Crystal structure of Helicobacter pylori spermidine synthase: A Rossmann‐like fold with a distinct active site

Abstract

Spermidine synthase (putrescine aminopropyltransferase, PAPT) catalyzes the transfer of the aminopropyl group from decarboxylated S-adenosylmethionine to putrescine during spermidine biosynthesis. Helicobacter pylori PAPT (HpPAPT) has a low sequence identity with other PAPTs and lacks the signature sequence found in other PAPTs. The crystal structure of HpPAPT, determined by multiwavelength anomalous dispersion, revealed an N-terminal beta-stranded domain and a C-terminal Rossmann-like domain. Structural comparison with other PAPTs showed that HpPAPT has a unique binding pocket between two domains, numerous non-conserved residues, a less acidic electrostatic surface potential, and a large buried space within the structure. HpPAPT lacks the gatekeeping loop that facilitates substrate binding in other PAPTs. PAPTs are essential for bacterial cell viability; thus, HpPAPT may be a potential antimicrobial drug target for H. pylori owing to its characteristic PAPT sequence and distinct conformation.

A multifaceted role for polyamines in bacterial pathogens

“…Finally, spermidine synthase (SpeE) converts putrescine to spermdine in the presence of decarboxylated SAM. The crystal structure of spermidine synthase from the human pathogen Helicobacter pylori has been reported (Lu et al ., 2007). Spermidine inhibits SAM decarboxylase activity in E. coli , implying that spermidine is a major regulator of this enzyme (Kashiwagi and Igarashi, 1988).…”

Three-dimensional structures ofPlasmodium falciparumspermidine synthase with bound inhibitors suggest new strategies for drug design

“…SpdS is one of the best-studied enzymes of the polyamine pathway. Crystal structures of bacterial (Thermotoga maritima, Escherichia coli, Pyrococcus horikoshii and Helicobacter pylori), Trypanosoma cruzi (PDB entries 3bwb and 3bwc; Structural Genomics of Pathogenic Protozoa Consortium, unpublished work), human, plant (Arabidopsis thaliana; PDB entry 1xj5; Center for Eukaryotic Structural Genomics, unpublished work), Caenorhabditis elegans and PfSpdS have been determined alone or in complex with various ligands (Korolev et al, 2002;Dufe et al, 2005;Lu et al, 2007;Wu et al, 2007;Zhou et al, 2010). The first SpdS X-ray structure to be determined was that from T. maritima (Korolev et al, 2002).…”

Spermine synthase

“…Although the first crystal structure of an aminopropyltransferase was reported only in 2002, there are now numerous published structures including those for spermidine synthases from Thermotoga maritima [9], Caenorhabditis elegans [10], Plasmodium falciparum [11], Helicobacter pylori [12], human [3], Arabidopsis thaliana (PDB code 2Q41) and Trypanosoma cruzi (PDB code 3BWC), aminopropylagmatine synthases from Thermus thermophilus (PDB code 1UIR), Pyrococcus horikoshii (PDB code 2ZSU), and Pyrococcus furiosus [4], and spermine synthase from humans [13]. A general mechanism for aminopropyl transfer has been proposed based on human and T. maritima spermidine synthase structures bound to substrates and inhibitors and the results of site-directed mutagenesis of key residues [3, 9].…”