Inhibition of heparan sulfate synthesis by chlorate.

Abstract

With the exception of hyaluronic acid, all glycosaminoglycans are O-sulfated. Heparins and heparan sulfates are, in addition, N-sulfated on many of their glucosamine residues. Other naturally occurring structures are also sulfated. For example, some proteins contain sulfotyrosine residues (1), and some complex lipids are O-sulfated. In addition, certain N-linked oligosaccharides are sulfated (2). In all of these cases, the enzymes that add sulfate residues to these structures utilize 3'-phosphoadenosine5'-phosphosulfate (PAPS) as the sulfate donor. If PAPS cannot be synthesized, these biological sulfation reactions will not proceed. Chlorate is a competitive inhibitor of PAPS synthesis and, as such, can block all sulfation reactions. PAPS is synthesized by a two-step process utilizing ATP sulfurylase (reaction 1) and adenosine-5'-phosphosulfate kinase (reaction 2), activities that are in some cases catalyzed by a single bifunctional enzyme that may localize to the nucleus in mammalian cells (3,4).