Anti-infectives Targeting the isoprenoid pathway of Toxoplasma gondii

Abstract

Background: Isoprenoids are an extensive group of natural products with diverse structures consisting of various numbers of five carbon isopentenyl diphosphate (IPP) units. Objective: We review here what is known about the isoprenoid pathway in T. gondii. Methods: Recent primary literature is reviewed. Results/conclusion: Genomic evidence points toward the presence of a 1-deoxy-D-xylulose 5-phosphate/2-C-methyl-D-erythritol 4-phosphate (DOXP/MEP) pathway, similar to the one found in plants, which will produce isopentenyl diphosphate (IPP). The DOXP/MEP pathway has been validated as a target in the related Apicomplexan parasite Plasmodium. The DOXP/MEP pathway in Toxoplasma has not been characterized. Downstream in the pathway, the enzyme farnesyl diphosphate synthase (FPPS) has a central role in forming important intermediates since farnesyl diphosphate (FPP) is a precursor of critical molecules with fundamental biological function such as dolichols, heme a, cholesterol, farnesylated proteins and others. Strong evidence indicates that this enzyme is a valid target for drugs since bisphosphonates, which are specific FPPS inhibitors, inhibited parasite growth in vitro and in vivo. Our hypothesis is that the isoprenoid pathway constitutes a major novel target for the treatment of toxoplasmosis.

Keywords::

• bisphosphonates
• farnesyl diphosphate synthase
• isoprenoid pathway
• prenyl transferase
• toxoplasma

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