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Proc Natl Acad Sci U S A. 2018 Dec 18;115(51):12967-12972. doi: 10.1073/pnas.1812781115. Epub 2018 Dec 3.

Ferredoxin-linked flavoenzyme defines a family of pyridine nucleotide-independent thioredoxin reductases.

Author information

Metabolic Engineering Group, Departamento de Microbiología y Genética, Universidad de Salamanca, 37007 Salamanca, Spain.
Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas and Universidad de Salamanca, 37007 Salamanca, Spain.
Laboratoire de Biologie Moléculaire et Cellulaire, Université de Neuchâtel, 2000 Neuchâtel, Switzerland.
Department of Plant & Microbial Biology, University of California, Berkeley, CA 94720;
Instituto de Recursos Naturales y Agrobiología de Salamanca, Consejo Superior de Investigaciones Científicas, 37008 Salamanca, Spain


Ferredoxin-dependent thioredoxin reductase was identified 35 y ago in the fermentative bacterium Clostridium pasteurianum [Hammel KE, Cornwell KL, Buchanan BB (1983) Proc Natl Acad Sci USA 80:3681-3685]. The enzyme, a flavoprotein, was strictly dependent on ferredoxin as reductant and was inactive with either NADPH or NADH. This early work has not been further pursued. We have recently reinvestigated the problem and confirmed that the enzyme, here designated ferredoxin-dependent flavin thioredoxin reductase (FFTR), is a flavoprotein. The enzyme differs from ferredoxin-thioredoxin reductase (FTR), which has a signature [4Fe-4S] cluster, but shows structural similarities to NADP-dependent thioredoxin reductase (NTR). Comparative amino acid sequence analysis showed that FFTR is present in a number of clostridial species, some of which lack both FTR and an archetypal NTR. We have isolated, crystallized, and determined the structural properties of FFTR from a member of this group, Clostridium acetobutylicum, both alone and in complex with Trx. The structures showed an elongated FFTR homodimer, each monomer comprising two Rossmann domains and a noncovalently bound FAD cofactor that exposes the isoalloxazine ring to the solvent. The FFTR structures revealed an alternative domain organization compared with NTR that enables the enzyme to accommodate Fdx rather than NADPH. The results suggest that FFTR exists in a range of conformations with varying degrees of domain separation in solution and that the stacking between the two redox-active groups for the transfer of reducing equivalents results in a profound structural reorganization. A mechanism in accord with the findings is proposed.


ferredoxin; flavoprotein; protein conformational dynamics; redox-active disulfide; thioredoxin reductase

[Available on 2019-06-18]

Conflict of interest statement

Conflict of interest statement: B.B.B. and I.A.B. are coauthors of a 2017 retrospective article.

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