Gramicidin A. V. The Structure of Valine- and Isoleucine-gramicidin A

Sarges, Reinhard; Witkop, Bernhard

doi:10.1021/ja01087a027

Cited by 352 publications

(177 citation statements)

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“…These highly cytotoxic peptides -isolated from a marine sponge, but probably of microbial origin -feature two other types of non-ribosomal amino acids, i.e., d-amino acids and N-methyl amino acids, which are both known to prevent peptidase cleavage (cf. the antibiotic gramicidin A, which consists of a chain of alternating l-and d-aminoacid residues [12], or the immunosuppressive cyclic undecapeptide cyclosporin A, containing six N-methyl, and three non-proteinogenic (Bmt, Abu, d-Ala) amino acid moieties [13]). Peptides consisting entirely of d-amino acids with proteinogenic side chains are completely stable towards peptidases; they are often used to study those properties of their normal counterparts (enantiomers!…”

mentioning

confidence: 99%

ADME Investigations of Unnatural Peptides: Distribution of a ¹⁴C‐Labeled β ³‐Octaarginine in Rats

Weiss

Wirz

Schweitzer

et al. 2007

Chemistry & Biodiversity

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The highly positively charged, cell-penetrating beta3-octaarginine has been prepared with a radioactive label by acetylation at the N-terminus with a doubly (14)C-labeled acetyl group ((14)CH3-(14)CO). With the radioactive compound, an ADME study (Absorption, Distribution, Metabolism, Excretion) was performed in male rats following an intravenous or oral dose of 1 mg/kg. Sampling was carried out after periods ranging from 5 min to 4 d or 7 d for blood/excretia and quantitative whole-body autoradioluminography (QWBA), respectively. After p.o. dosing, no systemic exposure to peptide-related radioactivity was observed, and the dose was completely excreted in the feces within 24 h suggesting the absence of relevant absorption; less than 3% of the i.v. dose was excreted from the animals within 4 d. Blood levels, after i.v. dosing, dropped within 4 d to less than 2% of Cmax and decreased afterwards only very slowly. No metabolites were observed in the systemic circulation. QWBA Data indicated that the distribution of the acetyl-beta-octaarginine-related radioactivity in the organs and tissues shifted over time. Notably, after 7 d, the highest concentration was measured in the lymph nodes, and the largest amount was found in the liver. A comparison with the results of two previous ADME investigations of beta-peptides (cf. Table 1) reveals that the distribution of the compounds within the animals is structure-dependent, and that there is a full range from oral availability with rather rapid excretion (of a tetrapeptide) to essentially complete lack of both oral absorption and excretion after i.v. administration (of a highly charged octapeptide). A discussion is presented about the in vivo stability and 'drug-ability' of peptides. In general, beta-peptides bearing proteinogenic side chains are compared with peptides consisting entirely of D-alpha-amino acid residues (the enantiomers of the 'natural' building blocks), and suggestions are made regarding a possible focus of future biomedical investigations with beta-peptides.

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confidence: 99%

ADME Investigations of Unnatural Peptides: Distribution of a ¹⁴C‐Labeled β ³‐Octaarginine in Rats

Weiss

Wirz

Schweitzer

et al. 2007

Chemistry & Biodiversity

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“…The specific type of gramicidin is determined by the 11th amino acid in the 15 amino acid sequence. For example, gramicidin A has the sequence [22,23] …”

Section: Methodsmentioning

confidence: 99%

Analysis of Amphiphilic Lipids and Hydrophobic Proteins Using Nonresonant Femtosecond Laser Vaporization with Electrospray Post-Ionization

Brady

Judge

Levis

2011

J. Am. Soc. Mass Spectrom.

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Amphiphilic lipids and hydrophobic proteins are vaporized at atmospheric pressure using nonresonant 70 femtosecond (fs) laser pulses followed by electrospray post-ionization prior to being transferred into a time-of-flight mass spectrometer for mass analysis. Measurements of molecules on metal and transparent dielectric surfaces indicate that vaporization occurs through a nonthermal mechanism. The molecules analyzed include the lipids 1-monooleoyl-rac-glycerol, 1,2-dihexanoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, and the hydrophobic proteins gramicidin A, B, and C. Vaporization of lipids from blood and milk are also presented to demonstrate that lipids in complex systems can be transferred intact into the gas phase for mass analysis.

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“…The specificity of charging is of a lower order than that achieved by the nucleic acid-coded adaptor system of protein synthesis, as amino acid substitutions have been reported, for example, in tyrocidines"9 20 and gramicidins. 21 It was already reported that the fraction II enzyme catalyzes, in addition to ATP-PP032, an ATP-AMP exchange dependent on either L-or D-phenylalanine.1 This indication of a transfer of phenylalanine from adenylate to an unknown acceptor site is confirmed by the excess of bound phenylalanine over bound adenylate, while retaining carboxyl activation. The excess is equal to the amount of acyl adenylate when L-phenylalanine is used as a substrate or is much greater when D-phenylalanine is used.…”

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confidence: 86%

Interrelation Between Activation and Polymerization in Gramicidin S Biosynthesis

Kleinkauf

Gevers

Lipmann

1969

Proc. Natl. Acad. Sci. U.S.A.

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and Summary.-The nucleic acid-independent biosynthesis of the peptide antibiotic gramicidin S results from the interaction of an enzyme bearing phenylalanine in activated form with a polyenzyme system charged with the other four component amino acids.After reaction with ATP, magnesium, and any or all of its amino acid substrates, the polyenzyme system (mol wt 280,000) yields complexes containing AM\P and the respective amino acids in the proportion of 1 to 2. Similar complexes are formed by another enzyme (mol wt 100,000) on incubation with ATP, magnesium, and L-or D-phenylalanine. The (ATCC 8185).5We will report here on the formation of bound intermediates by the two fractions and on the interaction between them in polymerization. No dissociation of the activities of the heavy fraction was obtained on further purification. After incubation with its four L-amino acid substrates in the presence of ATP, a complex containing adenylate and amino acids in the proportion of 1:2 could be isolated, indicating that in addition to aminoacyl adenylates, the enzyme bound each of the amino acids in a different form. The binding of phenylalanine by the light fraction was similar. It appears that after formation of aminoacyl adenylates there are transfers of amino acids to other acceptors, retaining activation. Combination of the charged complexes induced the synthesis of gramicidin S, which occurred by "head growth" of a bound peptide chain.6Methods and Materials.-Purification of enzymes: The procedure previously described' 226

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Gramicidin A. V. The Structure of Valine- and Isoleucine-gramicidin A

Cited by 352 publications

References 4 publications

ADME Investigations of Unnatural Peptides: Distribution of a ¹⁴C‐Labeled β ³‐Octaarginine in Rats

ADME Investigations of Unnatural Peptides: Distribution of a ¹⁴C‐Labeled β ³‐Octaarginine in Rats

Analysis of Amphiphilic Lipids and Hydrophobic Proteins Using Nonresonant Femtosecond Laser Vaporization with Electrospray Post-Ionization

Interrelation Between Activation and Polymerization in Gramicidin S Biosynthesis

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Gramicidin A. V. The Structure of Valine- and Isoleucine-gramicidin A

Cited by 352 publications

References 4 publications

ADME Investigations of Unnatural Peptides: Distribution of a 14C‐Labeled β 3‐Octaarginine in Rats

ADME Investigations of Unnatural Peptides: Distribution of a 14C‐Labeled β 3‐Octaarginine in Rats

Analysis of Amphiphilic Lipids and Hydrophobic Proteins Using Nonresonant Femtosecond Laser Vaporization with Electrospray Post-Ionization

Interrelation Between Activation and Polymerization in Gramicidin S Biosynthesis

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ADME Investigations of Unnatural Peptides: Distribution of a ¹⁴C‐Labeled β ³‐Octaarginine in Rats

ADME Investigations of Unnatural Peptides: Distribution of a ¹⁴C‐Labeled β ³‐Octaarginine in Rats