Phospho Protein Modulators (PPMs), our second class of global regulators target Protein Phosphatase 2A (PP2A), the major phosphoprotein phosphatase in the CNS and a central player in the regulation of insulin secretion in pancreatic islet beta-cells. There is strong evidence for a correlation between PP2A deregulation in Alzheimer’s disease (AD), Parkinson’s disease (PD) and diabetes, emphasizing the important regulatory functions of PP2A. Signum has intensified its efforts to discover and develop PPMs from natural extracts that affect PP2A activity. We anticipate this PPM development effort will be effective in several therapeutics areas including:
Assembly of PP2A
Cellular regulation is highly dependent upon the addition and removal of phosphate groups. Interestingly, two phosphatases (PP1A and PP2A) account for the major portion (~90%) of protein dephosphorylation in cells. Of these two, PP2A plays the larger role and is especially important in the CNS. PP2A heterodimers, composed of catalytic C subunits associated with scaffold A subunits, are methylated (see figure below). The PP2A methylation system consists of a specific PP2A methyltransferase (PPMT) that adds the methyl group and a specific PP2A methylesterase (PPME) that removes the methyl group. Methylation facilitates the binding of regulatory B subunits to AC dimers, thereby controlling the assembly of PP2A heterotrimers with different regulatory outputs. Signum’s PPM compounds target PP2A and its methylation system, playing a key modulatory role in its ability to assemble and disassemble.
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