In conclusion, the results obtained from investigating for the presence of HBoV DNA in archived DNA samples from a large and previously well described case-control study of IID suggest that HBoV, including HBoV-2,do not appear to be a significant cause of gastroenteritis in the UK population, and particularly in the paediatric population. Although HBoVs are relatively frequent across all ages, and in particular in preschool age children, they are found just as frequently among children and adults without symptoms of gastroenteritis. Structural Origins for the Loss of Catalytic Activities of Bifunctional Human LTA4H Revealed through Molecular Dynamics Simulations Human leukotriene A4 hydrolase (hLTA4H), which is the final and rate-limiting enzyme of arachidonic acid pathway, converts the unstable epoxide LTA4 to a proinflammatory lipid mediator LTB4 through its hydrolase function. The LTA4H is a bi-functional enzyme that also exhibits aminopeptidase activity with a preference over arginyl tripeptides. Various mutations including E271Q, R563A, and K565A have completely or partially abolished both the functions of this enzyme. The crystal structures with these mutations have not shown any structural changes to address the loss of functions. Molecular dynamics simulations of LTA4 and tripeptide complex structures with functional mutations were performed to investigate the structural and conformation changes that scripts the observed differences in catalytic functions. The observed protein-ligand hydrogen bonds and distances between the important catalytic components have correlated well with the experimental results. This study also confirms based on the structural observation that E271 is very important for both the functions as it holds the catalytic metal ion at its location for the catalysis and it also acts as N-terminal recognition residue during peptide binding. The comparison of binding modes of substrates revealed the structural changes explaining the importance of R563 and K565 residues and the required alignment of substrate at the active site. The results of this study provide valuable information to be utilized in designing potent hLTA4H inhibitors as anti-inflammatory agents. Leukotriene cascade is associated with the biosynthesis of variety of leukotrienes (LT) from the phospholipids of the nuclear membrane of the leukocytes [1] . The LTs are a group of lipid mediators associated with acute and chronic inflammatory diseases such as asthma, rhinitis, psoriasis, chronic obstructive pulmonary disease, and atherosclerosis [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] . Cytosolic phospholipase A2 (cPLA2) hydrolyzes the ester bond present in sn-2 position of phospholipids and yields lysophospholipids and free fatty acid, arachidonic acid (AA) [1, 14] . This increases the level of free AA available for the synthesis of inflammatory leukotrienes upon the action of more enzymes. The enzyme 5-lipoxygenase (5-LO) assisted by file-lipoxygenase-activating protein (FLAP) converts the AA into the highly unstable allylic epoxide, leukotriene A4 (LTA4) [15] [16] [17] [18] [19] [20] [21] . This unstable intermediate is converted into two different products LTB4 and LTC4 by the action of two different enzymes LTA4 hydrolase (LTA4H) and LTC4 synthase (LTC4S), respectively [1, [22] [23] [24] [25] . The LTC4 is subsequently converted to LTD4 and LTE4 substances by the action of different enzymes. All of these LTB4, LTC4, LTD4, and LTE4 are powerful proinflammatory mediators [1, 26] . The LTA4H, which catalyzes the conversion of LTA4 to the chemotactic agent LTB4, was identified as a bi-functional enzyme capable of processing two highly diverse substrates such as LTA4 (a fatty acid) and peptide through its epoxide hydrolase and aminopeptidase activities [27, 28] . This enzyme was first discovered for its epoxide hydrolase activity and later for its aminopeptidase activity based on the presence of consensus Zn binding motif (HEXXH-X 18 -E), which was found in M1 family of Zn containing aminopeptidases [29] [30] [31] [32] . The natural peptide substrate for this enzyme is still not known but preference is shown over arginyl di-and tripeptide and can selectively be blocked by the mutation of either E296 or Y383 residues [33] [34] [35] [36] . Upon the determination of LTA4H crystal structures it was revealed that this enzyme is composed of three domains, a fully beta N-terminal domain, a mixed alpha/beta catalytic domain, and a fully alpha-helical C-terminal domain ( Figure 1 ) [37] [38] [39] [40] [41] [42] . In terms of the hydrolase activity of the enzyme, D375 from a narrow hydrophobic pocket is specifically required as it is involved in the nucleophilic attack targeting C12 atom of LTA4 [43] . In addition, this residue belongs to the peptide K21 (L365-K385) segment identified by Lys-specific peptide mapping of suicide inactivated LTA4H. The carboxylate moiety of LTA4 was observed to form direct electrostatic interactions with the two positively charged conserved R563 and K565 residues present at the entrance of the active center [28, 44] . These interactions are very much essential in aligning LTA4 along with the catalytic elements of the active site. Based on the mutagenic experiments, E271 residue from another conserved GXMEN motif in the family of zinc peptidases was found to be important for both the functions of the enzyme [14] as the mutagenic replacements abrogated both the activities. A crystal structure of LTA4H with E271Q mutation has revealed only minimal conformational changes and did not explain the loss of enzyme function [14] . It was also suggested that the carboxylate of E271 participates in an acid-induced opening of the epoxide moiety of LTA4 and as N-terminal recognition site in terms of peptide substrates [14, 26, 45] . Some mutagenic experiments have also reported the critical role of R563 residue in epoxide hydrolase reaction by positioning the carboxylate tail along the catalytic elements of the active site [28, 34] . In aminopeptidase reaction, both R563 and K565 residues co-operate each other to ensure the necessary binding strength and productive alignment of the substrate. Altogether, R563 plays important roles in both the functions of the enzyme whereas K565 residue assists R563 in catalyzing the peptide substrate but not in hydrolase reaction, which catalyzes the fatty acid substrate [27] . These residues were reported to be the common carboxylate recognition site for both lipid and peptide substrates in the active site of LTA4H [27] .