Background: Polyamines are essential for cell growth and differentiation; c
ompounds interfering with their metabolism are potential anticancer agents.
Polyamine oxidase (PAO) plays a central role in polyamine homeostasis. The
enzyme utilises an FAD cofactor to catalyse the oxidation of the secondary
amino groups of spermine and spermidine.
Results: The first crystal structure of a polyamine oxidase has been determ
ined to a resolution of 1.9 Angstrom. PAO from Zea mays contains two domain
s, which define a remarkable 30 Angstrom long U-shaped catalytic tunnel at
their interface. The structure of PAO in complex with the inhibitor MDL7252
7 reveals the residues forming the catalytic machinery and unusual enzyme-i
nhibitor CH ... O hydrogen bonds. A ring of glutamate and aspartate residue
s surrounding one of the two tunnel openings contributes to the steering of
the substrate towards the inside of the tunnel.
Conclusions: PAO specifically oxidises substrates that have both primary an
d secondary amino groups. The complex with MDL72527 shows that the primary
amino groups are essential for the proper alignment of the substrate with r
espect to the flavin. Conservation of an N-terminal sequence motif indicate
s that PAO is a member of a novel family of flavoenzymes. Among these, mono
amine oxidase displays significant sequence homology with PAO, suggesting a
similar overall folding topology.