The phosphoprotein phosphatase family of Ser/Thr phosphatases as principal targets of naturally occurring toxins

Abstract

Phosphoprotein phosphatases (PPPs) constitute one of three otherwise unrelated families of enzymes that specialize in removing the phosphate group from phosphorylated serine and threonine residues. The involvement of PPP enzymes in the regulation of processes such as gene expression, DNA replication, morphogenesis, synaptic transmission, glycogen metabolism, and apoptosis has underscored their potential as targets for the treatment of a variety of conditions such as cancer, diabetes, or Alzheimer’s disease. Interestingly, PPP enzymes also constitute the physiological target of multiple naturally occurring toxins, including microcystins from cyanobacteria and cantharidin from beetles. This review is devoted to the PPP family of enzymes—with a focus on the human PPPs—and the naturally occurring toxins that are known to potently impair their activity. The interaction of the toxins with the enzymes is evaluated in atomic detail to obtain insight on two complementary aspects: (1) which specific structural differences within the similarly folded catalytic core of the PPP enzymes explain their diverse sensitivities to toxin inhibition and (2) which structural features presented by the various toxins account for the differential inhibitory potency towards each PPP. These analyses take advantage of numerous site-directed mutagenesis studies, structure-activity evaluations, and recent crystallographic structures of PPPs bound to different toxins.

Keywords::

• Calyculins
• cantharidin
• cyclosporin A
• cytostatin
• fostriecin
• microcystins
• nodularins
• okadaic acid
• phoslactomycins
• PPP family
• serine/threonine-specific phosphatases
• tacrolimus
• tautomycetin
• tautomycin
• thyrsiferyl-23-acetate

Acknowledgements

The authors would like to thank Dr. Warren E. Johnson, LGD, NCI-NIH, for the critical editing of the manuscript. Comments made by the Associate Editor and two anonymous referees improved an earlier version of the manuscript.

Declaration of interest

The authors’ affiliations are as shown on the first page. The authors have sole responsibility for the writing and content of the paper. S.R.P. was supported by the grant SFRH/BPD/26639/2006 from the Portuguese Foundation for Science and Technology (FCT). This work was also partly funded by FCT projects PTDC/BIA-BDE/69144/2006 and PTDC/AAC-AMB/104983/2008.