Abstract
S-adenosyl-l-homocysteine hydrolase (SAHase) is a major regulator of cellular methylation reactions that occur in eukaryotic and prokaryotic organisms. SAHase activity is also a significant source of l-homocysteine and adenosine, two compounds involved in numerous vital, as well as pathological processes. Therefore, apart from cellular methylation, the enzyme may also influence other processes important for the physiology of particular organisms. Herein, presented is the structural characterization and comparison of SAHases of eukaryotic and prokaryotic origin, with an emphasis on the two principal domains of SAHase subunit based on the Rossmann motif. The first domain is involved in the binding of a substrate, e.g., S-adenosyl-l-homocysteine or adenosine and the second domain binds the NAD+ cofactor. Despite their structural similarity, the molecular interactions between an adenosine-based ligand molecule and macromolecular environment are different in each domain. As a consequence, significant differences in the conformation of d-ribofuranose rings of nucleoside and nucleotide ligands, especially those attached to adenosine moiety, are observed. On the other hand, the chemical nature of adenine ring recognition, as well as an orientation of the adenine ring around the N-glycosidic bond are of high similarity for the ligands bound in the substrate- and cofactor-binding domains.
Highlights
The Rossmann fold is one of the evolutionarily oldest and at the same time it is the most common protein motif responsible for selective binding of nucleosides and nucleotides [1,2,3,4,5]
Binding modes of particular ligands present in substrate-binding domain (SBD) and cofactor-binding domain (CBD) were described in detail for the enzymes of various origins
None of those studies were to compare: (i) two major domains of S-adenosyl-l-homocysteine hydrolase (SAHase) subunit, (ii) recognition modes of nucleoside and nucleotide ligands bound in a SAHase subunit, and (iii) conformation of ligand molecules present in SBD and CBD of the subunit of SAHase that derived from various organisms, to highlight any possible similarities and/or differences
Summary
The Rossmann fold is one of the evolutionarily oldest and at the same time it is the most common protein motif responsible for selective binding of nucleosides and nucleotides [1,2,3,4,5]. The second enzyme is S-adenosyl-l-homocysteine hydrolase (SAHase), which converts SAH to adenosine (Ado) and l-homocysteine (Hcy), whose subunit contains two Rossmann-fold domains. The differences reflect the absence of eight to eleven amino acid residues at the C-terminal tail of archaeal-type SAHases and the presence of an insert of approximately forty amino acid residues in most bacterial sequences. This additional segment is present in all plant SAHases and some other eukaryotic enzymes, but it is absent in fungal, insect, and vertebrate enzymes. A SAHase subunit is folded into three domains: substrate- and cofactor-binding domains, and a smaller C-terminal dimerization domain (DD). 3H9U 3G1U 5HM8 6UK3 5V96 3OND [21] 3ONE [21] 3ONF [21] 3CE6 [22] 4LVC [23] 4LVC [23] 6GBN [25] 6F3M [26] 6F3P [26] 6F3Q [26] 3D64 3GLQ 3N58 6APH 3X2E [27] 3X2F [27]
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