期刊
PROTEIN SCIENCE
卷 20, 期 11, 页码 1836-1844出版社
WILEY
DOI: 10.1002/pro.717
关键词
polyamine; spermidine; aminopropyltransferase; spermidine synthase; S-adenosylmethionine; S-adenosylhomocysteine
资金
- National Cancer Institute [PO1 CA-94000]
- National Center for Research Resources at the National Institutes of Health [RR-15301]
- U.S. DOE [DE-AC02-06CH11357]
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 angstrom 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 mu M in the absence of putrescine and 3.2 +/- 0.1 mu M in the presence of putrescine. These results indicate a potential for further inhibitor development based on the dcSAH scaffold.
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