Purification and Molecular Characterization of cGMP-dependent Protein Kinase from Apicomplexan Parasites

Gurnett, Anne; Liberator, Paul; Dulski, Paula M.; Salowe, Scott P.; Donald, Robert G. K.; Anderson, Jennifer W.; Wiltsie, Judyann; Dı́az, Carmen; Harris, Georgiana; Chang, Ben; Darkin-Rattray, Sandra J.; Nare, Bakela; Crumley, Tami; Blum, Penny S.; Misura, Andrew S.; Tamas, Tamas; Sardana, Mohinder K.; Yuan, Jeffrey; Biftu, Tesfaye; Schmatz, Dennis M.

doi:10.1074/jbc.m108393200

Cited by 159 publications

(174 citation statements)

References 49 publications

(54 reference statements)

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“…PKG has been shown to be essential in Eimeria (a pathogen of poultry) and Toxoplasma [6], and the tri-substituted pyrrole pyrimidine Compound 1that targets Eimeria PKG has a much lower effect (by 3 orders of magnitude) on chicken PKG. This was shown to be due to the presence of a gatekeeper residue that is smaller in the apicomplexan (a Thr) than in metazoan (a Gln) PKG.…”

Section: The Agc Groupmentioning

confidence: 99%

“…Many PKs of parasitic organisms show a profound structural and functional divergence from their orthologues in the infected hosts (when they exist), suggesting that parasite-specific inhibition might be achieved. A striking example is given by the elegantly documented selective inhibition allowed by small gatekeeper residues displayed by some kinases from apicomplexan parasites [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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The kinomes of apicomplexan parasites

Miranda‐Saavedra

Gabaldón

Barton

et al. 2012

Microbes and Infection

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Protein phosphorylation plays a fundamental role in the biology and invasion strategies of apicomplexan parasites. Many apicomplexan protein kinases are substantially different from their mammalian orthologues, and thus constitute a landscape of potential drug targets. Here, we integrate genomic, biochemical, genetic and evolutionary information to provide an integrated and up-to-date analysis of twelve apicomplexan kinomes. All kinome sequences are available through the Kinomer database.2

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Section: The Agc Groupmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The kinomes of apicomplexan parasites

Miranda‐Saavedra

Gabaldón

Barton

et al. 2012

Microbes and Infection

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“…In Eimeria growth was negatively affected by trisubstituted pyrrole, a potent cGK inhibitor (Gurnett et al 2002). cGKs participate in gliding motility of Plasmodium (Moon et al 2009), Eimeria and Toxoplasma and is involved in the host invasion of the latter two parasites (Wiersma et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the cGMP-dependent protein kinase SmcGK1 of Schistosoma mansoni

Leutner

Beckmann

Grevelding

2011

An. Acad. Bras. Ciênc.

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Schistosomes are trematode parasites and of worldwide medical importance for humans and animals. Growth and development of these parasites require a specific host environment, but also permanent communication processes between the two genders. Accumulating molecular evidence indicates that the responsible interactions are mediated by signal transduction processes. Conserved signaling molecules were identified, and first approaches made for their characterization. However, no representative of the conserved family of cGMP-dependent protein kinases (cGKs) has been described in this parasite yet. Within the Schistosoma mansoni genome data-set we identified cGK homologs, of which one was investigated in more detail in this study. We present the cloning of SmcGK1, whose sequence shows homology to cGKs of higher eukaryotes. SmcGK1 was found to be gender-independently transcribed in adult schistosomes. The occurrence of SmcGK1 sense and antisense transcripts suggests that the expression of this gene is controlled at the post-transcriptional level. In situ hybridization experiments demonstrated a gonad-preferential expression profile in both genders indicating a role of SmcGK1, at least during sexual development of schistosomes. Using a cGK-specific inhibitor to treat adult schistosomes in vitro finally resulted in a multifaceted phenotype including slow motion, oocyte congestion, and reduced egg production.

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“…The PKAs are essential for completion of schizogony (asexual reproduction) in Plasmodium parasites [42]. Further, S. neurona contains a putative PKG (SRCN_4518) which shows high homology (92%) to the T. gondii TgPKG1 ( Table 1); PKGs are in essential apicomplexans [43].…”

Section: The Agc Groupmentioning

confidence: 99%

<em>Sarcocystis neurona</em> Protein Kinases: Computational Identification, Evolutionary Analysis and Putative Inhibitor Docking

Murungi

Kariithi

2017

Preprint

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Abstract:The apicomplexan parasite, Sarcocystis neurona causes the degenerative neurological equine protozoal myeloencephalitis (EPM) disease of horses. Due to its host range expansion, S. neurona is an emerging threat that requires close monitoring. In apicomplexans, protein kinases (PKs) have been implicated in a myriad of critical functions such as host cell invasion, cell cycle progression and host immune responses evasion. Here, we used various bioinformatics methods to define the kinome of S. neurona and phylogenetic relatedness of its PKs to other apicomplexans. Further, three-dimensional (3D) homology models for selected S. neurona putative PKs were constructed and evaluated for inhibitor docking. We identified 92 putative PKs clustering within the AGC, CAMK, CK1, CMGC, STE, TKL, aPK and OPK groups. Although containing the universally conserved PKA (AGC group), S. neurona kinome was devoid of PKB and PKC, but contained the six apicomplexan conserved CDPKs (CAMK group). The OPK group was represented by ROPKs 19A, 27, 30, 33, 35 and 37, but was devoid of the virulence-associated ROPKs 5, 6, 18 and 38. Two out of the three S. neurona CK1 enzymes had high sequence similarities to T. gondii TgCK1-α and TgCK1-β and the Plasmodium PfCK1. Docking of four inhibitors onto homology models of putative ROP27 and PKA indicated that inhibition of S. neurona PKs is feasible, but needs to be experimentally tested. The essentiality of apicomplexan PKs makes the elucidation of S. neurona kinome a key milestone for development of novel therapeutics for EPM.

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Purification and Molecular Characterization of cGMP-dependent Protein Kinase from Apicomplexan Parasites

Cited by 159 publications

References 49 publications

The kinomes of apicomplexan parasites

The kinomes of apicomplexan parasites

Characterization of the cGMP-dependent protein kinase SmcGK1 of Schistosoma mansoni

<em>Sarcocystis neurona</em> Protein Kinases: Computational Identification, Evolutionary Analysis and Putative Inhibitor Docking

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