Peptidolipids

Several characterized NRPSs utilize alternative methods for chain termination. In some synthetases, the TE domain of the final module is replaced by an NAD(P)H-dependent reductase domain. Reduction of a peptidyl-S-PCP substrate through a two-electron reaction leads to the formation of a transient aldehyde, which is subsequently converted into a cyclic imine or hemiaminal through intramolecular cyclization. This two-electron reaction is utilized in the biosynthesis of nostocyclopeptides, the saframycins, ° and anthramycin. Alternatively, a four-electron reduction to the primary alcohol is observed in the biosynthesis of mycobacterial peptidolipids, linear gramicidin," " the myxalamides, lyngbyatoxin, " and myxochelin A 75,76 alternative four-electron reduction pathway involving aldehyde formation, transamination, and reduction to a primary amine occurs in the biosynthesis of myxochelin B. ... 

Arima, K., Kakinuma, A. Tamura, G. (1968). Surfactin, a crystalline peptidolipid surfactant produced by Bacillus subtilis isolation, characterization and its inhibition of fibrin clot formation. Biochemical and Biophysical Research Communication, 31, 488-94. 

Peptidolipids are also present in bioorganic materials. Hydrolysis of bacterial phospholipids, for example, frequently generates amino acids such as lysine, ornitine, and arginine. One proposed structure for this type of compound is shown below [3]. 

P. J. Brennan, G. O. Aspinall, and J. E. Shin, Structure of the specific oligosaccharides from the glyco-peptidolipid antigens of serovars in the Mycobacterium avium-Mycobacterium intracellulare-Mycobac-terium scrofulaceum complex,/. Biol. Chem., 256 (1981) 6817-6822. 

The peptidolipids which occur in Mycobacteria and Nocardia spp. are V-acyl oligopeptides. They often occur as glycoside derivatives (Kates, 1972). 

Pentanoic acid, 1, 350, 351 Pentene, 457 Peptidoglycan, 157 Peptidolipids, 39 Perch, 134 Perciformes, 147 Perilla oil, 52... 

The polymyxins are a group of closely related lipopeptide antibiotics produced by B. polymyxa and related bacilli. As seen in O Fig. 10.5, polymyxin B is a decapeptide in which amino acids 3 through 10 form a cyclic octapeptide. A branched-chain fatty acid is connected to the terminal 2,4-diaminobutyric acid (DAB). The structures of polymyxins differ in substituents at residues 3 (DAB or D-Ser), 6 (o-Leu or L-Ileu), or 7 (d- or l-DAB) (Suzuki et al. 1965). The cationic 7y-amino groups of the DAB residues, together with the hydrophobic side chain of the fatty acid, give these antibiotics the surface-active properties of a cationic detergent. Pseudomonas strains produce viscosin, a peptidolipid biosurfactant which lowers surface tension of water to 27 mN/m (Neu et al. 1992). 

Glycosides of Peptidolipids Isolated from R/iodococcMS eryt/iropo/is.. .. 59... 

More recently, thanks to improvements in fractionation and analytical techniques and because of the increase of interest in bacterial metabolites, particularly metabolites exhibiting antibiotic or enzyme inhibiting properties, many new peptidolipids have been discovered. 

Whereas in the currently known cases peptides are always linked to fatty material by amide bonds, the amino acids in peptidolipids may be linked through amide or through ester bonds. The present review will be limited to compounds containing amide bonds. In the case of peptidolipids, an arbitrary limitation has been introduced Only compounds... 

It is usual to distinguish between peptidolipids which exhibit lipid characteristics and are soluble in lipid solvents and lipopeptides, which exhibit polar characteristics and may be soluble in water. No such distinction has been made here because of the difficulty in applying these criteria to compounds that are insoluble in water as well as in chloroform. In fact, when derivatives of lipids and peptides are considered, no clear-cut separation into two classes of compounds becomes evident, but a progressive variation in the polarity of the molecules may be observed. 

The lipid was mainly located in the chromatophores and membrane material of Rh. sphaeroides (20). Similar results on its location were found in a reinvestigation of the lipids of subcellular fractions of Rh. sphaeroides (27) besides the ornithine-containing lipid a minor peptidolipid, designated as aminolipid X , was observed. Hydrolysis of this lipid gave ornithine, an unidentified amine and fatty acids. 

D-Amino acids are frequently encountered in these bacterial constituents. The formation of D-a//othreonine can be explained by the action of racemases on the a-carbon atom of L-threonine 69), Similarly, d-fl//oisoleucine can be produced from L-isoleucine (70) (see for example peptidolipin NA or cerexin A). However, in two cases, L-a//othreonine and L-a//oisoleucine have been found no information is available on their biosynthesis. Unusual amino acids have also been observed in some of these peptidolipids, for instance pipecolic acid (amphomycin), L-threo- -hydroxyglutamic and L-t/ireo-P-methylglutamic acids (neopeptines), or D- or L- 2,4-diaminobutyric acid (octapeptines). 

Hydrolysis of the polar peptidolipids which consisted of four components gave glycine, L-leucine, D-a//oisoleucine, L-threonine, L-serine, l-homoserine and o-alanine in the molar ratio 3 3 2 2 2 1 1. Two of these compounds contained glucose bound to the hydroxyl group of serine or threonine and thus were glucosides of peptidolipids all of them contained mycolic acids 74). Their complete structures have not yet been established. 

The N-terminal amino acid was acylated by a fatty acid molecule. Acid hydrolysis gave a mixture of saturated fatty acids, all with an even number of carbon atoms (C16-C24 major members C20 and C q). Partial hydrolysis gave N-acyl-D-phenylalanine, so the location of the D-amino acid residue became known (77). The hydrophobic character of this peptidolipid is to be noted. 

A peptidolipid called fortuitin was isolated from M.fortuitum. After purification, it had a m.p. of 199-202°C and an optical rotation of Md 72° (chloroform). Acid hydrolysis furnished approximately equi-molecular quantities of eicosanoic and docosanoic acid and amino acids. The amino acid composition was found to be Val3, Thr2, Ala, Proj. The carboxyl group of the C-terminal amino acid of the oligopeptide moiety was esterified by methanol. A preliminary structure was reported... 

Bacillus cereus produces a peptidolipid fraction exhibiting antibiotic activity against Gram positive bacteria which has been called cerexin. Cerexin is a complex mixture of peptidolipids of similar structures (Table 4). The structure of the main product, cerexin A, was established first (54, 55). It behaved like an amphoteric compound and had an optical rotation of + 19.5° (dimethylformamide). Short acid hydrolysis gave a fatty acid the methyl ester of which exhibited a single peak... 

Table 4. Composition of the Peptidolipids of the Cerexin Group (from 88)...

After purification by counter-current distribution this peptidolipid was obtained as an amorphous powder of m.p. 230°C (dec.) and optical rotation [oi] + 9.5° (ethanol). Acid hydrolysis gave a mixture of fatty acids, the major components of which were identical with (+)-anteisotridec-3-enoic and isododec-3-enoic acids. The amino acids consisted of L-aspartic acid (3 moles), glycine (2 moles), L-tftreo-P-methyl-aspartic acid, L-proline, L-valine, D-pipecolic acid, L-tftreo-2,3-diaminobutyric acid (DAB,) and D- ryt/iro-2,3-diaminobutyric acid (DABJ (1 mole each). 

Several other peptidolipids differing from amphomycin only in the structure of the fatty acid constituent are listed in Table 6. 

This peptidolipid has been found in four species of Actinomycetales, Streptomyces halstedii, Streptoverticillium cinnamoneum, Streptomyces... 

An incompletely characterized peptidolipid with the same amino acid composition as surfactin has been isolated from the Marburg strain of Bacillus subtilis, and appeared to be located in the cell membrane. It was synthesized continuously during the growth of the bacteria and its content increased in phosphate-limited cultures (100). 

From B. mesentericus a peptidolipid exhibiting antibiotic properties was isolated and called esperin. It had m.p. 238 °C and — 24° (methanol). Mild saponification opened a lactone ring, thus giving esperinic acid of m.p. 195 °C, [a]p + 12.5° (methanol). A tentative structure (41) was proposed (103). However, because of differences in the properties of esperinic acid and a synthetic sample of the peptidolipid (41) the proposed structure was found to be incorrect (104),... 

A peptidolipid fraction was isolated from Nocardia asteroides ATCC 9969. The main component of the mixture, obtained by counter-current distribution, was called peptidolipin NA. After purification, it had m.p. 232-233 "C, [a]o + 42° (chloroform) (106). 

Countercurrent distribution gave peptidolipin NA as the major component of a peptidolipid fraction obtained from N. asteroides ATCC 9969. Two minor components were isolated. The first of these was Val -peptidolipin NA of m.p. 221-223 °C, [a] + 70° (chloroform). Chemical and mass spectrometric investigations showed that it differed from peptidolipin NA by replacement of the L-alanine residue in position 6 by a residue of L-valine. Beside 3D-hydroxyeicosanoic acid small amounts of the higher homologues C21 and C22 were observed (772). The second minor component, Abu -peptidolipin NA , differed from peptidolipin NA by replacement of the threonine residue in position 1 by a residue of a-aminobutyric acid (Abu) which is a deoxythreonine. The lipid moiety was a mixture of the p-hydroxy fatty acids C205 C21 and C22 (775). 

The presence of a lactone group was shown by isolation of an open-chain peptidolipid, [a] — 72° (methanol) after mild treatment with alkali. This derivative was hydrolyzed by carboxypeptidase with release of glutamic acid. The mixture of compounds obtained by refluxing a solution of lipopeptin A in dilute acetic acid was separated into free aspartic acid, N-acylthreonine, N-acyl-Thr-Asp and an hexapeptide [(45) in Scheme 8]. Structures of the N-acyl derivatives were established by El mass spectrometry of the methyl esters. 

A peptidolipid exhibiting antibiotic properties against mycobacteria and viruses produced by Pseudomonas viscosa was obtained as a crystalline compound of m.p. 270-273 °C, [a]o — 168° (ethanol). The N-3d-hydroxydecanoyl-hexapeptide structure (49) proposed originally (118) was later shown to be incorrect because the synthetic product was different from natural viscosin (119). 

A strain of Streptomyces recognized as Str. olivaceus and isolated from a sample of soil obtained in Turkey was found to produce a family of peptidolipidic antibiotics along with prodigiosin and metacyclo-prodigiosin. These antibiotics interfered with the biosynthesis of murein and only the growth of actinomycetes was inhibited 123). 

As peptidolipids having a fatty acid component with less than 10 carbon atoms are not within the scope of this review, the N-acylundeca-peptide brevistin 122) will not be discussed here. 

A group of peptidolipids produced by strains of Bacillus subtilis is characterized by the presence of P-amino fatty acids as lipid components. The peptide chain forms a macrocyclic lactam by reaction between the amino group of the fatty acid and the carboxyl group of the C-terminal amino acid. These compounds are isolated from the culture medium of the bacteria and have mainly antifungal properties. 

B. subtilis produced a peptidolipid fraction named iturin because the bacterial strain had been isolated from the soil in a village called Ituri in Zaire. By chromatography on silicic acid three components (A, B and C) were obtained (136). In fact the mixture was more complex as it proved possible to resolve iturin A into seven components by HPLC (137). 

Another antifungal agent is produced by another strain of B. subtilis as a mixture of peptidolipids. Two homologous peptidolipids are the major components of the mixture they contain p-amino fatty acids easily characterized by a strong peak at m/z 240 in the mass spectrum of the N-trifluoroacetyl butyl ester (149). 

The application of mass spectrometry to structure determination of the peptidolipids has played an important role in development of this... 

Fig. 4. El-mass spectrum of the peptidolipid isolated from Mycobacterium paratuberculosis...

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