Strained Conformations of Nucleosides in Active Sites of Nucleoside Phosphorylases

• Main Authors: Irina A. Il’icheva, Konstantin M. Polyakov, Sergey N. Mikhailov
• Format: Article
• Language: English
• Published: MDPI AG 2020-04-01
• Series: Biomolecules
• Subjects: nucleoside phosphorylases; X-ray structures of nucleoside phosphorylases; nucleoside conformations
• Online Access: https://www.mdpi.com/2218-273X/10/4/552

Nucleoside phosphorylases catalyze the reversible phosphorolysis of nucleosides to heterocyclic bases, giving α-<span style="font-variant: small-caps;">d</span>-ribose-1-phosphate or α-<span style="font-variant: small-caps;">d</span>-2-deoxyribose-1-phosphate. These enzymes are involved in salvage pathways of nucleoside biosynthesis. The level of these enzymes is often elevated in tumors, which can be used as a marker for cancer diagnosis. This review presents the analysis of conformations of nucleosides and their analogues in complexes with nucleoside phosphorylases of the first (NP-1) family, which includes hexameric and trimeric purine nucleoside phosphorylases (EC 2.4.2.1), hexameric and trimeric 5′-deoxy-5′-methylthioadenosine phosphorylases (EC 2.4.2.28), and uridine phosphorylases (EC 2.4.2.3). Nucleosides adopt similar conformations in complexes, with these conformations being significantly different from those of free nucleosides. In complexes, pentofuranose rings of all nucleosides are at the W region of the pseudorotation cycle that corresponds to the energy barrier to the N↔S interconversion. In most of the complexes, the orientation of the bases with respect to the ribose is in the high-syn region in the immediate vicinity of the barrier to <i>syn ↔ anti</i> transitions. Such conformations of nucleosides in complexes are unfavorable when compared to free nucleosides and they are stabilized by interactions with the enzyme. The sulfate (or phosphate) ion in the active site of the complexes influences the conformation of the furanose ring. The binding of nucleosides in strained conformations is a characteristic feature of the enzyme–substrate complex formation for this enzyme group.