Evolution of the ferric reductase domain (FRD) superfamily: modularity, functional diversification, and signature motifs

PLoS One. 2013;8(3):e58126. doi: 10.1371/journal.pone.0058126. Epub 2013 Mar 7.


A heme-containing transmembrane ferric reductase domain (FRD) is found in bacterial and eukaryotic protein families, including ferric reductases (FRE), and NADPH oxidases (NOX). The aim of this study was to understand the phylogeny of the FRD superfamily. Bacteria contain FRD proteins consisting only of the ferric reductase domain, such as YedZ and short bFRE proteins. Full length FRE and NOX enzymes are mostly found in eukaryotic cells and all possess a dehydrogenase domain, allowing them to catalyze electron transfer from cytosolic NADPH to extracellular metal ions (FRE) or oxygen (NOX). Metazoa possess YedZ-related STEAP proteins, possibly derived from bacteria through horizontal gene transfer. Phylogenetic analyses suggests that FRE enzymes appeared early in evolution, followed by a transition towards EF-hand containing NOX enzymes (NOX5- and DUOX-like). An ancestral gene of the NOX(1-4) family probably lost the EF-hands and new regulatory mechanisms of increasing complexity evolved in this clade. Two signature motifs were identified: NOX enzymes are distinguished from FRE enzymes through a four amino acid motif spanning from transmembrane domain 3 (TM3) to TM4, and YedZ/STEAP proteins are identified by the replacement of the first canonical heme-spanning histidine by a highly conserved arginine. The FRD superfamily most likely originated in bacteria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Biological Evolution*
  • Cluster Analysis
  • Conserved Sequence
  • FMN Reductase / chemistry*
  • FMN Reductase / classification
  • FMN Reductase / genetics
  • FMN Reductase / metabolism*
  • Heme / chemistry
  • Heme / metabolism
  • Models, Biological
  • Multigene Family
  • NADH, NADPH Oxidoreductases / chemistry
  • NADH, NADPH Oxidoreductases / metabolism
  • Phylogeny
  • Position-Specific Scoring Matrices
  • Protein Interaction Domains and Motifs*
  • Reactive Oxygen Species / metabolism


  • Reactive Oxygen Species
  • Heme
  • FMN Reductase
  • NADH, NADPH Oxidoreductases
  • ferric citrate iron reductase

Grant support

This work was supported in part by the Swiss Federal Government through the Federal Office of Education and Science (BB) and by a Swiss National Science Foundation ProDoc Research Module, PDFMP3_127302 (TS and KHK). Funding for open access charge: Swiss Institute of Bioinformatics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.