PMC:5056897 / 13761-23365 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/5056897","sourcedb":"PMC","sourceid":"5056897","source_url":"https://www.ncbi.nlm.nih.gov/pmc/5056897","text":"Classification of the HPs\nFor the ease of the approach for understanding the probable involvement of these HPs in pathogenesis, we categorized all 104 HPs into various functional groups on the basis of their individual molecular function and their involvement in various biological processes (Fig. 1). We found 27 HPs showing similarities with various enzyme classes like oxidoreductases, hydrolases, transferases, etc. Ten HPs are categorized as transporters, 26 showing features of binding proteins, 23 HPs have predicted to be involved in various cellular and regulatory processes and 18 HPs are listed in the category of proteins showing miscellaneous functions. These HPs are further studied and extensively analyzed using previously available literature and experimental studies.\nEnzymes, having catalytic properties, play a substantial role in the life of a living organism to provide biochemical machinery for various cellular and regulatory processes. We found 27 HPs showing similarities experimentally characterized enzymes representatives of enzyme classes. HP O25317 showed similarity with disulfide bond formation protein DsbB. Disulfide bonds provide stability and maturation strength to the protein thus, DsbB has a critical role in the development of substantial protein machinery that may be involved in the metabolic or regulatory pathways [58] of that pathogen, therefore, helping in the pathogenesis. Out of 27 enzymes, five HPs are categorized as transferases. HPs O25589 and O25870 are showing similarity with acetyltransferase family protein and glycosyltransferase family 9 (heptosyltransferase), respectively. Both these HPs are predicted virulent in virulent factors analysis. Glycosyltranferases facilitate the \"biosynthesis of disaccharides, oligosaccharides, and polysaccharides\" by catalyzing the transfer of sugar moieties [59]. HP O25870 is predicted heptosyltransferase may be a potential drug target. Heptosyltranferase help in the formation of the core region of lipopolysaccharides which constitute the major component outer membrane structure in Gram-negative bacteria [60]. About 60% of all predicted enzymes belong to hydrolases enzyme class and most of them are involved in metabolic pathways. In the predicted hydrolases, there are ATPases, restriction endonucleases, phosphoesterases, etc., that facilitate the processes of transcription, translation, functional group localization, and other such essential activities that help in the development and propagation of the pathogen inside the host. There are four HPs showing similarities with member proteins of lyase enzyme class. HP O25309 is showing similarity with aminodeoxychorismate lyase and is predicted as virulent factor. Aminodeoxychorismate lyase is a class member of pyridoxal-phosphate-binding protein class IV which helps in the biosynthesis of tetrahydrofolate by aminodeoxychorismate to para-aminobenzoate. Tetrahydrofolate is an essential precursor in purine biosynthesis [61].\nTransporters have always remained a subject of interest during the process of novel drug discovery against the pathogenic diseases. Transporters, due to their specific evolution making them capable of transporting essential molecules, are involved in a wide range of metabolic pathways and other important cellular processes. H. pylori genome has an ample amount of genes that encode a large number of transporter proteins, mainly ATP-binding cassette (ABC) transporters. In the predicted HPs, we found 10 HPs showing characteristic similarity with transporters. HPs O26020, and O26021 are showing similarity with ABC-2 family transporter proteins. ABC transporters, specific to prokaryotes, are the leading molecules that fulfill the energy requirement of the organism for diverse biological processes [62]. The required amount energy that they provide comes from the hydrolysis of ATP molecules performed by ABC transporters [63] having specifically evolved domains for ATP hydrolysis. We found HP O26042 is showing similarity with ferrichrome iron receptor (fhuA). Iron uptake is believed to be preferential activity in H. pylori for the survival in the host system [64]. fhuA is an outer membrane transport protein which catalyzes the transport of ferrichrome and also acts as a receptor for T5 phages in Escherichia coli and other toxic substances [65]. HP O26042 is also predicted virulent in virulence factors analysis. Thus, it can be considered potential drug target.\nTwenty-six HPs are characterized as binding proteins. These proteins are further specified according to their functions as adhensin, DNA-, RNA-, protein-, nucleotide-, metal- and lipid-binding proteins. Some of the representative members of this group are may be known involved in leading cell activities, transcription, translation, and other regulatory processes. In this group, we have identified four HPs showing characteristics of restriction modification proteins, three of which belong to type I and one belong to type II. All these proteins may have an essential role in DNA modification. HP O25934 is showing similarity with type-1 restriction enzyme ecoKI specificity protein (hsdS) and predicted virulent by both VICMpred and VirulentPred. Type-1 restriction enzyme ecoKI specificity protein belongs to the class of S-adenosyl-L-methionine dependent endonucleases that are constituents of bacterial DNA restriction-modification mechanisms, which guards the organism from foreign DNA invasion [66]. We identified HP O25749 showing positive virulence and exhibiting similarity with tetratricopeptide repeat (TPR) protein. TPR is a signature motif of proteins regulating protein-protein interaction and the formation of multiprotein complexes [67]. Proteins with TPR motifs are involved in important biological processes such as cell cycle, protein folding, transcriptional regulation, etc. [68]. Involvement in leading processes makes them liable to be treated as potential drug targets. We found two HPs O25618 and O25619 are showing significant similarity to dynamin like GTPases. The function of dynamin GTPases is well studied in eukaryotes. They are involved in membrane fusion and fission mediated by the hydrolysis of GTP molecules but the exact function of their prokaryotic counterparts, despite the existence of structural data, is not well understood and needs a further probe to straighten out their role in prokaryotes [69].\nWe have identified 23 HPs may be involved in diverse cellular processes and regulatory mechanisms. Proteins mediating the formation of cell envelope such flagellar biosynthesis proteins, flagellar motility proteins are signature members of this group. Flagella is responsible for bacterial motility in a host environment which helps in the colonization of the pathogen [70]. H. pylori is equipped with \"five to seven unipolar\" flagella that are protected against gastric acidity due to the presence of a covering sheath formed of phospholipids [71]. There are a relatively higher number of genes in H. pylori that encodes flagellar proteins supporting the fact that motility facilitates the colonization of the pathogen in the host body; thus, their association with bacterial virulence is also subjected to consideration in the course of drug discovery. HP O26095 is showing similarity with flagellar biosynthetic protein flhb that mediates the formation of flagella. It may be a potential drug target. We found HP O25564 similar to flagellar hook-length control protein FliK that controls the length of the flagellar hook during flagellar biosynthesis [72]. In the H. pylori genome, there are seven known genes encoding molecular chaperons. We have identified HP O25894 is showing homology with molecular chaperon. DnaJ, is signature member of the family of molecular chaperons that exhibit a diverse number of molecular functions such ATP binding, metal ion binding, unfolded protein binding and is involved in a number of leading biological processes like protein folding, protein unfolding, DNA replication, and response to heat shock, etc. [73]. The involvement of chaperons in essential cellular processes required for survival and propagation of pathogen make them potential drug targets for the development of effective drugs against pathogenicity.\nThough we have categorized HPs in the definite functional classes on the basis of their molecular functions and their involvement in diverse biological processes, but there HPs which exhibit some unique functions or functions are not clearly classified in the available literature. We put those HPs in the group of proteins exhibiting miscellaneous functions. HP O25579 is identified as toxin like outer membrane protein and showing significant virulence in virulence factors analysis. We found HP O25993 similar to lipoprotein with positive virulence. Despite the fact that H. pylori infects the host in the free environment, evidence for adherence to epithelial cells of the gastric tissues of the host are also found [64]. Outer membrane proteins and lipoproteins have an effective role in cell adhesion in H. pylori [5]; thus, they may be taken as strong candidates for drug targets. We identified HP O25713 similar to neuraminyllactose-binding hemagglutinin (NLBH) with substantial virulence. In H. pylori, NLBH, which is also a lipoprotein, has an effective role in adhesion to the gastric epithelium of the host [74]. We identified three characterized genes in the H. pylori genome that encodes NLBH proteins at distant locations. 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