Conservation of the Enzyme–Coenzyme Interfaces in FAD and NADP Binding Adrenodoxin Reductase—A Ubiquitous Enzyme

Israel Hanukoglu

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


FAD and NAD(P) together represent an ideal pair for coupled redox reactions in their capacity to accept two electrons and their redox potentials. Enzymes that bind both NAD(P) and FAD represent large superfamilies that fulfill essential roles in numerous metabolic pathways. Adrenodoxin reductase (AdxR) shares Rossmann fold features with some of these superfamilies but remains in a group of its own in the absence of sequence homology. This article documents the phylogenetic distribution of AdxR by examining whole genome databases for Metazoa, Plantae, Fungi, and Protista, and determines the conserved structural features of AdxR. Scanning these databases showed that most organisms have a single gene coding for an AdxR ortholog. The sequence identity between AdxR orthologs is correlated with the phylogenetic distance among metazoan species. The NADP binding site of all AdxR orthologs showed a modified Rossmann fold motif with a GxGxxA consensus instead of the classical GxGxxG at the edge of the first βα-fold. To examine the hypothesis that enzyme–coenzyme interfaces represent the conserved regions of AdxR, the residues interfacing FAD and NADP were identified and compared with multiple-sequence alignment results. Most conserved residues were indeed found at sites that surround the interfacing residues between the enzyme and the two coenzymes. In contrast to protein–protein interaction hot-spots that may appear in isolated patches, in AdxR the conserved regions show strict preservation of the overall structure. This structure maintains the precise positioning of the two coenzymes for optimal electron transfer between NADP and FAD without electron leakage to other acceptors.

Original languageEnglish
Pages (from-to)205-218
Number of pages14
JournalJournal of Molecular Evolution
Issue number5-6
StatePublished - 1 Dec 2017


  • Consensus sequence
  • Enzyme evolution
  • FDXR
  • Flavoprotein
  • Rossmann fold


Dive into the research topics of 'Conservation of the Enzyme–Coenzyme Interfaces in FAD and NADP Binding Adrenodoxin Reductase—A Ubiquitous Enzyme'. Together they form a unique fingerprint.

Cite this