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Translocation of solutes and proteins across the glycosomal membrane of trypanosomes; possibilities and limitations for targeting with trypanocidal drugs

Published online by Cambridge University Press:  23 August 2012

MELISA GUALDRÓN-LÓPEZ ,
ANA BRENNAND ,
LUISANA AVILÁN  and
PAUL A. M. MICHELS
MELISA GUALDRÓN-LÓPEZ
Affiliation:
Research Unit for Tropical Diseases, de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 74, Postal Box B1.74.01, B-1200 Brussels, Belgium
ANA BRENNAND
Affiliation:
Research Unit for Tropical Diseases, de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 74, Postal Box B1.74.01, B-1200 Brussels, Belgium
LUISANA AVILÁN
Affiliation:
Laboratorio de Fisiología, Facultad de Ciencias, Universidad de los Andes, La Hechicera, 5101 Mérida, Venezuela
PAUL A. M. MICHELS*
Affiliation:
Research Unit for Tropical Diseases, de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 74, Postal Box B1.74.01, B-1200 Brussels, Belgium
*
*Corresponding author: Research Unit for Tropical Diseases, de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 74, Postal Box B1.74.01, B-1200 Brussels, Belgium. Tel: +32 (0) 2 7647473. E-mail: [email protected]
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Summary

Glycosomes are specialized peroxisomes found in all kinetoplastid organisms. The organelles are unique in harbouring most enzymes of the glycolytic pathway. Matrix proteins, synthesized in the cytosol, cofactors and metabolites have to be transported across the membrane. Recent research on Trypanosoma brucei has provided insight into how these translocations across the membrane occur, although many details remain to be elucidated. Proteins are imported by a cascade of reactions performed by specialized proteins, called peroxins, in which a cytosolic receptor with bound matrix protein inserts itself in the membrane to deliver its cargo into the organelle and is subsequently retrieved from the glycosome to perform further rounds of import. Bulky solutes, such as cofactors and acyl-CoAs, seem to be translocated by specific transporter molecules, whereas smaller solutes such as glycolytic intermediates probably cross the membrane through pore-forming channels. The presence of such channels is in apparent contradiction with previous results that suggested a low permeability of the glycosomal membrane. We propose 3 possible, not mutually exclusive, solutions for this paradox. Glycosomal glycolytic enzymes have been validated as drug targets against trypanosomatid-borne diseases. We discuss the possible implications of the new data for the design of drugs to be delivered into glycosomes.

Keywords

trypanosomesglycosomeglycosomal membraneABC transporterschannelsmatrix protein importsolute translocationmulti-enzyme complexmetabolite channellingdrug targeting
Type
Review Article
Information
Parasitology , Volume 140 , Issue 1 , January 2013 , pp. 1 - 20
Copyright
Copyright © Cambridge University Press 2012

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