“NDH-2”的意思、由来-开放百科全书

The structure/fold from these proteins may be divided into three domains: first dinucleotide binding domain (green in the figure), second dinucleotide binding domain (orange in the figure) and C-terminal domain (blue in the figure).

The first domain is responsible for the noncovalent binding of FAD, while the second dinucleotide binding domain binds NADH. Both these domain are structurally organized in [https://en.wikipedia.org/wiki/Rossmann_fold Rossmann folds], with the characteristic GxGxxG motif present.

The third domain, C-terminal, is responsible for the protein-membrane interaction. Upon expression of a C-terminal truncated version of NDH-2, it was observed an intracelular delocalization from the membrane to the cytoplasm.^[4] The third domain, together with part of the first domain, is also partially responsible for the binding of the electron acceptor (quinone).

There are currently crystalographic structures for NDH-2 from four different organisms:

Reaction

The enzymatic oxidoreduction reaction catalyzed by NDH-2 may be described as follows:

In this case, the electron donor is NADH and the electron acceptor is the quinone. Depending on the organism, the reduced quinone changes between menaquinone, ubiquinone ou plastoquinone. The mechanism of the reaction may be divided in two half-reactions: 1stHR and 2ndHR.

In the 1stHR, 2 electrons and 1 proton from NADH are transferred (simultaneously with an additional proton from the bulk) to the prosthetic group (FAD), giving rise to its protonated form FADH₂. In this phase, an Enzyme-Substrate complex is established, characterized by the appearance of a "[https://en.wikipedia.org/wiki/Charge-transfer_complex Charge-transfer complex]".

Na 2stHR, the quinone binds and the 2 electrons and one of the FAD protons are transferred for this second substrate (again, with an additional proton from the bulk), forming the product quinol.

It is now accepted that the overall mechanism occurs by a [https://en.wikipedia.org/wiki/Ternary_complex ternary complex] (simultaneous binding of both substrates to the enzyme),^[9] instead of the previously proposed [https://pt.wikipedia.org/wiki/Cin%C3%A9tica_enzim%C3%A1tica#Mecanismos_ping.E2.80.93pong ping-pong mechanism].

Philogenetic Distribution

The presence of NDH-2 in organisms which genome as already been fully sequenced was studied by Bioinformatics.^[10] In this study, NDH-2 were identified in 83% of Eukaryotes, 60% of Bacterias and in 32% of Archaeas. It was also observed the absence of NDH-2 in phylla composed of anaerobic organisms.

Despite being considered absent (hence being considered as drug targets), in this same study, the presence of a gene coding for a NDH-2 homolog was observed in the human genome.

References

1. ^B.C. Marreiros, F. Calisto, P.J. Castro, A.M. Duarte, F. V. Sena, A.F. Silva, F.M. Sousa, M. Teixeira, P.N. Refojo, M.M. Pereira, Exploring membrane respiratory chains, Biochim. Biophys. Acta - Bioenerg. 1857 (2016) 1039–1067.
2. ^Kerscher, S., Dröse, S., Zickermann, V., and Brandt, U. (2007) The Three Families of Respiratory NADH Dehydrogenases, in Bioenergetics (Schäfer, G., and Penefsky, H. S., Eds.), pp 185-222, Springer Berlin Heidelberg.
3. ^F. V. Sena, A.P. Batista, T. Catarino, J.A. Brito, M. Archer, M. Viertler, T. Madl, E.J. Cabrita, M.M. Pereira, Type-II NADH: Quinone oxidoreductase from Staphylococcus aureus has two distinct binding sites and is rate limited by quinone reduction, Mol. Microbiol. 98 (2015) 272–288. doi:10.1111/mmi.13120.
4. ^Y. Feng, W. Li, J. Li, J. Wang, J. Ge, D. Xu, Y. Liu, K. Wu, Q. Zeng, J.-W. Wu, C. Tian, B. Zhou, M. Yang, Structural insight into the type-II mitochondrial NADH dehydrogenases., Nature. 491 (2012) 478–82. doi:10.1038/nature11541
5. ^{{Cite journal|last=Sousa|first=Filipe M.|last2=Sena|first2=Filipa V.|last3=Batista|first3=Ana P.|last4=Athayde|first4=Diogo|last5=Brito|first5=José A.|last6=Archer|first6=Margarida|last7=Oliveira|first7=A. Sofia F.|last8=Soares|first8=Cláudio M.|last9=Catarino|first9=Teresa|date=October 2017|title=The key role of glutamate 172 in the mechanism of type II NADH:quinone oxidoreductase of Staphylococcus aureus|url=https://linkinghub.elsevier.com/retrieve/pii/S0005272817301159|journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics|volume=1858|issue=10|pages=823–832|doi=10.1016/j.bbabio.2017.08.002|pmid=28801048|issn=0005-2728}}
6. ^Y. Feng, W. Li, J. Li, J. Wang, J. Ge, D. Xu, Y. Liu, K. Wu, Q. Zeng, J.-W. Wu, C. Tian, B. Zhou, M. Yang, Structural insight into the type-II mitochondrial NADH dehydrogenases., Nature. 491 (2012) 478–82. doi:10.1038/nature11541
7. ^A. Heikal, Y. Nakatani, E. Dunn, M.R. Weimar, C.L. Day, E.N. Baker, J.S. Lott, L.A. Sazanov, G.M. Cook, Structure of the bacterial type II NADH dehydrogenase: a monotopic membrane protein with an essential role in energy generation, Mol Microbiol. 91 (2014) 950–964. doi:10.1111/mmi.12507.
8. ^{{Cite journal|last=Yang|first=Yiqing|last2=Yu|first2=You|last3=Li|first3=Xiaolu|last4=Li|first4=Jing|last5=Wu|first5=Yue|last6=Yu|first6=Jie|last7=Ge|first7=Jingpeng|last8=Huang|first8=Zhenghui|last9=Jiang|first9=Lubin|date=2017-02-22|title=Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with Small Molecule To Eliminate Drug-Resistant Malaria|journal=Journal of Medicinal Chemistry|volume=60|issue=5|pages=1994–2005|doi=10.1021/acs.jmedchem.6b01733|pmid=28195463|issn=0022-2623}}
9. ^{{Cite journal|last=Sena|first=Filipa V.|last2=Batista|first2=Ana P.|last3=Catarino|first3=Teresa|last4=Brito|first4=José A.|last5=Archer|first5=Margarida|last6=Viertler|first6=Martin|last7=Madl|first7=Tobias|last8=Cabrita|first8=Eurico J.|last9=Pereira|first9=Manuela M.|date=2015-07-30|title=Type-II NADH:quinone oxidoreductase from Staphylococcus aureushas two distinct binding sites and is rate limited by quinone reduction|journal=Molecular Microbiology|volume=98|issue=2|pages=272–288|doi=10.1111/mmi.13120|pmid=26172206|issn=0950-382X}}
10. ^B.C. Marreiros, F. V Sena, F.M. Sousa, A.P. Batista, M.M. Pereira, Type II NADH:Quinone oxidoreductase family: Phylogenetic distribution, Structural diversity and Evolutionary divergences., Environ. Microbiol. 0 (2016). doi:10.1111/1462-2920.13352.