Abstract
Diflavin reductases are essential proteins capable of splitting the two-electron flux from reduced pyridine nucleotides to a variety of one electron acceptors. The primary sequence of diflavin reductases shows a conserved domain organization harboring two catalytic domains bound to the FAD and FMN flavins sandwiched by one or several non-catalytic domains. The catalytic domains are analogous to existing globular proteins: the FMN domain is analogous to flavodoxins while the FAD domain resembles ferredoxin reductases. The first structural determination of one member of the diflavin reductases family raised some questions about the architecture of the enzyme during catalysis: both FMN and FAD were in perfect position for interflavin transfers but the steric hindrance of the FAD domain rapidly prompted more complex hypotheses on the possible mechanisms for the electron transfer from FMN to external acceptors. Hypotheses of domain reorganization during catalysis in the context of the different members of this family were given by many groups during the past twenty years. This review will address the recent advances in various structural approaches that have highlighted specific dynamic features of diflavin reductases.
Highlights
Flavoproteins represent 1%–3% of all proteins present in prokaryotic and eukaryotic genomes [1,2]and about half of the proteins involved in electron transfer [3]
They are central in redox processes and their originality comes from the particular properties of their flavinic cofactors that exist in three different redox states and can thereby catalyze both oneand two-electron transfer (ET) reactions
NOS displays the highest level of architecture complexity and possesses three to four additional regulatory elements between and/or within its domains: a CaM binding domain between the FMN and heme domains, a β-finger fold between the FAD and NADPH binding sites and, for endothelial NOS (eNOS) and neuronal NOS (nNOS), a 42–45 residue autoinhibitory insert (AI) in the middle of the FMN domain and a 21–42 residue C-terminal tail (CT) (Figure 1)
Summary
Flavoproteins represent 1%–3% of all proteins present in prokaryotic and eukaryotic genomes [1,2]. While FAD is responsible for the electron partition, the FMN prosthetic group functions as a shuttle between the FAD and the prosthetic group of the acceptor. This diflavin reductases family includes the NADPH-cytochrome P450 reductase MSR was cloned, expressed and assigned to the methionine synthase electron carrier using consensus sequences that predicted the binding sites for FMN, FAD, and NADPH [17,18]. Discovered that the primary sequence of NR1 was close to that of ATR3 [30] that deviates from the strictly conserved FMN, FAD and NADPH-binding domains present in all CPR. The in vivo function of NR1 remains uncertain due to the lack of information concerning its expression levels in cells [31]
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