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Binding and inhibition of human spermidine synthase by decarboxylated S-adenosylhomocysteine.


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 ?M in the absence of putrescine and 3.2 ± 0.1 ?M in the presence of putrescine. These results indicate a potential for further inhibitor development based on the dcSAH scaffold.

SUBMITTER: Seckute J 

PROVIDER: S-EPMC3267948 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Binding and inhibition of human spermidine synthase by decarboxylated S-adenosylhomocysteine.

Sečkutė Jolita J   McCloskey Diane E DE   Thomas H Jeanette HJ   Secrist John A JA   Pegg Anthony E AE   Ealick Steven E SE  

Protein science : a publication of the Protein Society 20110915 11


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  ...[more]

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