Methionine adenosyltransferase (MAT) catalyzes the biosynthesis of S‐adenosyl methionine from l ‐methionine and ATP. MAT enzymes are ancient, believed to share a common ancestor, and are highly conserved in all three domains of life. However, the sequences of archaeal MATs show considerable divergence compared with their bacterial and eukaryotic counterparts. Furthermore, the structural significance and functional significance of this sequence divergence are not well understood. In the present study, we employed structural analysis and ancestral sequence reconstruction to investigate archaeal MAT divergence. We observed that the dimer interface containing the active site (which is usually well conserved) diverged considerably between the bacterial/eukaryotic MATs and archaeal MAT. A detailed investigation of the available structures supports the sequence analysis outcome: The protein domains and subdomains of bacterial and eukaryotic MAT are more similar than those of archaea. Finally, we resurrected archaeal MAT ancestors. Interestingly, archaeal MAT ancestors show substrate specificity, which is lost during evolution. This observation supports the hypothesis of a common MAT ancestor for the three domains of life. In conclusion, we have demonstrated that archaeal MAT is an ideal system for studying an enzyme family that evolved differently in one domain compared with others while maintaining the same catalytic activity.

Methionine adenosyltransferase (MAT), which catalyzes the biosynthesis of S-adenosylmethionine from L-methionine and ATP, is an ancient, highly conserved enzyme present in all three domains of life. Although the MAT enzymes of each domain are believed to share a common ancestor, the sequences of archaeal MATs show a high degree of divergence from the sequences of bacterial and eukaryotic MATs. However, the structural and functional consequences of this sequence divergence are not well understood. Here, we use structural bioinformatics analysis and ancestral sequence reconstruction to analyze the evolution of archaeal MATs. We show that the dimer interface containing the active site, which would be expected to be well conserved across all three domains, diverged considerably between the bacterial/eukaryotic MATs and archaeal MATs. Furthermore, the characterization of reconstructed ancestral archaeal MATs showed that they probably had low substrate specificity which expanded during their evolutionary trajectory hinting towards the observation that all the modern day MAT enzymes from the three-kingdom probably originated from a common specific ancestor and then archaea MATs diverged in sequence, structure and substrate specificity. Altogether, our results show that the archaea MAT is an ideal system for studying an enzyme family which evolved to display high degrees of divergence at the sequence/structural levels and yet are capable of performing the same catalytic reactions as their orthologous counterparts.

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A 2018 systematic review and meta-analysis of two randomized controlled trials (RCTs; N5740) compared the efficacy of oral proton pump inhibitor (PPI) and H2 blockers for resolution of functional dyspepsia symptoms. 1 Participants were adults with epigastric symptoms present for at least four weeks in the absence of organic disease. The two included multicenter European trials examined omeprazole (10-20 mg/d) and lansoprazole (30 mg/d) compared with control (ranitidine 150 mg 1-2 times a day) administered for 2 to 8 weeks. The primary outcome was global symptoms of dyspepsia, measured at twoweek follow-up. PPIs did not show a significant reduction in global symptoms of dyspepsia compared with H2 blockers (risk ratio 0.88; 95% CI, 0.74-1.04, I 2 551%). The studies reported no serious side effects with short-term PPI or H2 blocker. Overall, the quality of evidence was low. One trial had inadequate reporting of randomization and allocation. The other had unclear risk of bias in nearly all domains and was funded by industry.A 2017 American College of Gastroenterology and Canadian Association of Gastroenterology produced consensus guidelines for the medical management of dyspepsia. 2 For patients younger than 60 years, the guideline recommended noninvasive testing for Helicobacter pylori infection, followed by empiric medical treatment for those with negative H pylori tests or continued symptoms after successful H pylori treatment, stating that PPI therapy was the medication of choice for dyspepsia compared with H2 blockers (strong recommendation, high-quality evidence). For patients aged 60 years or older, the guideline recommended initial endoscopy to exclude neoplasia and testing for H pylori disease; if these evaluations were negative then the authors recommended medical management similar to those younger than 60 years (strong recommendation, high-quality evidence). The guideline recommendations were in part based on several heterogeneous RCTs, which on pooled analysis showed no difference in symptom relief between PPIs and H2 blockers. However, the guideline authors gave PPIs first-line preference noting that there was not a major difference in cost between PPIs and H2 blockers, and they believed that most of the studies supported PPIs over H2 blockers.