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Aldolases Utilize Different Oligomeric States To Preserve Their Functional Dynamics.

ABSTRACT: Aldolases are essential enzymes in the glycolysis pathway and catalyze the reaction cleaving fructose/tagatose 1,6-bisphosphate into dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. To determine how the aldolase motions relate to its catalytic process, we studied the dynamics of three different class II aldolase structures through simulations. We employed coarse-grained elastic network normal-mode analyses to investigate the dynamics of Escherichia coli fructose 1,6-bisphosphate aldolase, E. coli tagatose 1,6-bisphosphate aldolase, and Thermus aquaticus fructose 1,6-bisphosphate aldolase and compared their motions in different oligomeric states. The first one is a dimer, and the second and third are tetramers. Our analyses suggest that oligomerization not only stabilizes the aldolase structures, showing fewer fluctuations at the subunit interfaces, but also allows the enzyme to achieve the required dynamics for its functional loops. The essential mobility of these loops in the functional oligomeric states can facilitate the enzymatic mechanism, substrate recruitment in the open state, bringing the catalytic residues into their required configuration in the closed bound state, and moving back to the open state to release the catalytic products and repositioning the enzyme for its next catalytic cycle. These findings suggest that the aldolase global motions are conserved among aldolases having different oligomeric states to preserve its catalytic mechanism. The coarse-grained approaches taken permit an unprecedented view of the changes in the structural dynamics and how these relate to the critical structural stabilities essential for catalysis. The results are supported by experimental findings from many previous studies.

SUBMITTER: Katebi AR

PROVIDER: S-EPMC6662587 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Aldolases Utilize Different Oligomeric States To Preserve Their Functional Dynamics.

Katebi Ataur R AR Jernigan Robert L RL

Biochemistry 20150527 22

Aldolases are essential enzymes in the glycolysis pathway and catalyze the reaction cleaving fructose/tagatose 1,6-bisphosphate into dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. To determine how the aldolase motions relate to its catalytic process, we studied the dynamics of three different class II aldolase structures through simulations. We employed coarse-grained elastic network normal-mode analyses to investigate the dynamics of Escherichia coli fructose 1,6-bisphosphate aldola ...[more]

PMID: 25982518

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Project description:BackgroundDespite the effectiveness of glucagon-like peptide-1 agonist (GLP-1A) in the treatment of diabetes, its large molecular weight and high hydrophilicity result in poor cellular permeability, thus limiting its oral bioavailability. To address this, we developed a chimeric GLP-1A that targets transporter-mediated endocytosis to enhance cellular permeability to GLP-1A by utilizing the transporters available in the intestine, particularly the apical sodium-dependent bile acid transporter (ASBT).MethodsIn silico molecular docking and molecular dynamics simulations were used to investigate the binding interactions of mono-, bis-, and tetra-deoxycholic acid (DOCA) (monoDOCA, bisDOCA, and tetraDOCA) with ASBT. After synthesizing the chimeric GLP-1A-conjugated oligomeric DOCAs (mD-G1A, bD-G1A, and tD-G1A) using a maleimide reaction, in vitro cellular permeability and insulinotropic effects were assessed. Furthermore, in vivo oral absorption in rats and hypoglycemic effect on diabetic db/db mice model were evaluated.ResultsIn silico results showed that tetraDOCA had the lowest interaction energy, indicating high binding affinity to ASBT. Insulinotropic effects of GLP-1A-conjugated oligomeric DOCAs were not different from those of GLP-1A-Cys or exenatide. Moreover, bD-G1A and tD-G1A exhibited improved in vitro Caco-2 cellular permeability and showed higher in vivo bioavailability (7.58% and 8.63%) after oral administration. Regarding hypoglycemic effects on db/db mice, tD-G1A (50 μg/kg) lowered the glucose level more than bD-G1A (50 μg/kg) compared with the control (35.5% vs. 26.4%).ConclusionGLP-1A was conjugated with oligomeric DOCAs, and the resulting chimeric compound showed the potential not only for glucagon-like peptide-1 receptor agonist activity but also for oral delivery. These findings suggest that oligomeric DOCAs can be used as effective carriers for oral delivery of GLP-1A, offering a promising solution for enhancing its oral bioavailability and improving diabetes treatment.

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Aldolases Utilize Different Oligomeric States To Preserve Their Functional Dynamics.

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Aldolases Utilize Different Oligomeric States To Preserve Their Functional Dynamics.

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