H pylori Functional Genomics

Features of the genome have yielded insight into the biology of H. pylori. In regard to gene regulation, both of the sequenced strains possess four orthologs of histadine kinase sensor proteins, seven orthologs of DNA-binding response regulators, and only three a factors: RpoD (a70), RpoN (a54), and FliA (a28). No stationary phase a factor RpoS or heat shock a factor RpoH are evident. Subsequent to the primary annotation of the genomes, the anti-a factor FlgM was identified and confirmed to regulate FliA-depen-dent gene expression (68,69). Remarkably, over 20 DNA restriction and modification systems are present in each strain (>4% of all genes), many of which are strain-specific. In some cases, the restriction component is not active, although the cognate methylase is, suggesting that they play a role in gene regulation. Another striking feature of the genome sequences is the large number of low-abundance outer membrane proteins, rather than a limited number of predominant outer membrane proteins seen in other bacteria. There are at least five paralogous families of outer membrane proteins containing 3-33 members each, some of which are strain-specific. Some of these genes, as well as the genes that encode glycosyltransferases involved in lipopolysaccharide biosynthesis, contain homopolymeric or dinucleotide repeats that can mediate metastable regulation (phase variation) by a slipped-strand mechanism. Some of these repeats are in open reading frames (ORFs) where changes in repeat number (owing to slippage of DNA polymerase) will lead to frameshifts and translation of truncated proteins, whereas others are in 5' intergenic regions where changes in repeat length affect promoter activity. Because many of these so-called contingency genes are predicted to affect the bacterial surface, it seems likely that they play a role in modulating antigenicity, perhaps to avoid immune recognition.

Information about H. pylori energy metabolism and biosynthetic pathways was also gained from the genome sequence, including identification of the membrane-embedded F0 and catalytic Fj components of ATP synthase, dehydrogenases, menaquinone, cytochromes, and a terminal oxidase for respiration-coupled oxidative phosphorylation. Fumarate reductase, which may play a role in anaerobic and/or aerobic respiration, as well as superoxide dismutase, catalase, and two peroxidases, presumably to detoxify oxygen species, are also present. Nonetheless, the genetic basis of microaerophily remains incompletely understood. Genes encoding enzymes for nitrogen assimilation, the tricar-boxylic acid cycle, and nucleotide metabolism have also been identified, and a metabolic model has been constructed from genomic information that provides an in silico network of almost 400 H. pylori enzymatic and transport reactions (70). More recently, a global transposon mutagenesis approach has been used to identify essential genes (71).

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