Biomedical Engineering Reference
In-Depth Information
parasitophorous membrane, which surrounds the parasite to isolate it from the
cytosol of the erythrocyte during developmental stages from the initial invasion
by a merozoite through the process of schizogony. The second step is rupture of
the erythrocyte membrane to release the new merozoites. The cysteine protease
specific inhibitor E-64 was used to show that the initial process of disruption of
the parasitophorous membrane was catalyzed by one or more members of that
enzyme class. The second step could be inhibited by several different com-
pounds that block proteases of the serine, cysteine, and aspartic classes. Thus,
the second step is not as well defined as the first.
In addition to the four malaria parasites infecting humans, nearly 100 dif-
ferent species of Plasmodium are known that infect other vertebrate host spe-
cies. One explanation for the species specificity of infection may be the
specificity for the host hemoglobin,
64
although this remains unproven. Some of
the non-human parasites may provide valuable model systems in which the
pharmacodynamics and pharmacokinetics of drugs could be studied. P. berghei
and P. chabaudi, which infect rodents, and P. gallinaceum, which infects
chickens, are among those that could be of value in this regard.
11.4.1 Plasmepsin V
The plasmepsin V gene was revealed by the sequencing of the total genome of
P. falciparum
15
following the analysis by Coombs et al.
16
The sequence of
plasmepsin V (PM V) is unusual in having three internal inserts of sequence;
most likely, these segments confer some targeting properties to the protein so
that it reaches the location where it can carry out its function.
Unlike the situation with plasmepsins II, IV, and HAP, reports on plas-
mepsin V are scarce. However, several important papers have appeared. First,
in 2005, Klemba and Goldberg
65
reported on properties of PM V derived from
parasites. In their paper, they discussed the importance of characterizing the
roles of plasmepsins V, IX, and X in parasite biology and for understanding the
effects of inhibitors against the individual enzymes. First, they showed that PM
V is expressed in several stages of the intraerythrocytic life cycle, being lowest in
the ring stage and increasing through schizogony. The protein is found in the
endoplasmic reticulum and is an integral membrane protein anchored through
a C-terminal tail containing a run of 25 hydrophobic amino acids. The authors
discussed the possibility that PM V could be involved in processing of proteins
that were exiting the parasite through the secretory pathway. An attempt to
show binding of pepstatin, the classic inhibitor of pepsin-like aspartic protei-
nases, was unsuccessful, either due to different active site architectures or due to
inaccessibility in the membrane environment. Attempts to create a knock-out
mutant parasite were unsuccessful, which could indicate a critical functional
role for this enzyme.
Following Klemba and Goldberg's paper, additional studies of the process of
export of proteins appeared.
66,67
In these reports, the important role of parasite
proteins in remodeling the erythrocyte membrane surface was described. The
formation of knobs on the outer surface of the red cell membrane helps to
