Crystal structure of oxidized flavodoxin, an essential protein in Helicobacter pylori

Abstract

The redox protein flavodoxin has been shown earlier to be reduced by the pyruvate-oxidoreductase (POR) enzyme complex of Helicobacter pylori, and also was proposed to be involved in the pathogenesis of gastric mucosa-associated lymphoid-tissue lymphoma (MALToma). Here, we report its X-ray structure, which is similar to flavodoxins of other bacteria and cyanobacteria. However, H. pylori flavodoxin has an alanine residue near the isoalloxazine ring of its cofactor flavin mononucleotide (FMN), while the other previously crystallized flavodoxins have a larger hydrophobic residue at this position. This creates a solute filled hole near the FMN cofactor of H. pylori flavodoxin. We also show that flavodoxin is essential for the survival of H. pylori, and conclude that its structure can be used as a starting point for the modeling of an inhibitor for the interaction between the POR-enzyme complex and flavodoxin.

Theoretical Analyses of Photoinduced Electron Transfer from Aromatic Amino Acids to the Excited Flavins in Some Flavoproteins

“…The redox potential of these two closely related flavodoxins is also slightly different, being E 1 = -434 and -440 mV for the Miyazaki and Hildenborough forms, respectively, for the oxidized-semiquinone reaction of flavodoxin, and E 2 = -151 and -143 mV for the semiquinone-2-electron reduced reaction, respectively (Kitamura et al, 1998). Recently, the three-dimensional structures of numerous flavodoxins have been determined, including Desulfovibrio vulgaris Hildenborough (Watenpauph, 1973) and the flavodoxins from Anacystis nidulans (Drennan et al, 1999), Clostridium beijerinckii , Escherichia coli (Hoover & Ludwig, 1997), Anabaena 7120 (Burkhart et al, 1995) a red algae (Fukuyama et al, 1992) Chondrus crispu (Fukuyama et al, 1990) and H. pylori (Freigang et al, 2002) by X-ray crystallography. The structure of flavodoxin, however, has not yet been determined, although the primary structure is known (Kitamura et al, 1998).…”

QSAR Models for Prediction of Binding and Inhibitory Properties of [(E)-2- R-vinyl]benzene Derivatives with Therapeutic Effects against Helicobacter pylori

“…No new drugs have been developed in recent years to treat Hp infection, but some selective targets (one of them being the protein flavodoxin: Hp-Fld) have been identified [16]. Hp-Fld is an electron carrier essential for Hp viability [17,18] and it has been used in previous works [19,20] as target for the discovery of novel compounds that could be potential drugs against Hp. Four different biological responses (BR) or biological activities were assayed for those novel compounds, which are mainly derived from a common substructure represented in Figure 1.…”

WrpA Is an Atypical Flavodoxin Family Protein under Regulatory Control of the Brucella abortus General Stress Response System

“…Flavodoxins and flavodoxin-like proteins are also known to promote pathogen virulence and to play a role in host infection and colonization (8,(11)(12)(13)(14)(15)(16)(17)(18), in addition to important roles in enzyme activation and metabolism (15). The flavodoxin-like protein WrbA (tryptophan [W] repressor binding protein) has been described for several microbial species, in which it is proposed to facilitate adaptation to varied chemical changes in the environment (13,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) …”

“…Insertion loop 1 distinguishes WrbA from classic flavodoxins (15). WrbA is tetrameric in solution (30,32,39,40) and in crystal structures (31,33,36,38), which is distinct from classic flavodoxins, which are monomeric/dimeric (15,16,32,(41)(42)(43)(44). The WrbA tetramer presents four active sites, each with a bound flavin cofactor.…”