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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

Binding of ATP to HArgS (a), l-arginine to HArgS without ATP (b), and l-arginine to HArgS with ATPc.
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fig4: Binding of ATP to HArgS (a), l-arginine to HArgS without ATP (b), and l-arginine to HArgS with ATPc.

Mentions: It is known [47] that ATP binds to the loop close to the binding site of arginine. This helps the forming of the arginyl-AMP. It interacts electrostatically with Arg325 (Figure 4(a)). When there is no ATP molecule attached to HArgS, arginine binds as shown in Figure 4(b). All the H-bonding capability of the substrate is used by the protein for the specific recognition. The α-amino group of arginine forms H-bonds with main chain carbonyls of Ser133 and Phe134, while α-carboxylate interacts with the amide nitrogen of Asn135 and phenyl oxygen of Tyr322. Residues Ser133 and Asn135 are very important for correct recognition of α-amino and α-carboxyl groups. The guanidinium group forms two salt bridges with two carboxylate residues: Glu130 and Asp326. If ATP binds, some conformational changes occur, and α-carboxyl group of arginine interacts with Arg325, and this facilitates forming the arginyl-AMP (Figure 4(c)).


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

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

Binding of ATP to HArgS (a), l-arginine to HArgS without ATP (b), and l-arginine to HArgS with ATPc.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Binding of ATP to HArgS (a), l-arginine to HArgS without ATP (b), and l-arginine to HArgS with ATPc.
Mentions: It is known [47] that ATP binds to the loop close to the binding site of arginine. This helps the forming of the arginyl-AMP. It interacts electrostatically with Arg325 (Figure 4(a)). When there is no ATP molecule attached to HArgS, arginine binds as shown in Figure 4(b). All the H-bonding capability of the substrate is used by the protein for the specific recognition. The α-amino group of arginine forms H-bonds with main chain carbonyls of Ser133 and Phe134, while α-carboxylate interacts with the amide nitrogen of Asn135 and phenyl oxygen of Tyr322. Residues Ser133 and Asn135 are very important for correct recognition of α-amino and α-carboxyl groups. The guanidinium group forms two salt bridges with two carboxylate residues: Glu130 and Asp326. If ATP binds, some conformational changes occur, and α-carboxyl group of arginine interacts with Arg325, and this facilitates forming the arginyl-AMP (Figure 4(c)).

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