Metabolism and genetics of Helicobacter pylori: the genome era

Abstract

The publication of the complete sequence of Helicobacter pylori 26695 in 1997 and more recently that of strain J99 has provided new insight into the biology of this organism. In this review, we attempt to analyze and interpret the information provided by sequence annotations and to compare these data with those provided by experimental analyses. After a brief description of the general features of the genomes of the two sequenced strains, the principal metabolic pathways are analyzed. In particular, the enzymes encoded by H. pylori involved in fermentative and oxidative metabolism, lipopolysaccharide biosynthesis, nucleotide biosynthesis, aerobic and anaerobic respiration, and iron and nitrogen assimilation are described, and the areas of controversy between the experimental data and those provided by the sequence annotation are discussed. The role of urease, particularly in pH homeostasis, and other specialized mechanisms developed by the bacterium to maintain its internal pH are also considered. The replicational, transcriptional, and translational apparatuses are reviewed, as is the regulatory network. The numerous findings on the metabolism of the bacteria and the paucity of gene expression regulation systems are indicative of the high level of adaptation to the human gastric environment. Arguments in favor of the diversity of H. pylori and molecular data reflecting possible mechanisms involved in this diversity are presented. Finally, we compare the numerous experimental data on the colonization factors and those provided from the genome sequence annotation, in particular for genes involved in motility and adherence of the bacterium to the gastric tissue.

FIG. 1

Glycolysis, gluconeogenesis, pentose phosphate, and Entner-Doudoroff pathways. Glycolysis: glk, glucokinase; pgi, phosphoglucose isomerase; pfk, phosphofructokinase; fda, fructose-1,6-bisphosphate aldolase; tpi, triose-phosphate isomerase; gap, glyceraldehyde-3-phosphate dehydrogenase; pgk, phosphoglycerate kinase; pgm, phosphoglycerate mutase; eno, enolase; pyk, pyruvate kinase. Gluconeogenesis: the same enzymes as in glycolysis but with unidirectional steps, i.e., ppsA, phosphoenol pyruvate synthase; fbp, fructose-1,6 bisphosphatase; and g6p, glucose-6 phosphatase. Pentose phosphate: g6pD (devB), glucose-6-phosphate dehydrogenase; lactonase; gnd, 6-phosphogluconate dehydrogenase; rpe, d-ribulose-5-phosphate 3 epimerase; tal, transaldolase; tkt, transketolase. Entner-Doudoroff: edd, 6-phosphosgluconate dehydratase; eda, 2-keto-3-deoxy-6-phosphogluconate aldolase. Asterisks denote enzymes for which no gene was identified in the H. pylori sequence. The circle denotes an enzyme whose enzymatic activity has not been observed but whose corresponding gene was identified.

FIG. 2

Dicarboxylic and tricarboxylic acid branches of the noncyclic Krebs cycle. gltA, citrate synthase; acnB, aconitase; icd, isocitrate dehydrogenase; sucAB, α-ketoglutarate dehydrogenase; frdABC, fumarate reductase; fumC, fumarase; mdh, malate dehydrogenase; aceB, malate synthase. Asterisks denote enzymes for which no genes were identified in the H. pylori sequence; crosses denote enzymes whose enzymatic activities were observed but the corresponding genes were not identified. Reprinted from reference with permission of the publisher.

FIG. 3

Initiation (A) and elongation (B) phases of fatty acid biosynthesis. Initiation: accA, carboxyltransferase (α subunit); accD, carboxyltransferase (β subunit); fadA, thiolase; fabD, malonyl-CoA:ACP transacylase. Elongation: fabF, 3-ketoacyl-ACP synthase; fabH, 3-ketoacyl-ACP synthase; fabI, enoyl-ACP reductase; fabG, 3-ketoacyl-ACP-reductase; fabZ, (3R)-hydroxymyristoyl-ACP dehydratase.

FIG. 4

Synthesis of phosphatidic acid, PS, PE, PGP, PG, and cardiolipin. plsX, glyceraldehyde-3-phosphate (G3P) acyltransferase; plsC, 1-acyl-G1P acyltransferase; cdsA, CDP-diglycerol synthase; pssA, PS synthase; psd, PS decarboxylase; pgsA, PGP synthase; pgp, PGP phosphatase; cls, cardiolipin synthase. Asterisks denote enzymes for which no genes were identified in the H. pylori sequence.

FIG. 5

De novo synthesis of UTP and CTP (A) and ATP and GTP (B). (A) pyrA, carbamoyl-phosphate synthase; pyrB, aspartate transcarbamoylase; pyrC, dihydroorotase; pyrD, dihydroorotase dehydrogenase; pyrE, orotate phosphoribosyltransferase; pyrF, OMP decarboxylase; pyrH, UMP kinase; ndk, nucleoside diphosphokinase; pyrG, CTP synthetase. (B) guaB, IMP dehydrogenase; guaA, GMP synthase; gmk, GMP kinase; purA, adenylosuccinate synthetase; purB, adenylosuccinate lyase; adk, adenylate kinase.

FIG. 6

Purine salvage pathways. deoD, purine nucleoside phosphorylase; apt, adenine phosphoribosyltransferase; gpt, xanthine/guanine phosphoribosyltransferase. Circles denote enzymes whose enzymatic activities have not been observed but whose corresponding genes were identified. Dashed arrows show steps given in detail in Fig. 5B.

FIG. 7

Deoxyribonucleotide biosynthesis. nrd, ribonucleoside diphosphate reductase; ndk, nucleoside diphosphokinase; dcd, dCTP deaminase; dut, deoxyuridinetriphosphatase; thyA, thymidylate synthase; tmk, thymidylate kinase. The asterisk denotes an enzyme for which no corresponding gene was identified. N can be A, C, and U.

FIG. 8

Ammonia assimilatory cycle in E. coli and in H. pylori.

FIG. 9

Diversity of the VacA protein.

FIG. 10

Conserved domains between VacA and related proteins encoded by H. pylori 26695. The different shadings represent regions of similarity. aa, amino acids.

FIG. 11

Schematic organization of the cag pathogenicity island. The orientations of the genes are indicated.