ABC Proteins by I Barry Holland

Author:I Barry Holland [Holland, I. Barry; Cole, Susan P.C.; Kuchler, Karl; Higgins, Christopher F.]
Language: eng
Format: epub
ISBN: 978-0-08-048187-6
Publisher: Elsevier Science
Published: 2003-03-14T16:00:00+00:00

Figure 16.2 Model for metal resistance in Leishmania. Pentavalent metals are probably reduced to the trivalent form, which is thought to be the active form of the metals. The site of reduction is uncertain and could be either in the macrophage or in the parasite. Resistance could arise if the reductase activity were lost and this idea has received support from the analysis of Pentostam-resistant L. donovani amastigote cells that lost their reductase activity (Shaked-Mishan et al., 2001). Elevated levels of the bisglutathione–spermidine conjugate trypanothione (TSH) are essential for resistance. This is achieved by amplification of GSH1 (Grondin et al., 1997) coding for γ-glutamylcysteine synthase and by overexpression of the ODC gene (Haimeur et al., 1999, 2000) coding for the enzyme ornithine decarboxylase, which are responsible for the rate-limiting steps in glutathione and spermidine biosynthesis, respectively. A reduction in TSH levels, using specific inhibitors of glutathione and spermidine biosynthesis, will reverse resistance (Haimeur et al., 1999). Although arsenite–TSH conjugates can form spontaneously in the test tube (Mukhopadhyay et al., 1996), a putative TSH–conjugase might be necessary inside the cell to increase the rate of generation of the substrate for the various X-thiol transporters. The metal–TSH conjugate can then be sequestered into the intracellular vesicular and tubular membrane organelle by PGPA (Légaré et al., 2001). These conjugates may then move outside the cell by exocytosis, which occurs exclusively through the flagellar pocket (FP). Alternatively, the metal-TSH conjugate might be extruded directly outside the cell by a plasma membrane thiol-X-efflux pump.

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