Einzeltreffer — DigiBib

Lactate oxidation with NAD + as electron acceptor is a highly endergonic reaction. Some anaerobic bacteria overcome the energetic hurdle by flavin-based electron bifurcation/confurcation (FBEB/FBEC) using a lactate dehydrogenase (Ldh) in concert with the electron-transferring proteins EtfA and EtfB. The electron cryo-microscopically characterized (Ldh-EtfAB) 2 complex of Acetobacterium woodii at 2.43 Å resolution consists of a mobile EtfAB shuttle domain located between the rigid central Ldh and the peripheral EtfAB base units. The FADs of Ldh and the EtfAB shuttle domain contact each other thereby forming the D (dehydrogenation-connected) state. The intermediary Glu37 and Glu139 may harmonize the redox potentials between the FADs and the pyruvate/lactate pair crucial for FBEC. By integrating Alphafold2 calculations a plausible novel B (bifurcation-connected) state was obtained allowing electron transfer between the EtfAB base and shuttle FADs. Kinetic analysis of enzyme variants suggests a correlation between NAD + binding site and D-to-B-state transition implicating a 75° rotation of the EtfAB shuttle domain. The FBEC inactivity when truncating the ferredoxin domain of EtfA substantiates its role as redox relay. Lactate oxidation in Ldh is assisted by the catalytic base His423 and a metal center. On this basis, a comprehensive catalytic mechanism of the FBEC process was proposed.

Competing Interests: KK, AK, CH, SW, JS, UE, VM No competing interests declared

Titel:	Structure-based electron-confurcation mechanism of the Ldh-EtfAB complex.
Autor/in / Beteiligte Person:	Kayastha, K ; Katsyv, A ; Himmrich, C ; Welsch, S ; Schuller, JM ; Ermler, U ; Müller, V
Link:	Full Text Finder (Volltext)
Zeitschrift:	ELife, Jg. 11 (2022-06-24)
Veröffentlichung:	Cambridge, UK : eLife Sciences Publications, Ltd., 2012-, 2022
Medientyp:	academicJournal
ISSN:	2050-084X (electronic)
DOI:	10.7554/eLife.77095
Schlagwort:	Electron Transport Kinetics Lactates NAD metabolism Oxidation-Reduction Electrons L-Lactate Dehydrogenase metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Elife] 2022 Jun 24; Vol. 11. <i>Date of Electronic Publication: </i>2022 Jun 24. MeSH Terms: Electrons* ; L-Lactate Dehydrogenase* / metabolism ; Electron Transport ; Kinetics ; Lactates ; NAD / metabolism ; Oxidation-Reduction References: Biochim Biophys Acta. 2013 Feb;1827(2):94-113. (PMID: 22800682) ; Appl Environ Microbiol. 2018 Nov 15;84(23):. (PMID: 30242008) ; Front Microbiol. 2015 Jun 26;6:606. (PMID: 26167158) ; Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14355-60. (PMID: 8962055) ; J Mol Biol. 2000 Jan 14;295(2):357-74. (PMID: 10623531) ; Methods Enzymol. 1988;158:357-64. (PMID: 3374387) ; Protein Sci. 2018 Jan;27(1):293-315. (PMID: 29067766) ; Nat Struct Biol. 2003 Mar;10(3):219-25. (PMID: 12567183) ; J Bacteriol. 2008 Feb;190(3):843-50. (PMID: 17993531) ; Antonie Van Leeuwenhoek. 1983 Sep;49(3):209-24. (PMID: 6354079) ; Proc Natl Acad Sci U S A. 2021 Jan 12;118(2):. (PMID: 33372143) ; Nature. 1970 Aug 15;227(5259):680-5. (PMID: 5432063) ; J Bacteriol. 2009 Jul;191(13):4451-7. (PMID: 19411328) ; J Biol Chem. 2012 Sep 7;287(37):31165-71. (PMID: 22810230) ; J Comput Chem. 2004 Oct;25(13):1605-12. (PMID: 15264254) ; Annu Rev Microbiol. 2018 Sep 08;72:331-353. (PMID: 29924687) ; J Struct Biol. 2016 Jan;193(1):1-12. (PMID: 26592709) ; Nat Methods. 2017 Mar;14(3):290-296. (PMID: 28165473) ; Anal Biochem. 1976 May 7;72:248-54. (PMID: 942051) ; J Biol Chem. 2019 Mar 1;294(9):3271-3283. (PMID: 30567738) ; Front Microbiol. 2018 Jul 03;9:1357. (PMID: 30018596) ; Methods Mol Biol. 2020;2112:29-42. (PMID: 32006276) ; Nat Protoc. 2008;3(7):1171-9. (PMID: 18600222) ; Nat Commun. 2017 Nov 17;8(1):1577. (PMID: 29146947) ; Biochemistry. 1997 Jan 28;36(4):806-11. (PMID: 9020778) ; Nature. 2021 Aug;596(7873):583-589. (PMID: 34265844) ; Environ Microbiol. 2015 Mar;17(3):670-7. (PMID: 24762045) ; J Biol Chem. 2022 Apr;298(4):101733. (PMID: 35176283) ; J Mol Biol. 2007 Sep 21;372(3):774-97. (PMID: 17681537) ; J Bacteriol. 2019 Oct 4;201(21):. (PMID: 31405915) ; J Biol Chem. 2014 Feb 21;289(8):5145-57. (PMID: 24379410) ; Science. 2021 Sep 03;373(6559):1151-1156. (PMID: 34516836) ; Curr Opin Chem Biol. 2016 Apr;31:146-52. (PMID: 27016613) ; J Bacteriol. 2013 Oct;195(19):4373-86. (PMID: 23893107) ; Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9413-8. (PMID: 10944213) ; Biochim Biophys Acta. 2013 Nov-Dec;1827(11-12):1362-77. (PMID: 23396004) ; Electrophoresis. 2007 Nov;28(21):3811-20. (PMID: 17960833) ; Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32. (PMID: 15572765) ; J Biol Chem. 2015 Sep 4;290(36):21985-95. (PMID: 26139605) ; Chem Rev. 2018 Apr 11;118(7):3862-3886. (PMID: 29561602) ; J Biol Chem. 2013 Apr 19;288(16):11304-11. (PMID: 23479729) ; Science. 2017 Aug 18;357(6352):699-703. (PMID: 28818947) ; Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. (PMID: 20124702) ; Biochim Biophys Acta Bioenerg. 2021 Jul 1;1862(7):148415. (PMID: 33727071) ; Elife. 2018 Nov 09;7:. (PMID: 30412051) ; J Biol Chem. 2016 Jun 3;291(23):11993-2002. (PMID: 27048649) ; FEBS J. 2021 Feb;288(3):1008-1026. (PMID: 32329961) ; FEBS J. 2007 Nov;274(21):5481-504. (PMID: 17941859) ; Trends Biochem Sci. 1998 Jun;23(6):206-7. (PMID: 9644973) ; J Biol Chem. 2013 Nov 1;288(44):31496-502. (PMID: 24045950) ; J Bacteriol. 2008 Feb;190(3):784-91. (PMID: 18039764) ; Arch Biochem Biophys. 2021 Apr 15;701:108796. (PMID: 33609536) ; Commun Biol. 2019 Jun 19;2:218. (PMID: 31240256) ; Nat Methods. 2017 Apr;14(4):331-332. (PMID: 28250466) ; FEBS Lett. 2018 Feb;592(3):332-342. (PMID: 29325219) ; Nat Chem Biol. 2017 Jun;13(6):655-659. (PMID: 28394885) ; FEBS Lett. 1978 May 15;89(2):219-22. (PMID: 658409) ; Extremophiles. 2021 Nov;25(5-6):513-526. (PMID: 34647163) ; Front Microbiol. 2018 Mar 14;9:401. (PMID: 29593673) ; Structure. 1997 Jul 15;5(7):907-20. (PMID: 9261083) ; Bioessays. 2012 Feb;34(2):106-9. (PMID: 22045626) ; J Bacteriol. 2017 Oct 3;199(21):. (PMID: 28808132) ; J Struct Biol. 2012 Dec;180(3):519-30. (PMID: 23000701) Contributed Indexing: Keywords: biochemistry; bioenergetics; chemical biology; cryo-EM structure; electron bifurcation; electron-transferring flavoprotein; flavin; lactate dehydrogenase Substance Nomenclature: 0 (Lactates) ; 0U46U6E8UK (NAD) ; EC 1.1.1.27 (L-Lactate Dehydrogenase) Entry Date(s): Date Created: 20220624 Date Completed: 20220628 Latest Revision: 20230712 Update Code: 20231215 PubMed Central ID: PMC9232219

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Structure-based electron-confurcation mechanism of the Ldh-EtfAB complex.