3RW9

Crystal Structure of human Spermidine Synthase in Complex with decarboxylated S-adenosylhomocysteine

Summary for 3RW9

• Entry DOI: 10.2210/pdb3rw9/pdb
• Descriptor: Spermidine synthase, 5'-S-(3-aminopropyl)-5'-thioadenosine (3 entities in total)
• Functional Keywords: aminopropyltransferase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 68786.43

Authors

Seckute, J.,McCloskey, D.E.,Thomas, H.J.,Secrist III, J.A.,Pegg, A.E.,Ealick, S.E. (deposition date: 2011-05-08, release date: 2011-09-21, Last modification date: 2024-02-28)

Primary citation

Seckute, J.,McCloskey, D.E.,Thomas, H.J.,Secrist, J.A.,Pegg, A.E.,Ealick, S.E.
Binding and inhibition of human spermidine synthase by decarboxylated S-adenosylhomocysteine.
Protein Sci., 20:1836-1844, 2011

PubMed Abstract: Aminopropyltransferases are essential enzymes that form polyamines in eukaryotic and most prokaryotic cells. Spermidine synthase (SpdS) is one of the most well-studied enzymes in this biosynthetic pathway. The enzyme uses decarboxylated S-adenosylmethionine and a short-chain polyamine (putrescine) to make a medium-chain polyamine (spermidine) and 5'-deoxy-5'-methylthioadenosine as a byproduct. Here, we report a new spermidine synthase inhibitor, decarboxylated S-adenosylhomocysteine (dcSAH). The inhibitor was synthesized, and dose-dependent inhibition of human, Thermatoga maritima, and Plasmodium falciparum spermidine synthases, as well as functionally homologous human spermine synthase, was determined. The human SpdS/dcSAH complex structure was determined by X-ray crystallography at 2.0 Å resolution and showed consistent active site positioning and coordination with previously known structures. Isothermal calorimetry binding assays confirmed inhibitor binding to human SpdS with K(d) of 1.1 ± 0.3 μM in the absence of putrescine and 3.2 ± 0.1 μM in the presence of putrescine. These results indicate a potential for further inhibitor development based on the dcSAH scaffold.

PubMed: 21898642
DOI: 10.1002/pro.717

Experimental method

X-RAY DIFFRACTION (2 Å)