Cyanolipids, Alkyl Cyanides and Isonitriles

A few plant species contain cyanolipids in which fatty acids are linked to cyanopropene-based moieties instead of glycerol, the function of which is presumed to be as a deterrent towards animal or insect predators, but lipids with alkyl groups linked directly to nitriles are only occasionally found in nature. Isonitrile-containing lipid molecules occur in bacteria, where their function is to sequester metal ions.

1.  Cyanolipids in Seed Oils

Cyanolipids are found as components of the lipids of seeds in some plants from the family Sapindaceae mainly, although some are known from the Hippocastaneaceae and Boraginaceae, where they occur together with conventional acylglycerols. There are four types of cyanolipid based on a five-carbon backbone that comprise a nitrile moiety together with a methylene group or double bond, and one or two hydroxyl groups to which long-chain fatty acids are esterified as illustrated.

The structures of cyanolipids from the Sapindaceae
Figure 1. The structures of cyanolipids from the Sapindaceae.

Thus, type I and II cyanolipids are diesters of 1-cyano-2-hydroxymethylprop-2-en-1-ol and 1-cyano-2-hydroxymethylprop-1-en-3-ol, respectively, while type III and IV cyanolipids are monoesters of 1-cyano-2-hydroxymethylprop-1-ene and 1-cyano-2-methylprop-2-en-1-ol, respectively. Of these, the type I cyanolipid appears to be most abundant, although it is often accompanied by the type II. The type III cyanolipid is only found with type II, while type IV is comparatively rare. It is important to note that type I and II cyanolipids are cyanohydrins with the cyanohydrin hydroxyl group esterified, and that they have a chiral centre, while type II and III cyanolipids are simply α,β-unsaturated nitriles and they do not have a chiral centre.

Formula of a mandelonitrileAnalogous glycosidic structures (cyanoglycosides) occur in the same seeds, i.e., with a glycosidic bond to glucose instead of the ester bond, and the two classes of compound are certainly related biosynthetically. In other plant families, cyanoglycosides occur with mandelonitrile (derived from mandelic acid) linked to a sugar.

Cyanolipids occur in seeds together with conventional triacylglycerols, with the two lipid classes often being present in comparable amounts. The fatty acid compositions are distinctive, depending upon the species, but typically comprise relatively high amounts of oleic (9-18:1), cis-vaccenic (11-18:1), eicosanoic (20:0), eicos-11-enoic (11-20:1) and eicos-13-enoic (paullinic or 13-20:1) acids. The fatty acid compositions of the cyanolipids and triacylglycerols of a representative species from the Sapindaceae are listed in Table 1.

Table 1. Fatty acid compositions of the cyanolipids and triacylglycerols of Paullinia cupana v. sorbilis (wt % of the total)
Fatty acid Cyanolipids Triacylglycerols
 
16:0 2 5
18:0 2 7
9-18:1 7 37
11-18:1 30 21
18:2(n-6) 6 10
20:0 2 4
11-20:1 39 12
13-20:1 7 4
Avato et al., Seed oil composition of Paullinia cupana var. sorbilis (Mart.) Ducke. Lipids, 38, 773-780 (2003);  DOI.

Information on the biosynthesis of these cyanolipids is limited, but it seems clear that leucine is a key precursor. There are several suggestions for the function of cyanolipids in seeds, and they may be a source of reduced nitrogen for the developing seedling, for example for alkaloid biosynthesis, as they disappear very rapidly on germination; at the same time, the cyanoglycosides increase in concentration. During the development of seedlings of Ungnadia speciosa, the cyanolipids (Type 1 with C20 fatty acids) are metabolized without liberation of free hydrogen cyanide to the atmosphere. Some are converted to cyanogenic glycosides, but most are converted to non-cyanogenic compounds, possibly amines. Alternatively, cyanolipids may simply have a protective role against attack by animals, insects or fungi by means of the facile release of hydrogen cyanide, which is toxic to predators. On hydrolysis by acid or base and by enzymes (hydroxynitrile lyases), cyanohydrins are released from type I and IV cyanolipids and decompose spontaneously with the production of hydrogen cyanide, i.e., they are cyanogenic, as illustrated below for a type IV cyanolipid.

Hydrolysis of cyanolipids
Figure 2. Hydrolysis of cyanolipids.

The various types of cyanolipids can be separated from each other by adsorption chromatography methods, especially thin-layer chromatography. More recently high-temperature gas chromatography coupled to mass spectrometry has enabled separation and identification of the main molecular species of cyanolipids together with those of the triacylglycerols in seed oils. Nuclear magnetic resonance spectroscopy of the intact lipids is an invaluable guide to identification of the types of cyanolipids present.

2.  Alkyl Cyanides and Isonitriles

Alkyl cyanides and thiocyanates:  The volatile compounds produced in cultures of Gram-positive Micromonospora and Gram-negative Pseudomonas species of bacteria can include long-chain aliphatic cyanides (nitriles), which can be either unbranched saturated or unsaturated with an omega-7 double bond, such as 11Z‑octadecenenitrile, or methyl-branched unsaturated cyanides with the double bond located at C-3, such as 13-methyltetradec-3Z-enenitrile. Fatty acids are the biosynthetic precursors, and these are first converted into their amides and then dehydrated. While their functions in the organisms are not yet known, some show antimicrobial activity. Aliphatic polyacetylenes with terminal nitrile groups, termed albanitriles A to G, have been isolated from a marine sponge of the Mycale genus, while alkyl thiocyanates have been identified in a number of marine organisms, such as Oceanapia sp.

Structures of an alkyl cyanide and thiocyanate

Isonitrile (isocyanide) lipids: Isonitrile resonance forms Aerocyanidin from the bacillus Chromobacterium violaceum is a fatty acid analogue containing an isonitrile epoxide and is an antibiotic that can be hydrolysed under acidic or basic conditions to generate cyanide. A related molecule, termed amycomycin, is produced by Amycolatopsis sp. The isonitrile group is linear and exists in two resonance forms, carbenoid and ionic: it can act as a nucleophile, an electrophile or a carbene, and thus can participate in many types of reaction, including binding to metal ions. Marine animals produce an extraordinary number of unusual lipids and amongst them is an isonitrile lipid, termed (-)‑actisonitrile, from the mantle of the nudibranch mollusc Actinocyclus papillatus; it is based on a 1,3‑propanediol ether skeleton. As it has cytotoxic properties, this novel lipid may be produced for defensive purposes. Sesquiterpenes containing nitrile or isonitrile moieties have been identified in marine invertebrates.

Structures of of aerocyanidin and actisonitrile

Formula of a kupyaphoreMany pathogenic bacteria, but especially Actinobacteria (including Streptomyces sp.) and Mycobacteria, produce a family of lipopeptides linked to fatty acids with isonitrile substituents, i.e. amphiphilic diisocyanolipopeptides, which are essential for the survival and pathogenicity of the organisms. In M. tuberculosis, a leading worldwide cause of disease mortality, these have been termed kupyaphores and contain two C12 (or longer) fatty acids with isonitrile substituents, derived biosynthetically from glycine, in position 3 and linked to a dipeptide core of ornithine and phenylalaninol. They are assembled through a hybrid fatty acid−nonribosomal peptide synthetase pathway. During infection, synthesis is induced, and they move in and out of cells in the charged resonance form to protect bacteria from host-mediated nutritional deprivation and acquire metal ions, such as zincII and copperI/II, as bidentate ligands. In experiments in vitro, it has been shown that they promote zincII transport across liposomes, suggesting a role as ionophores in metal acquisition and transport. As they inhibit Gram-positive Staphylococcus aureus and have low human toxicity, they have potential as novel antibacterial agents. They are a further addition to the astonishing range of novel lipids produced by Mycobacteria and listed here..

A family of comparable isonitrile lipopeptides have been identified from pathogenic M. fortuitum that bind to copper ions but not zinc and are termed 'chalkophores'.

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