Preprint Communication Version 1 Preserved in Portico This version is not peer-reviewed

Effect of the Marine β-carboline Alkaloid Manzamine A on RSK1 vs RSK2 Inhibition: a Biochemical and Computational Study

Version 1 : Received: 2 November 2020 / Approved: 4 November 2020 / Online: 4 November 2020 (08:27:07 CET)

How to cite: Mayer, A.; Hall, M.L.; Lach, J.M.; Clifford, J.; Chandrasena, K.; Canton, C.; Kontoyianni, M. Effect of the Marine β-carboline Alkaloid Manzamine A on RSK1 vs RSK2 Inhibition: a Biochemical and Computational Study. Preprints 2020, 2020110174 (doi: 10.20944/preprints202011.0174.v1). Mayer, A.; Hall, M.L.; Lach, J.M.; Clifford, J.; Chandrasena, K.; Canton, C.; Kontoyianni, M. Effect of the Marine β-carboline Alkaloid Manzamine A on RSK1 vs RSK2 Inhibition: a Biochemical and Computational Study. Preprints 2020, 2020110174 (doi: 10.20944/preprints202011.0174.v1).

Abstract

Manzamines are complex polycyclic marine-derived β-carboline alkaloids with reported anticancer, immunostimulatory, anti-inflammatory, antibacterial, antiviral, antimalarial, neuritogenic, hyperlipidemia and atherosclerosis suppression bioactivities, putatively associated with inhibition of glycogen synthase kinase-3, cyclin-dependent kinase 5, and vacuolar ATPases. We hypothesized that additional and yet undiscovered molecular targets might be associated with Manzamine A (MZA) reported pharmacological properties. We report herein for the first time to our knowledge that MZA inhibited a 90kDa ribosomal protein kinase S6 (RSK1) when screened against a panel of 30 protein kinases. Furthermore in vitro RSK kinase assays demonstrated a 10-fold selectivity in potency of MZA against RSK1 versus RSK2. MZA’s differential binding and selectivity toward the two isoforms is also supported by computational docking experiments. Specifically, the RSK1-MZA (N- and C-termini) complexes appear to have stronger interactions and preferable energetics contrary to the RSK2-MZA ones. In addition, our computational strategy suggests that MZA binds to the N-terminal kinase domain of RSK1 rather than the C-terminal domain. RSK is a vertebrate family of cytosolic serine-threonine kinases that act downstream of the ras-ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, which phosphorylates substrates shown to regulate several cellular processes including growth, survival and proliferation. Consequently, our findings have lead us to hypothesize that MZA and the 80 currently known manzamine-type alkaloids isolated from several sponge genera, may have novel pharmacological properties.

Subject Areas

MZA, Manzamine A; CTKD, C-terminal kinase domain; ras-ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway; RSK1, 90kDa ribosomal protein S6 kinase 1; RSK2, 90kDa ribosomal protein S6 kinase 2; NTKD, N-terminal kinase domain

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