title: Identification of chaulmoogric acid as a small molecule activator of protein phosphatase 5.
abstract: Protein phosphatase 5 (PP5) is an important protein phosphatase that is abundantly expressed in the central nervous system. Recent studies showed that PP5 activity in the neocortex from patients with Alzheimer's disease (AD) is decreased significantly, suggesting that small molecule PP5 activator may have therapeutic potential for AD. We performed a biochemical screening for PP5 activators with the microsource compound library. Chaulmoogric acid was identified to be an effective activator with EC(50) value of 134.5 microM. Importantly, results from circular dichroism (CD) and limited proteolysis study showed that chaulmoogric acid binds to a region of tetratricopeptide repeat (TPR) domain of PP5 resulting in complete loss of helical contents. These results demonstrate a different mechanism of action from that of arachidonic acid, a known activator for PP5 dephosphorylation activity. Synergistic activation of PP5 enzymatic activity was also observed with combined application of both compounds at relatively low concentrations. Therefore, further structure activity relationship study of chaulmoogric acid may facilitate the discovery of small molecules that can synergize with endogenous arachidonic acid for PP5 activation.
authors.affiliation: Department of Biology, CytRx Corporation, 3030 Bunker Hill Street, Suite 101, San Diego, CA 92109, USA.
authors.forename: Charmian
authors.initials: C
authors.lastname: Cher
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Tremblay
authors.forename: Jack R
authors.initials: JR
authors.lastname: Barber
authors.forename: Shi
authors.initials: S
authors.lastname: Chung Ng
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
mesh_terms: D016718:Arachidonic Acid / Q000737:chemistry / Q000494:pharmacology; D001681:Biological Assay; D002942:Circular Dichroism; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D005227:Fatty Acids / Q000737:chemistry / Q000494:pharmacology*; D008970:Molecular Weight; D009596:Nitrophenols / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D020536:Enzyme Activators; D005227:Fatty Acids; D009596:Nitrophenols; D009687:Nuclear Proteins; D009943:Organophosphorus Compounds; D054852:Small Molecule Libraries; D016718:Arachidonic Acid; C008644:nitrophenylphosphate; C017119:chaulmoogric acid; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5