Crystal Structure of Human Spermine Synthase

Wu, Hong; Min, Jinrong; Zeng, Hong; McCloskey, Diane E.; Ikeguchi, Yoshihiko; Loppnau, P.; Michael, Anthony J.; Pegg, Anthony E.; Plotnikov, A.N.

doi:10.1074/jbc.m710323200

Cited by 103 publications

(66 citation statements)

References 54 publications

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“…This is not the first case of a polyamine biosynthetic gene being found in a phage genome. Orthologues of the gene encoding S-adenosylmethionine decarboxylase are found in phage of cyanobacteria and Thermus thermophilus (56). Also shown in Figs.…”

Section: Resultsmentioning

confidence: 99%

Evolution and Multifarious Horizontal Transfer of an Alternative Biosynthetic Pathway for the Alternative Polyamine sym-Homospermidine

Shaw

Elliott

Kinch

et al. 2010

Journal of Biological Chemistry

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Polyamines are small flexible organic polycations found in almost all cells. They likely existed in the last universal common ancestor of all extant life, and yet relatively little is understood about their biological function, especially in bacteria and archaea. Unlike eukaryotes, where the predominant polyamine is spermidine, bacteria may contain instead an alternative polyamine, sym-homospermidine. We demonstrate that homospermidine synthase (HSS) has evolved vertically, primarily in the ␣-Proteobacteria, but enzymatically active, diverse HSS orthologues have spread by horizontal gene transfer to other bacteria, bacteriophage, archaea, eukaryotes, and viruses. By expressing diverse HSS orthologues in Escherichia coli, we demonstrate in vivo the production of co-products diaminopropane and N 1 -aminobutylcadaverine, in addition to sym-homospermidine. We show that sym-homospermidine is required for normal growth of the ␣-proteobacterium Rhizobium leguminosarum. However, sym-homospermidine can be replaced, for growth restoration, by the structural analogues spermidine and sym-norspermidine, suggesting that the symmetrical or unsymmetrical form and carbon backbone length are not critical for polyamine function in growth. We found that the HSS enzyme evolved from the alternative spermidine biosynthetic pathway enzyme carboxyspermidine dehydrogenase. The structure of HSS is related to lysine metabolic enzymes, and HSS and carboxyspermidine dehydrogenase evolved from the aspartate family of pathways. Finally, we show that other bacterial phyla such as Cyanobacteria and some ␣-Proteobacteria synthesize sym-homospermidine by an HSS-independent pathway, very probably based on deoxyhypusine synthase orthologues, similar to the alternative homospermidine synthase found in some plants. Thus, bacteria can contain alternative biosynthetic pathways for both spermidine and sym-norspermidine and distinct alternative pathways for sym-homospermidine.Polyamines are primordial, small flexible organic polycations found in almost all cells of bacteria, archaea, and eukaryotes (1). In bacteria and archaea, the key polyamines (see Fig. 1A) are the triamines spermidine, sym-norspermidine, and sym-homospermidine (referred to herein as norspermidine and homospermidine), and occasionally more than one triamine can be found in the same cell. In eukaryotes, which contain spermidine (and in some plants, yeasts, and animals, the tetraamine spermine), polyamines are required for growth, cell proliferation, and normal cellular physiology. Polyamine biosynthesis is essential in the fungi Saccharomyces cerevisiae (2), Schizosaccharomyces pombe (3), Aspergillus nidulans (4), and Ustilago maydis (5), the kinetoplastid parasites Trypanosoma brucei (6) and Leishmania donovani (7), and the diplomonad parasite Giardia lamblia (8). In mouse, polyamines are essential for early embryo development (9, 10), and they are also essential for seed development in the flowering plant Arabidopsis thaliana (11).The universal distribution of polyamines suggests that...

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Section: Resultsmentioning

confidence: 99%

Evolution and Multifarious Horizontal Transfer of an Alternative Biosynthetic Pathway for the Alternative Polyamine sym-Homospermidine

Shaw

Elliott

Kinch

et al. 2010

Journal of Biological Chemistry

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“…This gene encodes 5Ј-methylthioadenosine (MTA) phosphorylase, which degrades the MTA formed in polyamine synthesis (62). MTA is a potent inhibitor of spermine synthase (63,64), and the loss of MTA phosphorylase activity would be expected to reduce spermine levels. Very potent inhibitors of MTA phosphorylase are currently under development as antitumor agents (65), and their possible ototoxicity should be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine*

Wang

Levic

Gratton

et al. 2009

Journal of Biological Chemistry

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Male gyro (Gy) mice, which have an X chromosomal deletion inactivating the SpmS and Phex genes, were found to be profoundly hearing impaired. This defect was due to alteration in polyamine content due to the absence of spermine synthase, the product of the SpmS gene. It was reversed by breeding the Gy strain with CAG/SpmS mice, a transgenic line that ubiquitously expresses spermine synthase under the control of a composite cytomegalovirus-IE enhancer/chicken ␤-actin promoter. There was an almost complete loss of the endocochlear potential in the Gy mice, which parallels the hearing deficiency, and this was also reversed by the production of spermine from the spermine synthase transgene. Gy mice showed a striking toxic response to treatment with the ornithine decarboxylase inhibitor ␣-difluoromethylornithine (DFMO). Within 2-3 days of exposure to DFMO in the drinking water, the Gy mice suffered a catastrophic loss of motor function resulting in death within 5 days. This effect was due to an inability to maintain normal balance and was also prevented by the transgenic expression of spermine synthase. DFMO treatment of control mice or Gy-CAG/SpmS had no effect on balance. The loss of balance in Gy mice treated with DFMO was due to inhibition of polyamine synthesis because it was prevented by administration of putrescine. Our results are consistent with a critical role for polyamines in regulation of Kir channels that maintain the endocochlear potential and emphasize the importance of normal spermidine:spermine ratio in the hearing and balance functions of the inner ear.Polyamines are essential for viability in mammals. Knockouts of the genes for ornithine decarboxylase and S-adenosylmethionine decarboxylase, which are enzymes needed for the synthesis of putrescine, spermidine, and spermine, are lethal at early stages of embryonic development (1, 2). There is convincing evidence that the formation of hypusine in eIF5A, which requires spermidine as a precursor, is essential for eukaryotes (3). However, the function(s) of spermine is not so well established. Yeast mutants with inactivated spermine synthase grow at a normal rate (4). Mammalian cells in culture also grow normally in the presence of inhibitors of spermine synthase (5) or after inactivation of the spermine synthase gene (SpmS) (6 -8

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“…For some cases the homodimerization is necessary for the regulation [28,29,30]. For others, as in the case of the human spermine synthase protein, the dimerization works as a switch [27,31] and creates an electrostatic funnel which steers the delivery of the reactants to the active sites of the complex [32]. With this work, we explore the possibility that such an effect, the electrostatic steering effect, may be common among homodimeric proteins, to deliver the substrates to the active site(s) or to enhance the molecular recognition.…”

Section: Introductionmentioning

confidence: 99%

On the electrostatic properties of homodimeric proteins

Campbell

Petukh

Alexov

et al. 2014

J. Theor. Comput. Chem.

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A large fraction of proteins function as homodimers, but it is not always clear why the dimerization is important for functionality since frequently each monomer possesses a distinctive active site. Recent work (PLoS Computational Biology, 9(2), e1002924) indicates that homodimerization may be important for forming an electrostatic funnel in the spermine synthase homodimer which guides changed substrates toward the active centers. This prompted us to investigate the electrostatic properties of a large set of homodimeric proteins and resulted in an observation that in a vast majority of the cases the dimerization indeed results in specific electrostatic features, although not necessarily in an electrostatic funnel. It is demonstrated that the electrostatic dipole moment of the dimer is predominantly perpendicular to the axis connecting the centers of the mass of the monomers. In addition, the surface points with highest potential are located in the proximity of the interfacial plane of the homodimeric complexes. These findings indicate that frequently homodimerization provides specific electrostatic features needed for the function of proteins.

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Crystal Structure of Human Spermine Synthase

Cited by 103 publications

References 54 publications

Evolution and Multifarious Horizontal Transfer of an Alternative Biosynthetic Pathway for the Alternative Polyamine sym-Homospermidine

Evolution and Multifarious Horizontal Transfer of an Alternative Biosynthetic Pathway for the Alternative Polyamine sym-Homospermidine

Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine*

On the electrostatic properties of homodimeric proteins

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