Natural compounds often have complex molecular structures and unknown molecular targets. These characteristics make them difficult to analyse using a classical pharmacological approach.
Curcumin, the main
curcuminoid of turmeric, is a complex molecule possessing wide-ranging biological activities, cellular mechanisms and roles in potential therapeutic treatment, including
Alzheimer's disease and
cancer. Here, we investigate the physiological effects and molecular targets of
curcumin in Dictyostelium discoideum We show that
curcumin exerts acute effects on cell behaviour, reduces cell growth and slows multicellular development. We employed a range of structurally related compounds to show the distinct role of different structural groups in
curcumin's effects on cell behaviour, growth and development, highlighting active moieties in cell function, and showing that these cellular effects are unrelated to the well-known
antioxidant activity of
curcumin. Molecular mechanisms underlying the effect of
curcumin and one synthetic analogue (EF24) were then investigated to identify a
curcumin-resistant mutant lacking the
protein phosphatase 2A regulatory subunit (PsrA) and an EF24-resistant mutant lacking the
presenilin 1 orthologue (PsenB). Using in silico docking analysis, we then showed that
curcumin might function through direct binding to a key regulatory region of PsrA. These findings reveal novel cellular and molecular mechanisms for the function of
curcumin and related compounds.