TY - JOUR

T1 - Heparan sulfate degradation via reductive homolysis of its N-chloro derivatives

AU - Rees, Martin D

AU - Davies, Michael Jonathan

PY - 2006/3/8

Y1 - 2006/3/8

N2 - The highly basic heme enzyme myeloperoxidase (MPO), which is released by activated phagocytes, catalyzes the production of the potent oxidant hypochlorite (HOCl) from H(2)O(2) and chloride ions (Cl(-)). Heparan sulfate proteoglycans are key components of the extracellular matrix and cell surfaces and are known to bind MPO avidly via their negatively charged heparan sulfate chains. Reaction of heparan sulfate with HOCl generates polymer-derived N-chloro derivatives (chloramines, dichloramines, N-chlorosulfonamides, and chloramides). In this study, it is shown that heparan sulfate N-chloro derivatives are decomposed in the presence of redox-active transition-metal ions and superoxide (O(2)(*-)). These processes initiate polymer modification/fragmentation. Radical intermediates in these processes have been identified by EPR spectroscopy and spin trapping. Evidence has been obtained that the N-chloro derivatives undergo reductive homolysis to nitrogen-centered (aminyl, N-chloroaminyl, sulfonamidyl, and amidyl) radicals that generate carbon-centered radicals via rapid, intramolecular hydrogen atom abstraction reactions (1,2- and/or 1,5-shifts). In the case of the sulfonamidyl radicals, rearrangement via 1,2-shifts and beta-scission of the resultant C-2 carbon-centered radicals to yield SO(3)(*-) and C-2 imines is near quantitative based on the yield of SO(4)(2-), the decomposition product of SO(3)(*-). The formation of strand breaks and chromophores during these reactions is attributed to the formation and subsequent heterolytic rearrangement of the C-2 imines. The degradation of heparan sulfate via reductive homolysis of its N-chloro derivatives may be of significance at sites of inflammation, where MPO-derived HOCl is produced in high concentration and transition-metal ions and O(2)(*-) are known to be present or generated.

AB - The highly basic heme enzyme myeloperoxidase (MPO), which is released by activated phagocytes, catalyzes the production of the potent oxidant hypochlorite (HOCl) from H(2)O(2) and chloride ions (Cl(-)). Heparan sulfate proteoglycans are key components of the extracellular matrix and cell surfaces and are known to bind MPO avidly via their negatively charged heparan sulfate chains. Reaction of heparan sulfate with HOCl generates polymer-derived N-chloro derivatives (chloramines, dichloramines, N-chlorosulfonamides, and chloramides). In this study, it is shown that heparan sulfate N-chloro derivatives are decomposed in the presence of redox-active transition-metal ions and superoxide (O(2)(*-)). These processes initiate polymer modification/fragmentation. Radical intermediates in these processes have been identified by EPR spectroscopy and spin trapping. Evidence has been obtained that the N-chloro derivatives undergo reductive homolysis to nitrogen-centered (aminyl, N-chloroaminyl, sulfonamidyl, and amidyl) radicals that generate carbon-centered radicals via rapid, intramolecular hydrogen atom abstraction reactions (1,2- and/or 1,5-shifts). In the case of the sulfonamidyl radicals, rearrangement via 1,2-shifts and beta-scission of the resultant C-2 carbon-centered radicals to yield SO(3)(*-) and C-2 imines is near quantitative based on the yield of SO(4)(2-), the decomposition product of SO(3)(*-). The formation of strand breaks and chromophores during these reactions is attributed to the formation and subsequent heterolytic rearrangement of the C-2 imines. The degradation of heparan sulfate via reductive homolysis of its N-chloro derivatives may be of significance at sites of inflammation, where MPO-derived HOCl is produced in high concentration and transition-metal ions and O(2)(*-) are known to be present or generated.

KW - Chloramines

KW - Electron Spin Resonance Spectroscopy

KW - Glucosamine

KW - Heparitin Sulfate

KW - Hypochlorous Acid

KW - Peroxidase

KW - Sulfonic Acids

KW - Superoxides

U2 - 10.1021/ja0577239

DO - 10.1021/ja0577239

M3 - Journal article

C2 - 16506790

VL - 128

SP - 3085

EP - 3097

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 9

ER -