Structure, function and substrate preferences of archaeal S-adenosyl-l-homocysteine hydrolases

Abstract

Abstract S-Adenosyl-l-homocysteine hydrolase (SAHH) reversibly cleaves S-adenosyl-l-homocysteine, the product of S-adenosyl-l-methionine-dependent methylation reactions. The conversion of S-adenosyl-l-homocysteine into adenosine and l-homocysteine plays an important role in the regulation of the methyl cycle. An alternative metabolic route for S-adenosyl-l-methionine regeneration in the extremophiles Methanocaldococcus jannaschii and Thermotoga maritima has been identified, featuring the deamination of S-adenosyl-l-homocysteine to S-inosyl-l-homocysteine. Herein, we report the structural characterisation of different archaeal SAHHs together with a biochemical analysis of various SAHHs from all three domains of life. Homologues deriving from the Euryarchaeota phylum show a higher conversion rate with S-inosyl-l-homocysteine compared to S-adenosyl-l-homocysteine. Crystal structures of SAHH originating from Pyrococcus furiosus in complex with S lH and inosine as ligands, show architectural flexibility in the active site and offer deeper insights into the binding mode of hypoxanthine-containing substrates. Altogether, the findings of our study support the understanding of an alternative metabolic route for S-adenosyl-l-methionine and offer insights into the evolutionary progression and diversification of SAHHs involved in methyl and purine salvage pathways.