Physiological role of HMG-CoA reductase in regulating egg production by Schistosoma mansoni

Abstract

Pathological lesions observed in humans infected with Schistosoma mansoni are due to the eggs produced by the female parasite. Mevinolin, a potent inhibitor of the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) reductase, blocks egg production by this parasite. In this report, we demonstrate that cholesterol precursors, mevalonate and farnesol, stimulate egg production by the female parasite and that these precursors can reverse the mevinolin-induced inhibition of egg production. Because the parasite cannot synthesize cholesterol, we incubated parasites in a culture media containing radiolabeled acetate with and without mevinolin. We isolated nonsterol lipids from the parasite and observed that mevinolin dramatically reduced the conversion of acetate into the polyisoprenoid (dolichols) lipids of the parasite. Dolichols and other nonsterol lipids did not stimulate egg production. HMG-CoA reductase activity was observed in homogenates of the parasite and was inhibited by mevinolin (Ki = 52 nM), but its activity was tripled when the parasite was chronically exposed to low doses of the drug. Parasites with increased reductase activity produced five to six times more eggs. Lastly, chronic administration of large doses of mevinolin to infected mice resulted in a marked reduction of the pathology associated with the infection. These results suggest that egg production in S. mansoni is associated with the parasite's HMG-CoA reductase activity and that a nonsterol lipid produced in the biochemical pathway regulated by this enzyme stimulates egg production.

Characterization of Potential Drug Targets Farnesyl Diphosphate Synthase and Geranylgeranyl Diphosphate Synthase in Schistosoma mansoni

“…The FPPS enzyme assays were performed essentially as described previously (31), using 14 Clabeled IPP with DMAPP, GPP, and FPP. One hundred microliters of assay buffer containing 10 mM HEPES, pH 7.4, 5 mM MgCl 2 , 2 mM dithiothreitol, 47 M [4-…”

“…The GGPPS assays were performed as described previously (39,40), using 14 C-labeled IPP with DMAPP, GPP, and FPP. The 20-l assay setup consisted of 25 mM HEPES, 2 mM MgCl 2 , 0.5% n-octyl-␤-glycopyranoside, 10 M [4-…”

“…Consequently, it has been proposed that the parasite obtains its cholesterol from its human host (14). However, the mevalonate pathway that produces IPP and DMAPP is present in schistosomes (15), and isoprenoids derived from mevalonate have been identified in S. mansoni and are thought to be involved in posttranslational prenylation of proteins (with FPP and GGPP), as well as in nonsterol isoprenoid synthesis (16,17).…”

“…Statins, which are widely used in reducing hypercholesterolemia in humans via inhibition of HMGR (21)(22)(23), have been used in experimental S. mansoni infections, resulting in significant worm death (6). Statins such as mevinolin are also reported to inhibit egg production in S. mansoni, possibly due to the lack of nonsterol lipids involved in egg production (14,24). In the absence of mevinolin, parasites produced five to six times more eggs than worms cultured in mevinolin-containing media.…”

In Vitro Screening for Drug Repositioning

“…HMGCoA reductase inhibitors have been shown to have activity against schistosoma parasites (www.wipo.int/research/en/collaboration), and investigation of their potential continues. 57,58 Kinase inhibitors, many of which have been developed in the pharmaceutical industry as oncology treatments, are promising targets in parasitic protozoa, which have related kinases, 59 for example kinetoplastid protozoa. 60 An alternative approach is serendipitous screening of panels of mature compounds in whole-pathogen assays; for example, Gloeckner et al (2010) 61 used the Johns Hopkins Clinical Collection to identify Closantel, a veterinary antihelmintic, as active on Onchocerca volvulus, the nematode that causes river blindness; whereas Abdulla et al (2009) 62 have identified compounds that have hit-and lead-like properties for the treatment of schistosomiasis.…”