Inhibition of polyamine and spermine oxidases by polyamine analogues.
Polyamine oxidase (PAO) and spermine oxidase (SMO) are involved in the catabolism of polyamines--basic regulators of cell growth and proliferation. The discovery of selective inhibitors of PAO and SMO represents an important tool in studying the involvement of these enzymes in polyamine homeostasis and a starting point for the development of novel antineoplastic drugs. Here, a comparative study on murine PAO (mPAO) and SMO (mSMO) inhibition by the polyamine analogues 1,8-diaminooctane, 1,12-diaminododecane, N-prenylagmatine (G3), guazatine and N,N1-bis(2,3-butadienyl)-1,4-butanediamine (MDL72527) is reported. Interestingly, 1,12-Diaminododecane and G3 behave as specific inhibitors of mPAO, values of K(i) for mPAO inhibition being lower than those for mSMO inactivation by several orders of magnitude. The analysis of molecular models of mPAO and mSMO indicates a significant reduction of the hydrophobic pocket located in maize PAO (MPAO) at the wider catalytic tunnel opening. This observation provides a rationale to explain the lower affinity displayed by G3, guazatine and MDL72527 for mPAO and mSMO as compared to MPAO. The different behaviour displayed by 1,12-diaminododecane towards mPAO and mSMO reveals the occurrence of basic differences in the ligand binding mode of the two enzymes, the first enzyme interacting mainly with substrate secondary amino groups and the second one with substrate primary amino groups. Thus, the data reported here provide the basis for the development of novel and selective inhibitors able to discriminate between mammalian SMO and PAO activities.
Bianchi
Marzia
M
Dipartimento di Biologia, Università Roma Tre, Italy.
Polticelli
Fabio
F
Ascenzi
Paolo
P
Botta
Maurizio
M
Federico
Rodolfo
R
Mariottini
Paolo
P
Cona
Alessandra
A
D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D020134:Catalytic Domain; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010084:Oxidation-Reduction; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D000097667:Polyamine Oxidase
D004791:Enzyme Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D000097667:Polyamine Oxidase