Numerous studies on human
prostate cancer cell lines indicate a role for
arachidonic acid (AA) and its oxidative metabolites in
prostate cancer proliferation. The metabolism of AA by either the
cyclooxygenase (COX) or the
lipoxygenase (LOX) pathways generates
eicosanoids involved in
tumor promotion, progression, and
metastasis. In particular, products of the 5-LOX pathway (including 5-HETE and 5-oxo-EET) have been implicated as potential 'survival factors' that may confer escape after
androgen withdrawal
therapy through
fatty-acid (i.e., AA) drive. Potent natural dietary
antioxidant compounds such as
lycopene and
lycophyll, with tissue tropism for human prostate, have been shown to be effective in ameliorating generalized oxidative stress at the
DNA level. Suppressing the 5-LOX axis pharmacologically is also a promising avenue for intervention in human patients. The recently recognized direct interaction of the
astaxanthin-based soft-
drug Cardax to human 5-LOX with molecular modeling, and the downregulation of both
5-HETE and 5-oxo-EET in vivo in a murine
peritonitis model, suggest that other important dietary
carotenoids may share this
enzyme regulatory feature. In the current study, the acyclic tomato
carotene lycopene (in all-trans and 5-cis isomeric configurations) and its natural dihydroxy analog
lycophyll (also present in tomato fruit) were subjected to molecular modeling calculations in order to investigate their predicted binding interaction(s) with human 5-LOX. Two bioactive oxidative metabolites of
lycopene (4-methyl-8-oxo-2,4,6-nonatrienal and 2,7,11-trimethyl-tetradecahexaene-1,14-dial) were also investigated. A homology model of 5-LOX was constructed using 8-LOX and 15-LOX structures as templates. The model was validated by calculating the binding energy of
Cardax to 5-LOX, which was demonstrated to be in good agreement with the published experimental data. Blind docking calculations were carried out in order to explore the possible binding sites of the
carotenoids on 5-LOX, followed by focused docking to more accurately calculate the predicted energy of binding.
Lycopene and
lycophyll were predicted to bind with high affinity in the superficial cleft at the interface of the beta-barrel and the catalytic domain of 5-LOX (the 'cleavage site').
Carotenoid binding at this cleavage site provides the structural rationale by which polyenic compounds could modify the 5-LOX enzymatic function via an allosteric mechanism, or by radical scavenging in proximity to the active center. In addition, the two bioactive metabolites of
lycopene were predicted to bind to the catalytic site with high affinity--therefore suggesting potential direct competitive inhibition of 5-LOX activity that should be shared by both
lycopene and
lycophyll after in vivo supplementation, particularly in the case of the dial metabolite.