The reactions responsible for the synthesis and interconversion of polyamines in mammalian cells will be studied. The investigations wil focus on he aminopropyltransferases, spermidine synthase and spermine synthase, which transfer a propylamine group from decarboxylated S-adenosylmethionine to the appropriate acceptor to form thepolyamines and 5'-methylthioadenosine. A related enzyme, spermidine N(1)-acetyltransferase discovered in the first period of the grant will also be studied. This inducible enzyme was shown to be the rate-limiting step in the converson of spermidine back into putrescine since N(1)-acetylspermidine is the physiological substrate for polyamine oxidase. It is planned to: a. continue the purification of these enzymes to homogeneity and complete studies of their properties; b. to use methodology developed in the first grant period to measure the cellular content of decarboxylated S-adenosylmethionine, the propylamine donor and 5'-methylthioadenosine, the product of the reaction which we have shown to be strongly inhibitory to propylamine transfer. These measurements will be made under a variety of physiological situations and after administration of inhibitors of polyamine metabolism; c. to continue to develop and study specific inhibitors of these enzymes with particular emphasis on potent transition state inhibitors; d. to produce specific antibodies to spermidine N(1)-acetyltransferase and spermidine synthase and use these to study the regulation of thse enzymes, the mechanism of enhancement of activity and their turnover; e. to further establish the role of the acetyltransferase in he interconversion of polyamines and the produciton of 5'-methylthioadenosine. These experiments will provide new information on reactions in the polyamine biosynthetic scheme which have been very little studied, help in the understanding of polyamine function and advance the use of polyamine synthesis inhibitors for treatment of various diseases.
| Shi, Chenxu; Welsh, Patricia A; Sass-Kuhn, Suzanne et al. (2012) Characterization of transgenic mice with overexpression of spermidine synthase. Amino Acids 42:495-505 |
| Pegg, Anthony E; Wang, Xiaojing; Schwartz, Charles E et al. (2011) Spermine synthase activity affects the content of decarboxylated S-adenosylmethionine. Biochem J 433:139-44 |
| Wang, Xiaojing; Pegg, Anthony E (2011) Use of (Gyro) Gy and spermine synthase transgenic mice to study functions of spermine. Methods Mol Biol 720:159-70 |
| Green, Robert; Hanfrey, Colin C; Elliott, Katherine A et al. (2011) Independent evolutionary origins of functional polyamine biosynthetic enzyme fusions catalysing de novo diamine to triamine formation. Mol Microbiol 81:1109-24 |
| Pegg, Anthony E; Casero Jr, Robert A (2011) Current status of the polyamine research field. Methods Mol Biol 720:3-35 |
| Pegg, Anthony E; Michael, Anthony J (2010) Spermine synthase. Cell Mol Life Sci 67:113-21 |
| Pegg, Anthony E; Wang, Xiaojing (2009) Mouse models to investigate the function of spermine. Commun Integr Biol 2:271-4 |
| Pegg, Anthony E (2009) Mammalian polyamine metabolism and function. IUBMB Life 61:880-94 |
| Wang, Xiaojing; Levic, Snezana; Gratton, Michael Anne et al. (2009) Spermine synthase deficiency leads to deafness and a profound sensitivity to alpha-difluoromethylornithine. J Biol Chem 284:930-7 |
| Pegg, Anthony E (2009) S-Adenosylmethionine decarboxylase. Essays Biochem 46:25-45 |
Showing the most recent 10 out of 90 publications
