HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 23, 16135-16146, June 6, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/23/16135    most recent M710323200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, H. Articles by Plotnikov, A. N. Search for Related Content PubMed PubMed Citation Articles by Wu, H. Articles by Plotnikov, A. N. Related Collections Papers Of The Week Social Bookmarking                      What's this?

Crystal Structure of Human Spermine Synthase

IMPLICATIONS OF SUBSTRATE BINDING AND CATALYTIC MECHANISM^*

Hong Wu, Jinrong Min, Hong Zeng, Diane E. McCloskey, Yoshihiko Ikeguchi¹, Peter Loppnau, Anthony J. Michael^¶, Anthony E. Pegg², and Alexander N. Plotnikov^||3

From the Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L5, Canada, the Department of Cellular and Molecular Physiology, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, the ^¶Institute of Food Research, Norwich NR4 7UA, United Kingdom, and the ^||Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

The crystal structures of two ternary complexes of human spermine synthase (EC 2.5.1.22 [EC] ), one with 5'-methylthioadenosine and spermidine and the other with 5'-methylthioadenosine and spermine, have been solved. They show that the enzyme is a dimer of two identical subunits. Each monomer has three domains: a C-terminal domain, which contains the active site and is similar in structure to spermidine synthase; a central domain made up of four β-strands; and an N-terminal domain with remarkable structural similarity to S-adenosylmethionine decarboxylase, the enzyme that forms the aminopropyl donor substrate. Dimerization occurs mainly through interactions between the N-terminal domains. Deletion of the N-terminal domain led to a complete loss of spermine synthase activity, suggesting that dimerization may be required for activity. The structures provide an outline of the active site and a plausible model for catalysis. The active site is similar to those of spermidine synthases but has a larger substrate-binding pocket able to accommodate longer substrates. Two residues (Asp²⁰¹ and Asp²⁷⁶) that are conserved in aminopropyltransferases appear to play a key part in the catalytic mechanism, and this role was supported by the results of site-directed mutagenesis. The spermine synthase·5'-methylthioadenosine structure provides a plausible explanation for the potent inhibition of the reaction by this product and the stronger inhibition of spermine synthase compared with spermidine synthase. An analysis to trace possible evolutionary origins of spermine synthase is also described.

Received for publication, December 19, 2007 , and in revised form, March 19, 2008.

The atomic coordinates and structure factors (codes 3C6K and 3C6M) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the Structural Genomics Consortium and by United States Public Health Service Grant R01 GM26290 (to A. P.). The Structural Genomics Consortium is a registered charity (Number 1097737) supported by the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, and Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, the Karolinska Institute, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research, and the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

This article was selected as a Paper of the Week.

¹ Present address: Dept. of Biochemistry, Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama 350-0295, Japan.

² To whom correspondence may be addressed. Tel.: 717-531-8152; Fax: 717-531-5157; E-mail: aep1{at}psu.edu.

³ To whom correspondence may be addressed: Dept. of Structural and Chemical Biology, Icahn Medical Inst., Mount Sinai School of Medicine, New York, NY 10029-6574. Tel.: 212-659-8671; Fax: 212-849-2456; E-mail: alexander.plotnikov{at}mssm.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				X. Wang, S. Levic, M. A. Gratton, K. J. Doyle, E. N. Yamoah, and A. E. Pegg Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to {alpha}-Difluoromethylornithine J. Biol. Chem., January 9, 2009; 284(2): 930 - 937. [Abstract] [Full Text] [PDF]