Pseudodesmin

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General info

Original publicationSinnaeve, 2009b
Original sourceUndisclosed
Other known sources (non-putative)Pseudomonas sp. COR52 (Oni, 2020) Pseudomonas tolaasii DSM19342 (Hermenau, 2020)
Stereochemistry determined byX-ray and Marfey’s analysis (original) NMR spectral matching (P. sp. COR52 and P. tolaassi DSM19342)

Chemical properties

CASn.a.
Molecular formula1125.4170 g/mol
Molecular weightC54H96N10O15
Mono-isotopic mass1124.7057 Da (isobaric to other CLiPs, see text)
SolubilityAcetonitrile, methanol, DMSO, acetone, chloroform, ethylacetate, dimethylformamide, buffer (limited)
Not soluble in milliQ water.
CMCn.a.
Minimal surface tensionn.a.
3D conformationX-ray (Sinnaeve, 2009b), NMR solution structure (Acetonitrile) (Sinnaeve, 2009a, Geudens, 2014)
NMR data available in literatureAcetonitrile (Sinnaeve, 2009a, Geudens, 2014, Oni, 2020) Chloroform (Sinnaeve, 2009a, Geudens, 2014)

Introduction

Pseudodesmin is a cyclic lipodepsipeptide (CLiP) that – structurally speaking – belongs to the viscosin group. It is a secondary metabolite produced by non-ribosomal peptide synthetases (NRPSs) and was first isolated from Pseudomonas bacteria collected from the mucus layer in the skin of the black belly salamander. (Sinnaeve, 2009b) The CLiP appears to be somewhat rare, as no other non-putative sources were described until very recently. (Hermenau, 2020, Oni, 2020)

Biological activity

Viscosinamide features antagonistic activities against Gram-positive and mycobacteria while it appears inactive against the (limited number of) Gram-negative bacteria and fungi that were tested . There is no data available concerning activity against Gram-negative bacteria. Additionally, no data is available concerning antiprotozoal, antitumor or hemolytic activities. (reviewed in Geudens, 2018)

Chemical structure

The primary structure of pseudodesmin was first analyzed by means of liquid state NMR spectroscopy and Marfey’s analysis revealing amino acid sequence is 3-OH C10:0 – L-Leu1 – D-Gln2 – D-aThr3 – D-Val – D-Leu5 – D-Ser6 – L-Leu7 – D-Ser8 – L-Ile9 whereby the molecule is cyclized by means of an ester bond between the C-terminal carboxylic acid and the side-chain hydroxyl moiety of Thr3. (Sinnaeve, 2009b) A minor compound was also extracted, whereby Ile9 is replaced by Val9. This type of modification is common in Pseudomonas CLiPs, and is likely caused by substrate flexibility of the adenylation domain of the NRPS proteins. Very recently, pseudodesmin C has been described as being the linearized version of pseudodesmin A, whereby the C-terminal ester bond is hydrolyzed. (Hermenau, 2020)

Interestingly, the structure of pseudodesmin A is neutral under physiological conditions, which is rare in CLiPs. Indeed, the only other neutral Pseudomonas CLiP is the structurally similar viscosinamide A. Both CLiPs differ only in the stereochemistry of Leu5, featuring either an L-Leu5 (VA) or D-Leu (PsdA). Importantly, this also implies that both CLiPs cannot be discriminated based on high resolution MS or MS/MS, since only the configuration of Leu5 differs between both lipopeptides – the compounds are isobaric. The closed pseudodesmin-analogue that does have a charge is WLIP. Indeed, the latter only differs at position two, where it possesses a D-Glu2 instead of D-Gln2. This modification introduces a negative charge under physiological conditions. It is believed that the charge does have a (limited) impact on the biophysical and biological behavior. (Geudens, 2017)

Three-dimension structure

The three-dimensional structure (the conformation) of pseudodesmin A has been analyzed by means of X-ray crystallography (Sinnaeve, 2009b) and liquid state NMR spectroscopy (Sinnaeve, 2009a, Geudens, 2014). Both structures differ only slightly and consist of an N-terminal left-handed alpha-helix ranging from L-Leu1 to D-Ser6, followed by a rigid ‘loop’ which brings the C-terminal carbonyl in a suitable position for cyclization. Consequently, a part of the the helix is located within the macrocycle. The conformation is formed such that the hydrophobic residues (indicated in green in the figure below) are clearly separated from the polar residues (indicated in red), creating a amphiphilic molecule.

References

Geudens, et al. “Impact of a stereocentre inversion in cyclic lipodepsipeptides from the viscosin group: a comparative study of the viscosinamide and pseudodesmin conformation and self-assembly.” ChemBioChem15, 18 (2014): https://dx.doi.org/10.1002/cbic.201402389.

Geudens, et al. “Cyclic lipodepsipeptides from Pseudomonas spp. – Biological Swiss-Army Knives.” Frontiers in Microbiology9, 1867 (2018): https://dx.doi.org/10.3389/fmicb.2018.01867.

Geudens, et al. “Membrane interactions of natural cyclic lipodepsipeptides of the viscosin group.” Biochimica et Biophysica Acta – Biomembranes1859, 3 (2017): https://dx.doi.org/10.1016/j.bbamem.2016.12.013.

Hermenau, et al. “Helper bacteria halt and disarm mushroom pathogens by linearizing structurally diverse cyclolipopeptides.” Proc Natl Acad Sci U S A117, 38 (2020): https://dx.doi.org/10.1073/pnas.2006109117.

Oni, et al. “Biosynthesis and Antimicrobial Activity of Pseudodesmin and Viscosinamide Cyclic Lipopeptides Produced by Pseudomonads Associated with the Cocoyam Rhizosphere.” Microorganisms8, 7 (2020): https://dx.doi.org/10.3390/microorganisms8071079.

Sinnaeve, et al. “The solution structure and self-association properties of the cyclic lipodepsipeptide pseudodesmin A support its pore-forming potential.” Chemistry – A European Journal15, 46 (2009a): https://dx.doi.org/10.1002/chem.200901885.

Sinnaeve, et al. “Structure and X-ray conformation of pseudodesmins A and B, two new cyclic lipodepsipeptides from Pseudomonas bacteria.” Tetrahedron65, 21 (2009b): https://dx.doi.org/10.1016/j.tet.2009.03.045.

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