Reactive oxygen species inhibit catalytic activity of peptidylarginine deiminase

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 - 2017/1/1

Y1 - 2017/1/1

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

SN - 1475-6366

VL - 32

SP - 1203

EP - 1208

JO - Journal of Enzyme Inhibition and Medicinal Chemistry

JF - Journal of Enzyme Inhibition and Medicinal Chemistry

IS - 1

ER -