Molecular distribution of amino acid substitutions on neuraminidase from the 2009 (H1N1) human influenza pandemic virus

Abstract

The pandemic influenza AH1N1 (2009) caused an outbreak of human infection that spread to the world. Neuraminidase (NA) is an antigenic surface glycoprotein, which is essential to the influenza infection process, and is the target of anti-flu drugs oseltamivir and zanamivir. Currently, NA inhibitors are the pillar pharmacological strategy against seasonal and global influenza. Although mutations observed after NA-inhibitor treatment are characterized by changes in conserved amino acids of the enzyme catalytic site, it is possible that specific amino acid substitutions (AASs) distant from the active site such as H274Y, could confer oseltamivir or zanamivir resistance. To better understand the molecular distribution pattern of NA AASs, we analyzed NA AASs from all available reported pandemic AH1N1 NA sequences, including those reported from America, Africa, Asia, Europe, Oceania, and specifically from Mexico. The molecular distributions of the AASs were obtained at the secondary structure domain level for both the active and catalytic sites, and compared between geographic regions. Our results showed that NA AASs from America, Asia, Europe, Oceania and Mexico followed similar molecular distribution patterns. The compiled data of this study showed that highly conserved amino acids from the NA active site and catalytic site are indeed being affected by mutations. The reported NA AASs follow a similar molecular distribution pattern worldwide. Although most AASs are distributed distantly from the active site, this study shows the emergence of mutations affecting the previously conserved active and catalytic site. A significant number of unique AASs were reported simultaneously on different continents.

Keywords: Geographic regions; Influenza; Molecular distribution pattern; Neuraminidase; Pandemic H1N1 (2009); amino acid substitution.

Figure 1

Distribution of amino acid substitutions (AASs) from 2009 pandemic AH1N1 human influenza virus NA by active site and catalytic site. (┼) Potentially resistant AASs. (*) Confirmed resistant AASs. The number of AASs reported in each section is indicated with a gray bar. Circle color indicates residues that interact with oseltamivir (O, light blue), zanamivir (Z, light green) and sialic acid (S, black). Catalytic residues shown in red rectangles indicate direct contact with sialic acid (substrate). Based on Liu et al [34], the principal binding energy contribution for each site associated with an influenza drug or substrate is indicated with letters Z, O, and S.