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Acidocalcisomes as drug targets

A vacuolar proton translocating pyrophosphatase (V-H1-PPase) is involved in the acidification of the organelle in T. cruzi.200 The enzyme uses pyrophosphate instead of ATP as an energy source, is K1-stimulated (type I), and can be used as a marker for acidocalcisome purification.200 The gene encoding this pump has been functionally expressed in yeast.201 This enzyme is also found in the Golgi complex and in the plasma membrane of T. cruzi,202 but is absent in mammalian cells.

Pyrophosphate analogues, bisphosphonates (containing a nonhydrolyzable P-C-P, rather than a P-O-P, backbone) as well as imidodiphosphate (containing a nonhydrolyzable P-N-P group), are inhibitors of the plant (mung bean, Vigna radiata) V-H+-PPase.203 Imidodiphosphate and aminomethylenediphosphonate (AMDP), one of the best known inhibitors of the V-H+-PPase, inhibits the T. cruzi enzyme.200

Acidocalcisomes possess another enzyme that is absent in mammalian cells: a polyP kinase, also known as vacuolar transporter chaperone (VTC) complex.204,205 This complex is formed in yeast by four subunits: Vtc1—4, with Vtc4 the catalytic subunit.206 T. cruzi has genes homologous to those encoding Vtc1 and Vtc4 (204) and TcVtc4 is its catalytic subunit.207

Acidocalcisomes are also known to accumulate drugs. Ormerod observed that these organelles, known at that time as volutin granules, become more visible under light microscopy when cells are treated with drugs.208 Further work showed that drugs like stilbamidine, quinapyramine, suramin, hydroxystilbami- nine, and acriflavine accumulated in these organelles.209,210 For this reason they were also named as “chemotherapy granules.”211 Interestingly, some of these drugs are first concentrated in the kinetoplast and nucleus, then diffuse to the cytosol, and finally concentrate in acidocalcisomes. Such is also the case of diamidines like DB75 (furamidine) and DB820, which have been in phase III clinical trials against human African trypanosomiasis.212,213 However, the impact that acidocalcisome accumulation has on the mechanism of action of these compounds is not known.

 
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