Defining electron bifurcation in the electron-transferring flavoprotein family

Amaya M.Garcia Costas, Saroj Poudel, Anne Frances Miller, Gerrit J. Schut, Rhesa N. Ledbetter, Kathryn R. Fixen, Lance C. Seefeldt, Michael W.W. Adams, Caroline S. Harwood, Eric S. Boyd, John W. Peters

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


Electron bifurcation is the coupling of exergonic and endergonic redox reactions to simultaneously generate (or utilize) low- and high-potential electrons. It is the third recognized form of energy conservation in biology and was recently described for select electron-transferring flavoproteins (Etfs). Etfs are flavin-containing heterodimers best known for donating electrons derived from fatty acid and amino acid oxidation to an electron transfer respiratory chain via Etf-quinone oxidoreductase. Canonical examples contain a flavin adenine dinucleotide (FAD) that is involved in electron transfer, as well as a non-redox-active AMP. However, Etfs demonstrated to bifurcate electrons contain a second FAD in place of the AMP. To expand our understanding of the functional variety and metabolic significance of Etfs and to identify amino acid sequence motifs that potentially enable electron bifurcation, we compiled 1,314 Etf protein sequences from genome sequence databases and subjected them to informatic and structural analyses. Etfs were identified in diverse archaea and bacteria, and they clustered into five distinct well-supported groups, based on their amino acid sequences. Gene neighborhood analyses indicated that these Etf group designations largely correspond to putative differences in functionality. Etfs with the demonstrated ability to bifurcate were found to form one group, suggesting that distinct conserved amino acid sequence motifs enable this capability. Indeed, structural modeling and sequence alignments revealed that identifying residues occur in the NADH- and FAD-binding regions of bifurcating Etfs. Collectively, a new classification scheme for Etf proteins that delineates putative bifurcating versus nonbifurcating members is presented and suggests that Etf-mediated bifurcation is associated with surprisingly diverse enzymes.

Original languageEnglish
Article numbere00440-17
JournalJournal of Bacteriology
Issue number21
StatePublished - 2017

Bibliographical note

Publisher Copyright:
© 2017 American Society for Microbiology.


  • Electron bifurcation
  • Electron-transferring flavoprotein
  • Flavin
  • Nitrogen fixation
  • Nitrogenase

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology


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