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Long-lasting effects of oxy- and sulfoanalogues of L-arginine on enzyme actions.

Dzimbova TA, Milanov PB, Pajpanova TI - J Amino Acids (2013)

Bottom Line: We make use of modeling and docking studies of adenylate kinase (ADK) to reveal the effects produced by the incorporation of the arginine mimetics on the structure of ADK and its action.Mutation in the enzyme active center by arginine mimetics leads to conformational changes, which produce a decrease the rate of the enzyme catalyzed reaction and even a loss of enzymatic action.All these observations could explain the long-lasting nature of the effects of the arginine analogues.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.

ABSTRACT
Arginine residues are very important for the structure of proteins and their action. Arginine is essential for many natural processes because it has unique ionizable group under physiological conditions. Numerous mimetics of arginine were synthesized and their biological effects were evaluated, but the mechanisms of actions are still unknown. The aim of this study is to see if oxy- and sulfoanalogues of arginine can be recognized by human arginyl-tRNA synthetase (HArgS)-an enzyme responsible for coupling of L-arginine with its cognate tRNA in a two-step catalytic reaction. We make use of modeling and docking studies of adenylate kinase (ADK) to reveal the effects produced by the incorporation of the arginine mimetics on the structure of ADK and its action. Three analogues of arginine, L-canavanine (Cav), L-norcanavanine (NCav), and L-sulfoarginine (sArg), can be recognized as substrates of HArgS when incorporated in different peptide and protein sequences instead of L-arginine. Mutation in the enzyme active center by arginine mimetics leads to conformational changes, which produce a decrease the rate of the enzyme catalyzed reaction and even a loss of enzymatic action. All these observations could explain the long-lasting nature of the effects of the arginine analogues.

No MeSH data available.


Related in: MedlinePlus

Superposed active sites of ADK and Arg138 mutated ADK with bis(adenosine)-5′-tetraphosphate (a); focus on Arg138 residue in Arg138 mutated enzymes (b); superposed active sites of ADK and Arg175 mutated ADK with bis(adenosine)-5′-tetraphosphate (c).
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fig7: Superposed active sites of ADK and Arg138 mutated ADK with bis(adenosine)-5′-tetraphosphate (a); focus on Arg138 residue in Arg138 mutated enzymes (b); superposed active sites of ADK and Arg175 mutated ADK with bis(adenosine)-5′-tetraphosphate (c).

Mentions: All three analogues of arginine have the guanidinium group as a structural element. In all three cases, it is connected via more electronegative atoms (oxygen and sulfur) than the carbon atom; thus, it is less polar than guanidinium group of Arg. In all three mutations of Arg138 with its analogues, the typical site for ADP recognition still remains, and the purine moiety binds respectively, to oxy-, and sulfoguanidinium group. In the cases of Cav138 and sArg138 mutations, total energies of the enzyme-substrate complexes decrease, while in the case of Cav138 mutation, total energy increases. Fitness function value is almost the same when Arg138 is replaced by Cav, due to their structural similarity, and conformational changes in that case are very small (Figures 7(a) and 7(b)). When Arg138 is replaced by NCav and sArg, conformational changes in the binding site of the enzyme are bigger, and fitness function values are higher which is connected to the binding affinity of the substrate. The higher the fitness function value, the higher the affinity of the substrate to the enzyme and it will bind more strongly. This will decrease the rate of the enzymatic reaction and most probably will stop it in the case of NCan138 and sArg138.


Long-lasting effects of oxy- and sulfoanalogues of L-arginine on enzyme actions.

Dzimbova TA, Milanov PB, Pajpanova TI - J Amino Acids (2013)

Superposed active sites of ADK and Arg138 mutated ADK with bis(adenosine)-5′-tetraphosphate (a); focus on Arg138 residue in Arg138 mutated enzymes (b); superposed active sites of ADK and Arg175 mutated ADK with bis(adenosine)-5′-tetraphosphate (c).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824642&req=5

fig7: Superposed active sites of ADK and Arg138 mutated ADK with bis(adenosine)-5′-tetraphosphate (a); focus on Arg138 residue in Arg138 mutated enzymes (b); superposed active sites of ADK and Arg175 mutated ADK with bis(adenosine)-5′-tetraphosphate (c).
Mentions: All three analogues of arginine have the guanidinium group as a structural element. In all three cases, it is connected via more electronegative atoms (oxygen and sulfur) than the carbon atom; thus, it is less polar than guanidinium group of Arg. In all three mutations of Arg138 with its analogues, the typical site for ADP recognition still remains, and the purine moiety binds respectively, to oxy-, and sulfoguanidinium group. In the cases of Cav138 and sArg138 mutations, total energies of the enzyme-substrate complexes decrease, while in the case of Cav138 mutation, total energy increases. Fitness function value is almost the same when Arg138 is replaced by Cav, due to their structural similarity, and conformational changes in that case are very small (Figures 7(a) and 7(b)). When Arg138 is replaced by NCav and sArg, conformational changes in the binding site of the enzyme are bigger, and fitness function values are higher which is connected to the binding affinity of the substrate. The higher the fitness function value, the higher the affinity of the substrate to the enzyme and it will bind more strongly. This will decrease the rate of the enzymatic reaction and most probably will stop it in the case of NCan138 and sArg138.

Bottom Line: We make use of modeling and docking studies of adenylate kinase (ADK) to reveal the effects produced by the incorporation of the arginine mimetics on the structure of ADK and its action.Mutation in the enzyme active center by arginine mimetics leads to conformational changes, which produce a decrease the rate of the enzyme catalyzed reaction and even a loss of enzymatic action.All these observations could explain the long-lasting nature of the effects of the arginine analogues.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.

ABSTRACT
Arginine residues are very important for the structure of proteins and their action. Arginine is essential for many natural processes because it has unique ionizable group under physiological conditions. Numerous mimetics of arginine were synthesized and their biological effects were evaluated, but the mechanisms of actions are still unknown. The aim of this study is to see if oxy- and sulfoanalogues of arginine can be recognized by human arginyl-tRNA synthetase (HArgS)-an enzyme responsible for coupling of L-arginine with its cognate tRNA in a two-step catalytic reaction. We make use of modeling and docking studies of adenylate kinase (ADK) to reveal the effects produced by the incorporation of the arginine mimetics on the structure of ADK and its action. Three analogues of arginine, L-canavanine (Cav), L-norcanavanine (NCav), and L-sulfoarginine (sArg), can be recognized as substrates of HArgS when incorporated in different peptide and protein sequences instead of L-arginine. Mutation in the enzyme active center by arginine mimetics leads to conformational changes, which produce a decrease the rate of the enzyme catalyzed reaction and even a loss of enzymatic action. All these observations could explain the long-lasting nature of the effects of the arginine analogues.

No MeSH data available.


Related in: MedlinePlus