Dataset Information

Molecular dynamic simulations of Escherichia coli L-asparaginase to illuminate its role in deamination of asparagine and glutamine residues.

ABSTRACT: Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. L-Asparagine (L-Asn) and L-Glutamine (L-Gln) deamination play a crucial role in ALL treatment. Role of Elspar® (L-asparaginase from Escherichia coli) in regulation of L-Asn and L-Gln has been confirmed by the other researchers through experimental studies. Therapeutic research against ALL remained elusive with the lack of information on molecular interactions of Elspar® with amino acid substrates. In the present study, using different docking tools binding cavities, key residues in binding and ligand binding mechanisms were identified. For the apo state enzyme and ligand bound state complexes, MD simulations were performed. Trajectory analysis for 30 ns run confirmed the kinship of L-Asn with L-asparaginase enzyme in the dynamic system with less stability in comparison to L-Gln docked complex. Overall findings strongly supported the bi-functional nature of the enzyme drug. A good number of conformational changes were observed with 1NNS structure due to ligand binding. Results of present study give much more information on structural and functional aspects of E. coli L-asparaginase upon the interaction with its ligands which may be useful in designing effective therapeutics for ALL.

SUBMITTER: Erva RR

PROVIDER: S-EPMC4695448 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Molecular dynamic simulations of Escherichia coli L-asparaginase to illuminate its role in deamination of asparagine and glutamine residues.

Erva Rajeswara Reddy RR Rajulapati Satish Babu SB Potla Durthi Chandrasai C Bhatia Mayuri M Pola Madhuri M

3 Biotech 20151229 1

Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. L-Asparagine (L-Asn) and L-Glutamine (L-Gln) deamination play a crucial role in ALL treatment. Role of Elspar<sup>®</sup> (L-asparaginase from Escherichia coli) in regulation of L-Asn and L-Gln has been confirmed by the other researchers through experimental studies. Therapeutic research against ALL remained elusive with the lack of information on molecular interactions of Elspar<sup>®</sup> with amino acid substrates. In the p ...[more]

PMID: 28330072

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Project description:We report the results of an investigation into the catalytic role of highly conserved amide (asparagine, glutamine) and OH-containing (serine, tyrosine) residues in several prenyltransferases. We first obtained the X-ray structure of cyclolavandulyl diphosphate synthase containing two molecules of the substrate analog dimethylallyl (S)-thiolodiphosphate (DMASPP). The two molecules have similar diphosphate group orientations to those seen in other ζ-fold (cis- head-to-tail and head-to-middle) prenyltransferases with one diphosphate moiety forming a bidentate chelate with Mg2+ in the so-called S1 site (which is typically the allylic binding site in ζ-fold proteins) while the second diphosphate binds to Mg2+ in the so-called S2 site (which is typically the homoallylic binding site in ζ-fold proteins) via a single P1O1 oxygen. The latter interaction can facilitate direct phosphate-mediated proton abstraction via P1O2, or more likely by an indirect mechanism in which P1O2 stabilizes a basic asparagine species that removes H+, which is then eliminated via an Asn-Ser shuttle. The universal occurrence of Asn-Ser pairs in ζ-fold proteins leads to the idea that the highly conserved amide (Asn, Gln) and OH-containing (Tyr) residues seen in many "head-to-head" prenyltransferases such as squalene and dehydrosqualene synthase might play similar roles, in H+ elimination. Structural, bioinformatics and mutagenesis investigations indeed indicate an important role of these residues in catalysis, with the results of density functional theory calculations showing that Asn bound to Mg2+ can act as a general (imine-like) base, while Gln, Tyr and H2O form a proton channel that is adjacent to the conventional (Asp-rich) "active site". Taken together, our results lead to mechanisms of proton-elimination from carbocations in numerous prenyltransferases in which neutral species (Asn, Gln, Ser, Tyr, H2O) act as proton shuttles, complementing the more familiar roles of acidic groups (in Asp and Glu) that bind to Mg2+, and basic groups (primarily Arg) that bind to diphosphates, in isoprenoid biosynthesis.

Dataset Information

Molecular dynamic simulations of Escherichia coli L-asparaginase to illuminate its role in deamination of asparagine and glutamine residues.

Publications

Molecular dynamic simulations of Escherichia coli L-asparaginase to illuminate its role in deamination of asparagine and glutamine residues.

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