Mammalian spermidine synthase--identification of cysteine residues and investigation of the putrescine binding site--

Biological & Pharmaceutical Bulletin
Hitomi GodaKeijiro Samejima

Abstract

Homology modeling and inhibitory studies using substrate analogs were undertaken to construct a possible three-dimensional structure, including the putrescine-binding site, of rat spermidine synthase based on its primary sequence. Of the ten cysteine residues of the enzyme, six residues were chemically determined as sulfhydryl; similarly, one residue (C25) was determined as the disulfide. Using the model obtained from the Swiss-Model protein-modeling server, and based on the crystal structure of the Thermotoga maritima enzyme, the three remaining residues were assigned as sulfhydryl. Discussions are presented on the counterpart of the C25 residue, based on the apparent role of the bacterial N-terminal peptide region in reinforcing the binding between protomers in a functional oligomeric form. The active sites of the bacterial and mammalian versions of the enzyme were very similar. The putrescine-binding site of the rat enzyme was investigated using IC(50) values of the analogs of two known potent inhibitors, n-butylamine and trans-4-methylcyclohexylamine (4MCHA). Our results indicated that 5-amino-1-pentene and 4MCHA possess comparable inhibitory activities towards the enzyme.

References

Mar 1, 1978·The Biochemical Journal·H Hibasami, A E Pegg
Jan 15, 1991·Biochemical Pharmacology·A ShirahataK Samejima
May 1, 1995·The International Journal of Biochemistry & Cell Biology·A E PeggJ K Coward
Aug 1, 1996·The International Journal of Biochemistry & Cell Biology·N SeilerJ P Moulinoux
Dec 4, 2001·Nature Structural Biology·Sergey KorolevAlexei Savchenko
Jul 5, 2003·Biological & Pharmaceutical Bulletin·Hideki DejimaKeijiro Samejima

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Citations

Apr 2, 2005·Biological & Pharmaceutical Bulletin·Masaki KobayashiKeijiro Samejima
Aug 2, 2006·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Keijiro Samejima
Apr 2, 2013·Enzyme and Microbial Technology·Alexander FosterMark A Keane
Aug 13, 2011·The Biochemical Journal·Lyn-Marie BirkholtzOlle Heby
Feb 6, 2015·Malaria Journal·Pieter B BurgerAbraham I Louw
Jan 24, 2006·Journal of Biochemistry·Yoshihiko IkeguchiAnthony E Pegg

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