Steve Ealick's Research Group
Human Spermidine Synthase
Polyamines are essential for normal cell growth and development. Spermidine synthase (SpdSyn) is any aminopropyltransferase that acts upon putrescine to convert it to spermidine in part of the polyamine biosynthetic pathway. This pathway has been of significant interest as a target for both anticancer and antiparasitic drugs. In this work, we tested decarboxylated S-adenosylhomocysteine (dcSAH) against spermidine synthase and found that it had good potency. To further investigate, we determined the structure of decarboxylated S-adenosylhomocysteine in complex with spermidine synthase.
When crystallized, each monomer of SpdSyn was found to include a bound dcSAH inhibitor (shown in ball-and-stick).
|The active form of human SpdSyn is a dimer that consists of a N-terminal β-sheet domain , a central core domain, and a C-terminal domain.|
The positively charged amino group of the aminopropyl moietyis positioned in the negatively charged polar binding pocket of Asp104 (absolutely conserved), Asp173 (absolutely conserved), and Gln80. The ribose ring forms hydrogen bonds with the side chains of Glu124 and an absolutely conserved Gln49.
Seckute J, McCloskey DE, Thomas JH, Secrist III JA, Pegg AE, and Ealick SE. Binding and Inhibition of Human Spermidine Synthase by Decarboxylated S-adenosylhomocysteine. Protein Sci. 20:1836-1844 (2011).