The dual function of flavodiiron proteins: oxygen and/or nitric oxide reductases

Abstract

Flavodiiron proteins have emerged in the last two decades as a newly discovered family of oxygen and/or nitric oxide reductases widespread in the three life domains, and present in both aerobic and anaerobic organisms. Herein we present the main features of these fascinating enzymes, with a particular emphasis on the metal sites, as more appropriate for this special issue in memory of the exceptional bioinorganic scientist R. J. P. Williams who pioneered the notion of (metal) element availability-driven evolution. We also compare the flavodiiron proteins with the other oxygen and nitric oxide reductases known until now, highlighting how throughout evolution Nature arrived at different solutions for similar functions, in some cases adding extra features, such as energy conservation. These enzymes are an example of the (bioinorganic) unpredictable diversity of the living world.

Spectroscopy and DFT Calculations of a Flavo-diiron Enzyme Implicate New Diiron Site Structures

“…From the more than six X-ray crystal structures of the diferric state available to date, 2 we used PDB 1VME (of Tm deflavo-FDP) as a representative structure to create our DFT model. The structural model adopted in the DFT calculations of FDP was modified from that in Figure 1 as shown in Figure S8 with fixed atom positions indicated.…”

“…Most FDPs show both dioxygen reductase (O 2 R) and nitric oxide reductase (NOR) activities, but the relative turnover rates vary significantly among FDPs. 1,2 …”

Origin of Nitric Oxide Reduction Activity in Flavo–Diiron NO Reductase: Key Roles of the Second Coordination Sphere

“…In view of the significant second coordination sphere effect found here,i t is notable that in all the active site pockets of diiron enzymes of sMMO,R NR, and Hr, there is no such second coordination sphere Ty rr esidue at nearby position of Ty r 197 in Tm FDP, [23,24] and Ty r 197 is conserved in almost all FDPs. [6,41] All these results and information strongly implicate that the second coordination sphere Hbonding from Ty r 197 could play ak ey role for FNORs in gaining the NOR activity.Interestingly,this H-bonding-based facilitation of NO reduction in non-heme FDP enzymes echoes recent findings in porphyrin iron-nitrosyl and porphyrinoid cobalt-nitrosyl systems,which revealed NO reduction is assisted by either Brønsted or Lewis acids. [42,43] In summary,wereport that the NO reduction reactivity of Tm FDP stems from the second coordination sphere interaction of Ty r 197 with the iron-nitrosyl intermediate.T his interaction was initially identified in the transient diirondinitrosyl species by QM/MM 57 Fe Mçssbauer modelings.…”

“…[4] As for O 2 activation/reduction,NOreduction can also be promoted in nature by diiron enzymes.F lavo-diiron NO reductases (FNORs), which belong to the widespread family of flavo-diiron proteins (FDPs), are found in all three life domains of bacteria, archaea, and protozoan pathogens,a re such non-heme diiron enzymes. [5][6][7] Further to the O 2 reductase activity of FDPs,F NORs exhibit NO reductase (NOR) activity by converting NO to N 2 Othat can directly modulate ab road range of ligand-gated ion channels in our body. Utilizing FNORs,p athogenic bacteria can detoxify NO, preventing it from reaching toxic levels,t hereby gaining resistance to the central immune agent NO in humans.…”

Oxidative and nitrosative stress defences ofHelicobacterandCampylobacterspecies that counteract mammalian immunity

“…In a large number of bacteria, two major families of proteins promote the enzymatic removal of NO, namely the flavohaemoglobins and flavodiiron NO reductases (Saraiva, Vicente and Teixeira 2004;Forrester and Foster 2012;Stern and Zhu 2014;Romao et al 2016). Although H. pylori is able to thrive in NO-enriched environments (Park et al 2003), such enzymes are apparently absent in the Helicobacter and Campylobacter genomes.…”