Citrullination of adenosine deaminase impairs its binding to dipeptidyl peptidase IV

Karapetnyan, Luiza; Sharoyan, Svetlana; Mardanyan, Sona; Lupidi, Giulio; Cuccioloni, Massimiliano; Angeletti, Mauro; Markarian, Shiraz A.; Shilajyan, Hasmik A.; Antonyan, Alvard

doi:10.1016/j.bpc.2022.106820

Cited by 3 publications

(4 citation statements)

References 33 publications

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“…3-5), there was no indication of the presence of citrullinated proteins in the native PAGE electropherograms. In contrary the slow mobility of citrullinated ADA from synovial fluids of RA patients was observed in our previous study [47].…”

Section: Groupcontrasting

confidence: 78%

“…Its large extracellular form (LADA, Mm ≥ 260 kDa) is a non-covalent complex of SADA with dipeptidyl peptidase 4 enzyme (DPP4). The described in our works accumulation of SADA in synovial fluids at RA was a consequence of autoimmune nature of this pathology [20], when SADA citrullination prevented its interaction with DPP4 and transformation into LADA [21,22]. At T2DM, the observed increase of ADA activity in blood plasma, can lead to changes in immunity and exacerbation of the pathogenesis [23,24].…”

mentioning

confidence: 86%

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Characteristics of Some Enzymes in Blood Plasma of Diabetic Humans

Balagyozyan,

Karapetyan,

Sharoyan

et al. 2023

Proc. YSU B: Chem. Biol. Sci.

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Тhe enzymes adenosine deaminase (ADA), dipeptidyl peptidase 4 (DPP4) and glutaminase (GL) are involved in the development of both the type 1 (T1DM) and type 2 diabetes mellitus (T2DM). They can be considered as targets in the prevention and/or treatment of these diseases. The autoimmune response of the body is caused by the post-translational protein modifications, one of which is protein citrullination, when arginine residue transforms to citrulline. This work compares the ADA, DPP4, GL enzymes and protein citrullination in blood plasma from T1DM, T2DM patients and relatively healthy individuals. The enzymes were isolated and purified from the blood samples. We found that DPP4 activity was significantly higher in the plasma of patients compared to controls, particularly in T1DM. Currently the medicines based on DPP4 inhibitors are used in the treatment of T2DM. Our results indicate that this treatment strategy can be recommended in the T1DM treatment as well.

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Section: Groupcontrasting

confidence: 78%

mentioning

confidence: 86%

Characteristics of Some Enzymes in Blood Plasma of Diabetic Humans

Balagyozyan,

Karapetyan,

Sharoyan

et al. 2023

Proc. YSU B: Chem. Biol. Sci.

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show abstract

“…Furthermore, DP4 is implicated to be involved in several physiological processes by binding proteins such as adenosine deaminase, collagen, fibronectin, HIV coat protein gp120, plasminogen, HIV tat protein and the tyrosine phosphatase, CD45. However, these protein interactions do not affect the proteolytic activity of the enzyme [8][9][10][11].…”

Section: Introductionmentioning

confidence: 96%

Contribution of amino acids in the Active site of Dipeptidyl Peptidase 4 to the catalytic action of the enzyme

Gnoth

Bär

Rosche

et al. 2023

Preprint

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Dipeptidyl peptidase 4 (DP4)/CD26 regulates the biological function of various peptide hormones by releasing dipeptides from their N?terminus. The enzyme is a prominent target for the treatment of type-2 diabetes and various DP4 inhibitors have been developed in recent years, but their efficacy and side effects are still an issue. Many available crystal structures of the enzyme give a static picture about enzyme-ligand interactions, but the influence of amino acids in the active centre on binding and single catalysis steps can only be judged by mutagenesis studies. In order to elucidate their contribution to inhibitor binding and substrate catalysis, especially in discriminating the P1 amino acid of substrates, the amino acids R125, N710, E205 and E206 were investigated by mutagenesis studies. Our studies demonstrated, that N710 is essential for the catalysis of dipeptide substrates. We found that R125 is not important for dipeptide binding but interacts in the P1'position of the peptide backbone. In contrast to dipeptide substrates both amino acids play an essential role in the binding and arrangement of long natural substrates, particularly if lacking proline in the P1 position. Thus, it can be assumed that the amino acids R125 and N710 are important in the DP4 catalysed substrate hydrolysis by interacting with the peptide backbone of substrates up- and downstream of the cleavage site. Furthermore, we confirmed the important role of the amino acids E205 and E206. However, NP Y, displaying proline in P1 position, is still processed without the participation of E205 or E206.

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Section: Introductionmentioning

confidence: 99%

Contribution of amino acids in the active site of dipeptidyl peptidase 4 to the catalytic action of the enzyme

Gnoth,

Bär,

Rosche

et al. 2024

PLoS ONE

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Dipeptidyl peptidase 4 (DP4)/CD26 regulates the biological function of various peptide hormones by releasing dipeptides from their N-terminus. The enzyme is a prominent target for the treatment of type-2 diabetes and various DP4 inhibitors have been developed in recent years, but their efficacy and side effects are still an issue. Many available crystal structures of the enzyme give a static picture about enzyme-ligand interactions, but the influence of amino acids in the active centre on binding and single catalysis steps can only be judged by mutagenesis studies. In order to elucidate their contribution to inhibitor binding and substrate catalysis, especially in discriminating the P1 amino acid of substrates, the amino acids R125, N710, E205 and E206 were investigated by mutagenesis studies. Our studies demonstrated, that N710 is essential for the catalysis of dipeptide substrates. We found that R125 is not important for dipeptide binding but interacts in the P1`position of the peptide backbone. In contrast to dipeptide substrates both amino acids play an essential role in the binding and arrangement of long natural substrates, particularly if lacking proline in the P1 position. Thus, it can be assumed that the amino acids R125 and N710 are important in the DP4 catalysed substrate hydrolysis by interacting with the peptide backbone of substrates up- and downstream of the cleavage site. Furthermore, we confirmed the important role of the amino acids E205 and E206. However, NP Y, displaying proline in P1 position, is still processed without the participation of E205 or E206.

show abstract

Citrullination of adenosine deaminase impairs its binding to dipeptidyl peptidase IV

Cited by 3 publications

References 33 publications

Characteristics of Some Enzymes in Blood Plasma of Diabetic Humans

Characteristics of Some Enzymes in Blood Plasma of Diabetic Humans

Contribution of amino acids in the Active site of Dipeptidyl Peptidase 4 to the catalytic action of the enzyme

Contribution of amino acids in the active site of dipeptidyl peptidase 4 to the catalytic action of the enzyme

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