Role of Structural Features in Oligomerization, Active-Site Integrity and Ligand Binding of Ribose-1,5-Bisphosphate Isomerase

Abstract

Pentose bisphosphate pathway, exclusively found in archaea, is similar to the pentose phosphate pathway present in bacteria and eukarya. In pentose bisphosphate pathway, the conversion of ribose moieties of nucleosides into 3-phosphoglycerate (3-PGA) involves multiple steps; one of them being the conversion of ribose-1,5-bisphosphate (R15P) to ribulose-1,5-bisphosphate (RuBP) catalyzed by an enzyme ribose-1,5-bisphosphate isomerase (R15Pi). The availability of the three-dimensional structure of R15Pi had facilitated the understanding of various structural and functional aspects of the enzyme. Nevertheless, the structure of R15Pi also left several significant questions unanswered that would aid in understanding the structure-function relationship of the enzyme. Thus, we have taken up a computational approach to further understand the role of various structural features of the enzyme R15Pi. Results obtained from molecular dynamics (MD) simulations aided in understanding the obligation of the enzyme R15Pi to oligomerize and also in deciphering the role of catalytic residue(s) in structural stability. Identification of invariant water molecules of the enzyme R15Pi helped in discerning their significance at the active-site pocket and structurally important regions. Further, molecular docking studies allowed the identification of the amino acid residues essential for holding the substrate (R15P) or product (RuBP) in the vicinity of the active site of the enzyme R15Pi. Interestingly, results of the molecular docking studies assisted in the identification of an “alternate binding site” for the substrate, R15P. Finally, based on these results, we propose a mechanism of “substrate sliding” for the enzyme R15Pi.