Abstract
Glutamine synthetase (GS) is an enzyme that regulates nitrogen metabolism and synthesizes glutamine via glutamate, ATP, and ammonia. GS is a homo-oligomeric protein of eight, ten, or twelve subunits, and each subunit-subunit interface has its own active site. GS can be divided into GS I, GS II, and GS III. GS I and GS III form dodecamer in bacteria and archaea, whereas GS II form decamer in eukaryotes. GS I can be further subdivided into GS I-α and GS I-β according to its sequence and regulatory mechanism. GS is an essential protein for the survival of Helicobacter pylori which its infection could promote gastroduodenal diseases. Here, we determined the crystal structures of the GS from H. pylori (Hpy GS) in its apo- and substrate-bound forms at 2.8 Å and 2.9 Å resolution, respectively. Hpy GS formed a dodecamer composed of two hexameric rings stacked face-to-face. Hpy GS, which belongs to GS I, cannot be clearly classified as either GS I-α or GS I-β based on its sequence and regulatory mechanism. In this study, we propose that Hpy GS could be classified as a new GS-I subfamily and provide structural information on the apo- and substrate-bound forms of the protein.
Highlights
In gram-negative bacteria, ammonia is a unique molecule required for nitrogen anabolism
Glutamine synthetase (GS) I-α enzymes are mainly feedback-inhibited by the end products of glutamine metabolism including AMP and glutamine, whereas GS I-β enzymes are inactivated by the adenylation of a tyrosine residue near the active site (NLYDLP)
The results demonstrated the formation of Hpy GS from a dimer of hexameric rings, and a comparison of the apo, substrate-bound form, and intermediate state revealed the catalytic mechanism upon substrate binding
Summary
In gram-negative bacteria, ammonia is a unique molecule required for nitrogen anabolism. The GS in H. pylori (Hpy GS) is a critical enzyme that is involved in processing the ammonia released by urease activity, and nitrogen metabolism[7]. GS is an enzyme involved in the biosynthetic reaction producing glutamine from the condensation of glutamate and ammonia[8]. This enzyme is present in all living organisms and is a large homo-oligomeric complex composed of eight, ten, or twelve subunits assembled into two face-to-face rings[9]. The GS from B. subtilis (Bsu GS) is categorized as GS I-α, which lacks both the adenylation regulatory mechanism and the specific 25-amino acid residues[22,23]. The crystal structures of Sty GS reports that a flexible loop (residues 324–329 in S. typhimurium) near the active site protects the intermediate and completes the ammonium binding site upon ATP and glutamate binding[12]
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