Reactive oxygen species inhibit catalytic activity of peptidylarginine deiminase
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Reactive oxygen species inhibit catalytic activity of peptidylarginine deiminase. / Damgaard, Dres; Bjørn, Mads Emil; Jensen, Peter Østrup; Nielsen, Claus Henrik.
In: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 32, No. 1, 12.2017, p. 1203-1208.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Reactive oxygen species inhibit catalytic activity of peptidylarginine deiminase
AU - Damgaard, Dres
AU - Bjørn, Mads Emil
AU - Jensen, Peter Østrup
AU - Nielsen, Claus Henrik
PY - 2017/12
Y1 - 2017/12
N2 - Protein citrullination catalysed by peptidylarginine deiminase (PAD) may play an important pathogenic role in several chronic inflammatory diseases and malignancies. PAD2, PAD4, and citrullinated proteins are found in the synovium of rheumatoid arthritis patients. PAD activity is dependent on calcium and reducing conditions. However, reactive oxygen species (ROS) have been shown to induce citrullination of histones in granulocytes. Here we examine the ability of H2O2 and leukocyte-derived ROS to regulate PAD activity using citrullination of fibrinogen as read-out. H2O2 at concentrations above 40 µM inhibited the catalytic activity of PAD2 and PAD4 in a dose-dependent manner. PMA-stimulated leukocytes citrullinated fibrinogen and this citrullination was markedly enhanced when ROS formation was inhibited by the NADPH oxidase inhibitor diphenyleneiodonium (DPI). In contrast, PAD released from stimulated leukocytes was unaffected by exogenously added H2O2 at concentrations up to 1000 µM. The role of ROS in regulating PAD activity may play an important part in preventing hypercitrullination of proteins.
AB - Protein citrullination catalysed by peptidylarginine deiminase (PAD) may play an important pathogenic role in several chronic inflammatory diseases and malignancies. PAD2, PAD4, and citrullinated proteins are found in the synovium of rheumatoid arthritis patients. PAD activity is dependent on calcium and reducing conditions. However, reactive oxygen species (ROS) have been shown to induce citrullination of histones in granulocytes. Here we examine the ability of H2O2 and leukocyte-derived ROS to regulate PAD activity using citrullination of fibrinogen as read-out. H2O2 at concentrations above 40 µM inhibited the catalytic activity of PAD2 and PAD4 in a dose-dependent manner. PMA-stimulated leukocytes citrullinated fibrinogen and this citrullination was markedly enhanced when ROS formation was inhibited by the NADPH oxidase inhibitor diphenyleneiodonium (DPI). In contrast, PAD released from stimulated leukocytes was unaffected by exogenously added H2O2 at concentrations up to 1000 µM. The role of ROS in regulating PAD activity may play an important part in preventing hypercitrullination of proteins.
KW - Biocatalysis
KW - Dose-Response Relationship, Drug
KW - Humans
KW - Hydrogen Peroxide
KW - Hydrolases
KW - Leukocytes
KW - Molecular Structure
KW - Reactive Oxygen Species
KW - Recombinant Proteins
KW - Structure-Activity Relationship
KW - Journal Article
U2 - 10.1080/14756366.2017.1368505
DO - 10.1080/14756366.2017.1368505
M3 - Journal article
C2 - 28933232
VL - 32
SP - 1203
EP - 1208
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
SN - 1475-6366
IS - 1
ER -
ID: 185936915