Structural Revision of Natural Cyclic Depsipeptide MA026 Established by Total Synthesis and Biosynthetic Gene Cluster Analysis

Abstract

A revised structure of natural 14-mer cyclic depsipeptide MA026, isolated from Pseudomonas sp. RtlB026 in 2002 was established by physicochemical analysis with HPLC, MS/MS, and NMR and confirmed by total solid-phase synthesis. The revised structure differs from that previously reported in that two amino acid residues, assigned in error, have been replaced. Synthesized MA026 with the revised structure showed a tight junction (TJ) opening activity like that of the natural one in a cell-based TJ opening assay. Bioinformatic analysis of the putative MA026 biosynthetic gene cluster (BGC) of RtIB026 demonstrated that the stereochemistry of each amino acid residue in the revised structure can be reasonably explained. Phylogenetic analysis with xantholysin BGC indicates an exceptionally high homology (ca. 90 %) between xantholysin and MA026. The TJ opening activity of MA026 when binding to claudin-1 is a key to new avenues for transdermal administration of large hydrophilic biologics.

An Nuclear Magnetic Resonance Fingerprint Matching Approach for the Identification and Structural Re-Evaluation of Pseudomonas Lipopeptides

“…RtlB026 with potent anti-hepatitis C activity. Discrepancies in physicochemical properties of synthetic and natural MA026 led Uchiyama et al ( 75 ) to revise its structure by exchanging residues at position 10 and 11, as previously suggested by Li et al ( 71 ), thus leading to a planar structure identical to xantholysin A. With more than 90% sequence similarity between their respective BGC, it was proposed that the stereochemistry of xantholysin A would be identical to that of MA026.…”

“…With more than 90% sequence similarity between their respective BGC, it was proposed that the stereochemistry of xantholysin A would be identical to that of MA026. However, Uchiyama et al ( 75 ) also noted that the stereochemical assignment for xantholysin A from Pseudomonas sp. 250J did not match with MA026, the latter containing l -Gln6 and d -Gln13, while the reverse configuration was proposed for the former.…”

An NMR fingerprint matching approach for the identification and structural re-evaluation ofPseudomonaslipopeptides

“…RtlB026 with potent anti-hepatitis C activity. Discrepancies in physicochemical properties of synthetic and natural MA026 led Uchiyama et al (73) to revise its structure by exchanging residues at position 10 and 11, as previously suggested by Li et al (69), thus leading to a planar structure identical to xantholysin A. With more than 90% sequence similarity between their respective BGC, it was proposed that the stereochemistry of xantholysin A would be identical to that of MA026.…”

Marine natural products

“…68 As with previous reviews in this series, a number of new bacterial MNPs were claimed during 2021, but the structures presented were not fully consistent with the spectroscopic evidence provided. 7,30,31 The rst total syntheses of 22 marine bacterial compounds was reported in the literature during 2021, caprolactin C 6, 5 akazaoxime 4 and A-76356 45, 16 MA026 67, 25 xiamycins D and E, 69 bacicyclin, 70 (+)-pseudonocardide A and (+)-pseudonocardide C, 71 nocardiotide A, 72 three 2-(p-hydroxybenzyl)prodigiosin-based MNPs, along with isoheptylprodigiosin, and tambjamine MYP1, 73 (+)-spiroindimicin A, 74 nesteretal A, 75 (+)-03219A, 76 enterocin, 77 nahuoic acid A, 78 piscibactin, 79 and aldgamycin N. 80 Over 80 reviews featuring some aspect of marine bacterial chemistry or biology were published during 2021. This is the highest number of reviews ever and no doubt reects the impact that COVID-19 has had on labs around the world.…”

“…source supported the absolute configuration assignments for all amino acid residues. 25 New uridine 68 and indole derivatives 69 were purified and characterised from the fermentation broth of a Pseudonocardia strain that was obtained from a scleractinian coral, 26 whilst another new indole NP, vibrindole B 70 , was identified from a sponge-associated Pseudovibrio denitrificans . 27 Other Pseudovibrio investigations involved the complete genome mapping of a sponge-derived isolate, Pseudovibrio brasiliensis , and the application of a reverse genetics methodology led to the discovery of a novel family of nonribosomal hexapeptides named pseudovibriamides A 1–6 71 , 72–76 and B 1–6 77–82 .…”