Biology Reference
In-Depth Information
electro-chemical potentials across membranes, and the trafficking of
important small molecules and/or ions linked to a variety of metabolic
pathways.
Key Classes of Enzymes
Enzymes with essential functions include peptidases, kinases, phos-
phatases, and GTPases. All of them, in parasites, represent attractive
targets for novel drugs or vaccines. The
A. suum
peptidome is repre-
sented by 456 sequences in the five major classes of peptidases (aspartic,
cysteine, metallo-, serine, and threonine), with the metallo- (
n
¼
184:
41.0%) and serine proteases (
n
132: 30.0%) predominating. Major,
abundant families within these classes included secreted peptidases
representing the M12A “astacins,” S09X cholinesterases and acetylcho-
linesterases, S33 prolyl aminopeptidases, and the C1A “papain” (e.g.
cathespins) and C2A “calpain-like” cysteine proteases. Such secreted
peptidases are of major interest, given their presence in the excretory/
secretory (ES) products of many parasitic helminths and central roles in
tissue invasion and degradation (e.g. during migration and/or feeding)
and/or immune evasion/modulation.
60,61
ES peptidases (including
aminopeptidases and/or cysteine proteases) are likely to play key roles
in these processes in
Ascaris
and represent important drug and/or
vaccine targets.
62
e
66
The kinases and phosphatases, which function in cell-cycle progres-
sion, metabolism, transcription, and DNA replication, are key enzymes
often associated with signal transduction pathways. Such molecules are
known to be highly transcribed in
C. elegans
sperm
67
and are male
enriched in some parasitic nematodes,
68,69
suggesting key functional roles
in major development and/or reproduction pathways. For example,
receptor kinases, such as
daf-1
and
daf-4
, are critical in dauer formation
70
;
homologues exist in parasitic nematodes which are thought to play
a major role in the establishment of larvae in the host animal.
68,69
Based
on homology with
C. elegans
genes and/or sequences in the KS-Sarfari
database, we defined the kinome and phosphatome of
A. suum
as
¼
600
kinases and 250 phosphatases, respectively. Among the
A. suum
kinome,
most abundant are the tyrosine, casein, CMGC, and CAMK kinases. The
phosphatome, although smaller, was represented by at least 17 receptor
and 68 conventional tyrosine, 64 serine/threonine, and 39 dual-specificity
phosphatases. Given their involvement in numerous essential signaling
(cell-cycle) pathways linked to developmental and/or reproductive
processes, these molecules are attractive as novel targets for anti-parasite
drugs.
71
e
74
Recent evidence suggests that norcantharidin analogues,
which appear to have specific inhibitory activity against PP1 and PP2A
phosphatases, are promising candidate nematocides.
75
w
