Structure of the peptide antibiotic amphomycin

Bodanszky, Miklos; Sigler, Gerald F.; Bodánszky, Agnes

doi:10.1021/ja00788a040

Cited by 96 publications

(37 citation statements)

References 3 publications

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“…In addition, such data will be beneficial for the exploitation of related Ca2+-dependent antibacterials produced by Actinomycetes, such as CDA from Streptomyces coelicolor 1441, and various amphomycin-related peptides and peptidolactones produced from Streptomycetes and Actinoplunes sp. [45].…”

Section: Discussionmentioning

confidence: 99%

Biosynthesis of Acylpeptidolactones of the Daptomycin Type

Wessels

Döhren

Kleinkauf

1996

European Journal of Biochemistry

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A21978C and A541 45 are antibacterial 13-residue peptides with a medium-chain-acylated amino terminus and a 10-residue lactone ring; they are produced by strains of Streptomyces roseosporus and Streptomyces frudiue, respectively. The structural differences in their peptide chains, which include amino acid replacements and modifications (~-Glu2-+~-Asn, ~-Asn(oH)3-~-Asp, SarS+Gly, ~-Ala6-+~-Om, ~-L y s 8 -+~-A l a , ~-Asp(OMe)9+~-Asp, L-Asnl I-D-Ser, and ~-I l e l 3 +~-K y n ; Sar = sarcosine; L-Orn = L-ornithine, L-Kyn = L-kynurenine), reside in the multienzymatic templates directing their biosynthesis. We have examined the peptide synthetases employing immunodetection and substrate activation detected by the amino-acid-dependent ATP-PP,-exchange reaction. Two different antibodies specific for actinomycin synthetase 2 and a peptide sequence characteristic of acyl-CoA-synthetaseslpeptide synthetases were applied. For the A21978 system two peptide synthetases of 670 and 240 kDa were detected, together with two similar proteins of 630 and 440 kDa occurring in varying amounts. The latter are suggested to be degradation products of an unstable multienzyme. Activation of L -A s~, L-Thr, Gly, ~-Orn, L-Ala and L-Ser were assigned to the high-molecular-mass components of 670, 630 and 440kDa. The 240-kDa protein was purified to homogeneity and shown to catalyse activation of L-kynurenine. The A54145 system consisted of three peptide synthetases of 690, 590 and 250 kDa. Activations of L-Asn, L-Thr and Gly were found. The 250-kDa synthetase was capable of activating isoleucine and valine. Both systems thus show a comparable organisation ; implications for the modular construction of their peptide synthetases are discussed.Keywords: daptomycin biosynthesis ; multienzyme ; peptide synthetase; lipopeptide; protein purification.The biosynthesis of peptides by multienzyme systems is directed by an ordered array of domains [I -51. Each domain catalyses a set of enzyme functions directing a complete elongation step in peptide as well as polyketide forming pathways [5, 61. The arrangement of domain-encoding modules at the DNA level, as well as their alteration or exchange, is thought to originate from recombinational events [7]. In peptide-forming systems so far only modules adding L-and D-amino acids, as well as N-methylated amino acids, have been studied. No information is yet available on changes in specificity, hydroxylated or 0-methylated amino acids, and exchanges of residues. A unique system for studying such processes are two antibacterial lipopeptides, A21978C and A54145, which were discovered by Debono et al. 18, 91 and Fukuda et al. [lo].Daptomycin is a semisynthetic acylated 13-residue lipopeptide with a 10-residue peptidolactone-ring antibiotic derived from the A21978C factor complex produced by Streptomyces roseosporus (Fig. 1 A). Its action against gram-positive bacteria is apparently exerted from the Ca2+ complex that interferes with an early step in peptidoglycan formation [ 111 and seems to inhibit lipoteichoic ac...

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Section: Discussionmentioning

confidence: 99%

Biosynthesis of Acylpeptidolactones of the Daptomycin Type

Wessels

Döhren

Kleinkauf

1996

European Journal of Biochemistry

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“…Heinemann and Bodanzky reported the isolation from hydrolysates of three fatty groups linked to Amp: ∆3-anteisotridecenoic acid (10-methyl-3-dodecenoic acid), the lactone of 4-hydroxy-anteiso-tridecanoic acid (4-hydroxy-10-methyl-dodecanoic acid), and 4-hydroxyisodecanoic acid (4-hydroxy-10-methyl-hendecanoic acid) [79,80]. From acid hydrolysate of Amp, L-aspartic acid, L-glycine, L-threo-β-methylaspartic acid, L-proline, L-valine, D-pipecolic acid, L-threo-α,β-diaminobutyric acid, and D-erythro-α,β-diaminobutyric acid were also isolated and identified [81].…”

Section: Amphomycin and Derivativesmentioning

confidence: 99%

Lipopeptides as anti-infectives: a practical perspective

et al. 2009

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Abstract:Lipopeptide antibiotics represent an old class of antibiotics that were discovered over 50 years ago, which includes the old polymyxins but also new entries, such as the recently approved daptomycin. They generally consist of a hydrophilic cyclic peptide portion attached to a fatty acid chain which facilitates insertion into the lipid bilayer of bacterial membranes. This review presents an overview of this class of antibiotics, focusing on their therapeutic applications and putting particular emphasis on chemical modifications introduced to improve their activity.

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“…The chemical structure of major component of amfomycin complex, amfomycin A 1 , a side-chain-cyclized lipopeptide (Table 17), was originally published by Bodanszky et al in 1973. 42 This antibiotic complex consists of a highly conserved side-chain-cyclized undecapeptide portion that is acylated by one variable unsaturated and branched (iso or anteiso) fatty acid moiety.…”

Section: Amfomycin (Amphomycin)mentioning

confidence: 99%

“…42 This antibiotic complex consists of a highly conserved side-chain-cyclized undecapeptide portion that is acylated by one variable unsaturated and branched (iso or anteiso) fatty acid moiety. The complete structural identity of the fatty acid substituent was determined very recently by Vertesy et al, 43 and turned out to be (Z -anteiso-3-tridecenoic acid (amfomycin A 1 ).…”

Section: Amfomycin (Amphomycin)mentioning

confidence: 99%

Comparison of CID spectra of singly charged polypeptide antibiotic precursor ions obtained by positive‐ion vacuum MALDI IT/RTOF and TOF/RTOF, AP‐MALDI‐IT and ESI‐IT mass spectrometry

et al. 2006

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Various classes of polypeptide antibiotics, including blocked linear peptides (gramicidin D), side-chaincyclized peptides (bacitracin, viomycin, capreomycin), side-chain-cyclized depsipeptides (virginiamycin S), real cyclic peptides (tyrocidin, gramcidin S) and side-chain-cyclized lipopeptides (polymyxin B and E, amfomycin), were investigated by low-energy collision induced dissociation (LE-CID) as well as highenergy CID (HE-CID). Ion trap (IT) based instruments with different desorption/ionization techniques such as electrospray ionization (ESI), atmospheric pressure matrix-assisted laser desorption/ionization (AP-MALDI) and vacuum MALDI (vMALDI) as well as a vMALDI-time-of-flight (TOF)/curved fieldreflectron instrument fitted with a gas collision cell were used. For optimum comparability of data from different IT instruments, the CID conditions were standardized and only singly charged precursor ions were considered. Additionally, HE-CID data obtained from the TOF-based instrument were acquired and compared with LE-CID data from ITs. Major differences between trap-based and TOF-based CID data are that the latter data set lacks abundant additional loss of small neutrals (e.g. ammonia, water) but contains product ions down to the immonium-ion-type region, thereby allowing the detection of even single amino-acid (even unusual amino acids) substitutions. For several polypeptide antibiotics, mass spectrometric as well as tandem mass spectrometric data are shown and discussed for the first time, and some yet undescribed minor components are also reported. De novo sequencing of unusually linked minor components of (e.g. cyclic) polypeptides is practically impossible without knowledge of the exact structure and fragmentation behavior of the major components. Finally, the described standardized CID condition constitutes a basic prerequisite for creating a searchable, annotated MS n -database of bioactive compounds. The applied desorption/ionization techniques showed no significant influence on the type of product ions (neglecting relative abundances of product ions formed) observed, and therefore the type of analyzer connected with the CID process mainly determines the type of fragment ions.

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Structure of the peptide antibiotic amphomycin

Cited by 96 publications

References 3 publications

Biosynthesis of Acylpeptidolactones of the Daptomycin Type

Biosynthesis of Acylpeptidolactones of the Daptomycin Type

Lipopeptides as anti-infectives: a practical perspective

Comparison of CID spectra of singly charged polypeptide antibiotic precursor ions obtained by positive‐ion vacuum MALDI IT/RTOF and TOF/RTOF, AP‐MALDI‐IT and ESI‐IT mass spectrometry

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