Abstract
The highly conserved bacterial homospermidine synthase (HSS) is a key enzyme of the polyamine metabolism of many proteobacteria including pathogenic strains such as Legionella pneumophila and Pseudomonas aeruginosa; The unique usage of NAD(H) as a prosthetic group is a common feature of bacterial HSS, eukaryotic HSS and deoxyhypusine synthase (DHS). The structure of the bacterial enzyme does not possess a lysine residue in the active center and thus does not form an enzyme-substrate Schiff base intermediate as observed for the DHS. In contrast to the DHS the active site is not formed by the interface of two subunits but resides within one subunit of the bacterial HSS. Crystal structures of Blastochloris viridis HSS (BvHSS) reveal two distinct substrate binding sites, one of which is highly specific for putrescine. BvHSS features a side pocket in the direct vicinity of the active site formed by conserved amino acids and a potential substrate discrimination, guiding, and sensing mechanism. The proposed reaction steps for the catalysis of BvHSS emphasize cation-π interaction through a conserved Trp residue as a key stabilizer of high energetic transition states.
Highlights
The bacterial homospermidine synthase (HSS) is highly conserved and is proposed to be evolutionarily related to carboxy(nor)spermidine dehydrogenase (CA(N)SDH, EC: 1.5.1.43)[13]
Crystals from Blastochloris viridis HSS (BvHSS) and BvHSS variants with bound NAD+ in complex with various polyamines all belonged to space group P22121 with cell parameters in approximately the same order of magnitude
Different relative orientations of subunit A to subunit B were observed for all BvHSS structures
Summary
The bacterial HSS is highly conserved and is proposed to be evolutionarily related to carboxy(nor)spermidine dehydrogenase (CA(N)SDH, EC: 1.5.1.43)[13]. The essential function of HSP for growth, in addition to the difference in the mechanism and evolution of its synthesizing enzymes in bacteria and eukaryotes, suggests that bacterial HSS represents such a potential target[6,13]. Studying the evolution of plant HSS from eukaryotic DHS, we were interested whether there might be an evolutionary link to the bacterial HSS. Our study will lead to a better understanding of the enzyme function and elucidates potential similarities or differences to eukaryotic HSS/DHS. These insights are mandatory to assess the potential of the bacterial HSS as an antibiotic drug target. We present high resolution structures of BvHSS and variants with various bound polyamines, providing a detailed insight into substrate-binding properties and function of bacterial HSS
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