Journal:Acta Cryst D:S2059798321008937

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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'', ''Brucella spp.'', and various ''Pseudomonas aeruginosa'' strains<ref name="Shaw">PMID:20194510</ref>. The enzyme HSS is required for the NAD-dependent synthesis of the polyamine homospermidine (HSP) from the diamine putrescine (PUT) (Figure 1)<ref name="Tait">PMID:437275</ref>. Recently we have determined the crystal structures of two bacterial HSS, HSS from Blastochloris viridis (BvHSS) and from ''Pseudomonas aeruginosa'' (PaHSS). BvHSS exists as a homo-dimeric enzyme in solution, whereas the PaHSS is monomeric in solution but displays the <scene name='89/896623/Cv/7'>same dimeric arrangement in the crystal</scene> as BvHSS<ref name="Helfrich1">PMID:34605434</ref>,<ref name="Krossa">PMID:26776105</ref>.
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'', ''Brucella spp.'', and various ''Pseudomonas aeruginosa'' strains<ref name="Shaw">PMID:20194510</ref>. The enzyme HSS is required for the NAD-dependent synthesis of the polyamine homospermidine (HSP) from the diamine putrescine (PUT) (Figure 1)<ref name="Tait">PMID:437275</ref>. Recently we have determined the crystal structures of two bacterial HSS, HSS from Blastochloris viridis (BvHSS) and from ''Pseudomonas aeruginosa'' (PaHSS). BvHSS exists as a homo-dimeric enzyme in solution, whereas the PaHSS is monomeric in solution but displays the <scene name='89/896623/Cv/7'>same dimeric arrangement in the crystal</scene> as BvHSS<ref name="Helfrich1">PMID:34605434</ref>,<ref name="Krossa">PMID:26776105</ref>.
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The <scene name='89/896623/Cv/8'>THSS is composed of two domains</scene>, an “NAD(P)-binding Rossmann-like domain” and an “HSS-like domain” (Figure 2). The substrate binding pocket is located between these two domains. The cofactor NAD(H) is bound as a prosthetic group in the binding pocket with its nicotinamide ring being part of the active site. An “ionic slide” (BvHSS residues D94 and E117<ref name="Krossa">PMID:26776105</ref>) was proposed to lead positively charged amine substrates from the entrance of the binding pocket into the active site. The entrance tunnel is thereby lined by a so-called “track-and-trace” loop (BvHSS residues 114-130 <ref name="Krossa">PMID:26776105</ref>). Both enzymes display structural characteristics at their active site suggesting cation-π interaction through a highly conserved tryptophan as an important contribution for the catalyzed reaction.
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The <scene name='89/896623/Cv/8'>PaHSS is composed of two domains</scene>, an “NAD(P)-binding Rossmann-like domain” and an “HSS-like domain” (the NAD(P)-binding Rossmann-like
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domain colored yellow (residues 1–155 and 389–419) and the HSS-like domain in blue (residues 156–388 and 420–469)). The substrate binding pocket is located between these two domains. The cofactor NAD(H) is bound as a prosthetic group in the binding pocket with its nicotinamide ring being part of the active site. An “ionic slide” (BvHSS residues D94 and E117<ref name="Krossa">PMID:26776105</ref>) was proposed to lead positively charged amine substrates from the entrance of the binding pocket into the active site. The entrance tunnel is thereby lined by a so-called “track-and-trace” loop (BvHSS residues 114-130 <ref name="Krossa">PMID:26776105</ref>). Both enzymes display structural characteristics at their active site suggesting cation-π interaction through a highly conserved tryptophan as an important contribution for the catalyzed reaction.
Polyamines
Polyamines
Polyamines are involved in various processes in nearly all organisms in the three domains of life<ref name="Michael">PMID:27268252</ref>. In P. aeruginosa, polyamines and polyamine-related processes were demonstrated to be involved in growth<ref name="Bitonti">PMID:6818954</ref>, biofilm formation<ref name="Cardile">PMID:27864804</ref>,<ref name="Qu">PMID:26817804</ref>,<ref name="Williams">PMID:20149107</ref>, susceptibility to antibiotics and exogenous polyamines<ref name="Kwon">PMID:17438056</ref>,<ref name="Kwonb">PMID:16641427</ref>,<ref name="Kwona">PMID:16641426</ref>,<ref name="Yao">PMID:22869561</ref> as well as expression of the type III secretion system, a major virulence determinant<ref name="Anantharajah">PMID:27344210</ref>,<ref name="Wu">PMID:22300763</ref>,<ref name="Zhou">PMID:18074016</ref>. Therefore, enzymes like HSS might be promising targets for new antibiotics.
Polyamines are involved in various processes in nearly all organisms in the three domains of life<ref name="Michael">PMID:27268252</ref>. In P. aeruginosa, polyamines and polyamine-related processes were demonstrated to be involved in growth<ref name="Bitonti">PMID:6818954</ref>, biofilm formation<ref name="Cardile">PMID:27864804</ref>,<ref name="Qu">PMID:26817804</ref>,<ref name="Williams">PMID:20149107</ref>, susceptibility to antibiotics and exogenous polyamines<ref name="Kwon">PMID:17438056</ref>,<ref name="Kwonb">PMID:16641427</ref>,<ref name="Kwona">PMID:16641426</ref>,<ref name="Yao">PMID:22869561</ref> as well as expression of the type III secretion system, a major virulence determinant<ref name="Anantharajah">PMID:27344210</ref>,<ref name="Wu">PMID:22300763</ref>,<ref name="Zhou">PMID:18074016</ref>. Therefore, enzymes like HSS might be promising targets for new antibiotics.

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