Mode of action of the lanthionine-containing peptide antibiotics duramycin, duramycin B and C, and cinnamycin as indirect inhibitors of phospholipase A2

Märki, F; Hänni, E; Fredenhagen, Andreas; Oostrum, Jan van

doi:10.1016/0006-2952(91)90604-4

Cited by 135 publications

(76 citation statements)

References 25 publications

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“…Cell surface PtdEtn can be detected using cinnamycin and duramycin, two highly related lantibiotics that bind specifically to PtdEtn on the cell surface and induce cell death in a PtdEtn concentration‐dependent manner 32, 33. We had previously shown that the elevated levels of PtdEtn produced by presenilin‐mutant cells, including AD fibroblasts, were significantly more sensitive to both cinnamycin and duramycin than were wild‐type controls 7.…”

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ApoE4 upregulates the activity of mitochondria‐associated ER membranes

et al. 2015

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In addition to the appearance of senile plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by aberrant lipid metabolism and early mitochondrial dysfunction. We recently showed that there was increased functionality of mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM), a subdomain of the ER involved in lipid and cholesterol homeostasis, in presenilin‐deficient cells and in fibroblasts from familial and sporadic AD patients. Individuals carrying the ε4 allele of apolipoprotein E (ApoE4) are at increased risk for developing AD compared to those carrying ApoE3. While the reason for this increased risk is unknown, we hypothesized that it might be associated with elevated MAM function. Using an astrocyte‐conditioned media (ACM) model, we now show that ER–mitochondrial communication and MAM function—as measured by the synthesis of phospholipids and of cholesteryl esters, respectively—are increased significantly in cells treated with ApoE4‐containing ACM as compared to those treated with ApoE3‐containing ACM. Notably, this effect was seen with lipoprotein‐enriched preparations, but not with lipid‐free ApoE protein. These data are consistent with a role of upregulated MAM function in the pathogenesis of AD and may help explain, in part, the contribution of ApoE4 as a risk factor in the disease.

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Section: Resultsmentioning

confidence: 99%

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

et al. 2015

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“…h 90 cells were also treated with Duramycin and papuamide B, which are cytotoxic peptides that respectively bind extracellularly exposed phosphatidyl ethanolamine and phosphatidylserine and induce cell lysis (Marki et al 1991;Parsons et al 2006). Normally, flippases maintain these phospholipid components on the inner leaflet of the plasma membrane; thus, an increased sensitivity to Duramycin and to papuamide B would reflect a defective phospholipid organization in the plasma membrane.…”

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Membrane Organization and Cell Fusion During Mating in Fission Yeast Requires Multipass Membrane Protein Prm1

et al. 2014

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The involvement of Schizosaccharomyces pombe prm1 + in cell fusion during mating and its relationship with other genes required for this process have been addressed. S. pombe prm1D mutant exhibits an almost complete blockade in cell fusion and an abnormal distribution of the plasma membrane and cell wall in the area of cell-cell interaction. The distribution of cellular envelopes is similar to that described for mutants devoid of the Fig1-related claudin-like Dni proteins; however, prm1 + and the dni + genes act in different subpathways. Time-lapse analyses show that in the wild-type S. pombe strain, the distribution of phosphatidylserine in the cytoplasmic leaflet of the plasma membrane undergoes some modification before an opening is observed in the cross wall at the cellcell contact region. In the prm1D mutant, this membrane modification does not take place, and the cross wall between the mating partners is not extensively degraded; plasma membrane forms invaginations and fingers that sometimes collapse/retract and that are sometimes strengthened by the synthesis of cell-wall material. Neither prm1D nor prm1D dniD zygotes lyse after cell-cell contact in medium containing and lacking calcium. Response to drugs that inhibit lipid synthesis or interfere with lipids is different in wild-type, prm1D, and dni1D strains, suggesting that membrane structure/organization/dynamics is different in all these strains and that Prm1p and the Dni proteins exert some functions required to guarantee correct membrane organization that are critical for cell fusion. M EMBRANE fusion is essential for several developmental processes. The characterization of mating in yeasts represents a useful tool for understanding the mechanisms involved in intercellular membrane merger and their regulation. In the fission yeast Schizosaccharomyces pombe, heterothallic cells belong to one of two mating types, M (h 2 cells) or P (h + cells) while h 90 strains are homothallic (Arcangioli and Thon 2004). In rich medium, h + and h 2 cells can proliferate actively together without mating. When nitrogen becomes scarce the cAMP level decreases, which triggers the expression of genes required for sexual differentiation. Cells arrest in G1 and polarize, giving rise to specialized cells termed shmoos (Yamamoto et al. 1997;Davey 1998;Nielsen 2004;Yamamoto 2004). After agglutination, the cross wall separating both parental cells is degraded, allowing cell fusion. Efficient cell fusion requires the correct organization of the cytoskeleton (Petersen et al. 1995(Petersen et al. , 1998aKurahashi et al. 2002;Doyle et al. 2009). The S. cerevisiae FUS1 and the S. pombe fus1 + genes have the same name and both mutants exhibit cell fusion defects during mating, leading to an accumulation of prezygotes (mating intermediates in which the mating partners have established a stable contact but have not yet fused). However, the corresponding proteins are not related; while Saccharomyces cerevisiae Fus1p is a membrane protein (Trueheart et al. 1987), S. pombe Fus1p ...

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“…The duramycins B and C have been isolated as inhibitors of phospholipase A, with activities in the micromolar range [3]. They show specific interaction with phosphatidylethanolamine, but not with the closely related phosphatidylcholine [4].Lantibiotics share a common biosynthesis pathway which involves the ribosomal synthesis of a prepeptide with a Nterminal leader sequence followed by post-translational modification and processing [5]. The modification involves enzymic dehydration of the serine and threonine residues in the C-terminal propeptide part to didehydroalanine and 2,3-didehydrobutyrine.…”

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Solution structures of the lantibiotics duramycin B and C

Zimmermann

Freund

Fredenhagen

et al. 1993

European Journal of Biochemistry

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The solution structures of the lantibiotics duramycin B in H,O/'H,O (9 : 1) and duramycin C in (2H,)acetonitrile/H,0 (1 : 1) have been determined by NMR followed by distance-geometry and restrained-molecular-mechanics calculations. The constitution and location of three thioether bridges and a lysinoalanine ring system could be established by unambiguously assigned NOE contacts between the bridging side chains. Model building based on NMR constraints resulted in a U-shaped topology of the tetracyclic 19-peptides with a turn around Pro9 and a kink along a virtual line from residues 5 to 13. This clamp-like conformation is stabilized by the thioether bridges and is additionally supported by an antiparallel P-strand-like structure of the N-termini and C-termini and the inherent amphiphilicity of duramycin-type lantibiotics. The duramycins B and C differ mainly in the relative mobilities of their rings A, C and D. Duramycin B is closely related to cinnamycin with an exchange of PhelO to leucine, whereas duramycin C differs from duramycin B by three conserved and two non-conserved amino-acid exchanges.The duramycins B and C belong to the class of heterodet polycyclic peptide antibiotics which were named lantibiotics [ l , 21. Their common structural elements are thioether rings formed by lanthionine and 3-methyl-lanthionine residues. Further unusual amino acid residues occur in the duramycin family such as 3-hydroxy-aspartic acid and a lysinoalanine bridge. The duramycins B and C have been isolated as inhibitors of phospholipase A, with activities in the micromolar range [3]. They show specific interaction with phosphatidylethanolamine, but not with the closely related phosphatidylcholine [4].Lantibiotics share a common biosynthesis pathway which involves the ribosomal synthesis of a prepeptide with a Nterminal leader sequence followed by post-translational modification and processing [5]. The modification involves enzymic dehydration of the serine and threonine residues in the C-terminal propeptide part to didehydroalanine and 2,3-didehydrobutyrine. Through stereospecific addition of the thiol group of cysteine residues to the double bonds of the Abbreviations. NOESY, nuclear Overhauser enhancement spectroscopy ; COSY, correlated spectroscopy ; DQF, double quantum filter; TOCSY, total correlation spectroscopy; HMQC, heteronuclear multiple quantum coherence; HMBC, heteronucledr multiple bond correlation; DISCO, differences and sums of COSY spectra; ROESY, rotating frame nuclear overhauser enhancement spectroscopy ; Ah,, L-alanine moiety of (2S,6R)-lanthionine and (2S,3S,6R)-methyllanthionine; D-Ala,, D-alanine moiety of (2S,6R)-lanthionine; Abu, (2S,3S)-p-methylalanine moiety of (2S,3S,6R)-methyllanthionine; Ala,, L-alanine moiety of (2S,9S)-lysinoalanine; HyAsp, (2S,3R)-3-hydroxy-aspartic acid; MD, molecular dynamics.Dedication. Dedicated to Prof. Murray Goodman on occasion of his 65th birthday.2,3-didehydroamino acid residues, the thioether bridges of lanthionine and b-methyl-lanthionine are formed. Addition of lys...

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Mode of action of the lanthionine-containing peptide antibiotics duramycin, duramycin B and C, and cinnamycin as indirect inhibitors of phospholipase A2

Cited by 135 publications

References 25 publications

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

Membrane Organization and Cell Fusion During Mating in Fission Yeast Requires Multipass Membrane Protein Prm1

Solution structures of the lantibiotics duramycin B and C

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