 [pubmed]
PHST- 2020/07/03 06:00 [medline]
PHST- 2018/09/07 06:00 [entrez]
AID - 10.1089/ars.2017.7311 [doi]
PST - ppublish
SO  - Antioxid Redox Signal. 2019 Jun 1;30(16):1911-1947. doi: 10.1089/ars.2017.7311. 
      Epub 2018 Oct 18.