Initeractions of Glycosaminoglycans with DNA and RNA Synthesizing Enzymes in vitro

Abstract

The sulfated glycosaminoglycans chondroitin 4-sulfate, chondroitin 6-sulfate, keratan sulfate, dermatan sulfate, heparin, and a glycosaminoglycan polysulfate are competitive inhibitors of the DNA-dependent DNA polymerase, the DNA-dependent RNA polymerase and the RNA-dependent DNA polymerase (reverse transcriptase). The unsulfated glycosaminoglycans chondroitin and hyaluronate are without any influence on the synthesis of DNA and RNA.The strongest inhibitor is a glycosaminoglycan polysulfate with four sulfate groups per disaccharide unit. It has the following inhibitor constants: DNA polymerase,^ = 1.5 χ 10~6M;RNA polymerase, Κ· γ = 0.9 χ 10~6Μ; reverse transcriptase, K\ = 1.1 χ 10~6M. The inhibition is closely correlated to the degree of sulfation of the glycosaminoglycans. There is a relationship between the sulfate/hexosamine ratio and the degree of inhibition. The inhibition of the DNA and RNA synthesizing enzymes by sulfated glycosaminoglycans depends on the nature of the template. With double-stranded DNA as template, inhibition occurs only when sulfated glycosaminoglycans are added before or shortly after (30 s) initiation of the synthesis. There is no inhibition if the inhibitors are added after the onset of the synthesis. On the other hand, with a single-stranded template synthesis was blocked completely at each phase of reaction.

Effect of Heparin on Production of Basic Fibroblast Growth Factor and Transforming Growth Factor-Beta1 by Human Normal Skin and Hyperplastic Scar Fibroblasts

“…Heparin is taken into cells, such as fibroblasts, 18 by a process of cell-surface binding 19,20 followed by internalization and metabolism of the glycosaminoglycan into oligosaccharides. 21,22 Internalized heparin or its metabolites could change cellular metabolism, 23 resulting in an alteration in the production of extracellular matrix proteins. Alteration of cellular metabolism could also cause in a change in enzyme systems that affect cellular proliferation.…”

Cytotoxic and HIV-1 enzyme inhibitory activities of Red Sea marine organisms

“…In cases where marine organisms were able to inhibit this enzyme, it was always pure compounds which were hydrophilic in nature, suggesting that for activity against this enzyme, more aqueous extracts should be prepared [33]. On the other hand most of the extracts inhibited HIV-1 PR enzyme in the direct assays.…”

“…The fourth patent is for the use of carrageenan and other sulfated polysaccharides for the treatment of diseases (including AIDS) caused by retroviral infection [42]. In another study on the hydrophilic metabolites (sulfated oligo- or poly-saccharide compounds) from red algae, retroviral replication was suppressed and viral reverse transcriptase inhibited [33]. …”

Antiviral carbohydrates from marine red algae

“…This later was verified by colleagues in England and Japan . Studies as early as that of Solomon et al (1966) and other work in the 1970s (Schaffrath et al, 1976) showed that sulfated oligo-or poly-saccharide compounds supressed retroviral replication and inhibited viral reverse transcriptases . Tests run in Japan, using a reversetranscriptase inhibition assay, showed that nearly all of the 39 species we had collected contained an inhibitory substance (Table 1) .…”