Ornithine decarboxylase (ODC) is the sentinel
enzyme in
polyamine biosynthesis. Both ODC and
polyamines regulate cell division, proliferation, and apoptosis.
Sepiapterin reductase (SPR) catalyzes the last step in the biosynthesis of
tetrahydrobiopterin (BH4), an essential cofactor of
nitric oxide synthase, and has been implicated in neurological diseases but not yet in
cancer. In this study, we present compelling evidence that native ODC and SPR physically interact, and we defined the individual
amino acid residues involved in both
enzymes using in silico
protein-
protein docking simulations. The resulting heterocomplex is a surprisingly compact structure, featuring two energetically and structurally equivalent binding modes both in monomer and in dimer conformations. The novel interaction between ODC and SPR
proteins was confirmed under physiological conditions by co-immunoprecipitation and co-localization in
neuroblastoma (NB) cells. Importantly, we showed that
siRNA (
small interfering RNA)-mediated knockdown of SPR expression significantly reduced endogenous ODC
enzyme activity in NB cells, thus demonstrating the
biological relevance of the ODC-SPR interaction. Finally, in a cohort of 88 human NB
tumors, we found that high SPR
mRNA expression correlated significantly with poor survival prognosis using a Kaplan-Meier analysis (log-rank test, P=5 × 10(-4)), suggesting an oncogenic role for SPR in NB
tumorigenesis. In conclusion, we showed that ODC binds SPR and thus propose a new concept in which two well-characterized biochemical pathways converge via the interaction of two
enzymes. We identified SPR as a novel regulator of ODC
enzyme activity and, based on clinical evidence, present a model in which SPR drives ODC-mediated malignant progression in NB.