The Haemonchus contortus kinome - a resource for fundamental molecular investigations and drug discovery

Abstract

BackgroundProtein kinases regulate a plethora of essential signalling and other biological pathways in all eukaryotic organisms, but very little is known about them in most parasitic nematodes.MethodsHere, we defined, for the first time, the entire complement of protein kinases (kinome) encoded in the barber’s pole worm (Haemonchus contortus) through an integrated analysis of transcriptomic and genomic datasets using an advanced bioinformatic workflow.ResultsWe identified, curated and classified 432 kinases representing ten groups, 103 distinct families and 98 subfamilies. A comparison of the kinomes of H. contortus and Caenorhabditis elegans (a related, free-living nematode) revealed considerable variation in the numbers of casein kinases, tyrosine kinases and Ca2+/calmodulin-dependent protein kinases, which likely relate to differences in biology, habitat and life cycle between these worms. Moreover, a suite of kinase genes was selectively transcribed in particular developmental stages of H. contortus, indicating central roles in developmental and reproductive processes. In addition, using a ranking system, drug targets (n = 13) and associated small-molecule effectors (n = 1517) were inferred.ConclusionsThe H. contortus kinome will provide a useful resource for fundamental investigations of kinases and signalling pathways in this nematode, and should assist future anthelmintic discovery efforts; this is particularly important, given current drug resistance problems in parasitic nematodes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-015-1231-5) contains supplementary material, which is available to authorized users.

A Survey of the Kinome Pharmacopeia Reveals Multiple Scaffolds and Targets for the Development of Novel Anthelmintics

“…Despite the conservation of kinases, there are sequence differences that distinguish nematode orthologs from their vertebrate counterparts. For example, the pairwise sequence similarity between homologous kinases of H. contortus and its sheep host Ovis aries is considerably lower (25% identity) than between H. contortus and C. elegans (35% identity) [35]. A similar trend is found when comparing sequence similarity of orthologous kinases from the human nematode parasite Brugia malayi to that of C. elegans versus that of its human host system [22].…”

“…There is also a high degree of kinase conservation within the nematode phylum. For example, C. elegans has homologs of 95% of the kinases identified in the nematode parasite Haemonchus contortus [35]. Hence, drugs that target a particular vertebrate kinase may have utility against the respective ortholog in nematodes, and this kinase may be found broadly across the phylum.…”

Analyses of Compact Trichinella Kinomes Reveal a MOS-Like Protein Kinase with a Unique N-Terminal Domain

“… The numbers of kinases in individual groups for T. spiralis , T. pseudospiralis , C. elegans ( Ce ; Manning 2005 ), H. contortus ( Hc ; Stroehlein et al 2015 ) and H. sapiens ( Hs ; Manning et al 2002b ). For Trichinella species, the numbers of unique families and subfamilies and the numbers and percentages of kinases assigned to them (in brackets) are shown.…”

“…Approximately half of all sequences ( n = 106–108; 47%) were assigned to one or more biological (KEGG) pathways. Interestingly, although no RGC kinases were linked to environmental information processing, as they are in other nematodes ( Manning 2005 ; Ortiz et al 2009 ; Adachi et al 2010 ; Stroehlein et al 2015 ), 66 kinases in all other groups were (AGC, n = 13; Atypical, n = 3; CAMK, n = 11; CK1, n = 3; CMGC, n = 7–8; Other, n = 2; STE, n = 10; TK, n = 10–11; and TKL, n = 6). In contrast, for both Trichinella species, the smallest number of kinases ( n = 8) was associated with the KEGG category “metabolism.” The numbers of sequences assigned to the remaining KEGG categories “organismal systems,” “cellular processes,” and “genetic information processing” ranged from 18 to 63 ( Table S1 and Table S2 ).…”

“…In contrast, there was a considerably higher number of kinases (RGC group) in this KEGG category in both the extracellular, parasitic nematode H. contortus ( n = 13; cf . Stroehlein et al 2015 ) and the free-living nematode C. elegans ( n = 23). Whether the lack of kinases, such as RAD53, NEK, and TTK, which are principally associated with nonmetabolic pathways, can also be attributed to gene loss or simply to an efficient use of alternative or novel pathways, is presently unclear.…”