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Review
, 47 (4), 233-306

Biosynthesis and Function of Polyacetylenes and Allied Natural Products

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Review

Biosynthesis and Function of Polyacetylenes and Allied Natural Products

Robert E Minto et al. Prog Lipid Res.

Abstract

Polyacetylenic natural products are a substantial class of often unstable compounds containing a unique carbon-carbon triple bond functionality, that are intriguing for their wide variety of biochemical and ecological functions, economic potential, and surprising mode of biosynthesis. Isotopic tracer experiments between 1960 and 1990 demonstrated that the majority of these compounds are derived from fatty acid and polyketide precursors. During the past decade, research into the metabolism of polyacetylenes has swiftly advanced, driven by the cloning of the first genes responsible for polyacetylene biosynthesis in plants, moss, fungi, and actinomycetes and the initial characterization of the gene products. The current state of knowledge of the biochemistry and molecular genetics of polyacetylenic secondary metabolic pathways will be presented together with an up-to-date survey of new terrestrial and marine natural products, their known biological activities, and a discussion of their likely metabolic origins.

Figures

Fig. 1
Fig. 1
Historically and biosynthetically important acetylenic natural products.
Fig. 2
Fig. 2
Two distinct proposals for the biogenesis of acetylenic bonds. A. Desaturation of existing alkene functionality through an iron-catalyzed dehydrogenation with molecular oxygen [26]. Electrons are provided by either NADH or NADPH. B. The elimination of an activated enol carboxylate intermediate is thermodynamically driven by CO2 formation, which may be coupled to the hydrolysis of pyrophosphate [28]. In the original hypotheses, path A would be operative with full-length acyl lipids and path B would install acetylenic groups during de novo fatty acid biosynthesis. Although current paradigm and all experiments dealing with fatty acid biosynthesis are consistent with the desaturase pathway, the elimination hypothesis remains valid for PK-derived acetylenic natural products.
Fig. 3
Fig. 3
An overview of the reactions modifying the lipidome and their cellular localization during lipid metabolism. The known processes that synthesize acetylenic bonds and many other oxidatively modified lipids occur at the endoplasmic reticulum, where substrate conjugation to PC appears to be required. In plants, unusual fatty acids are strongly biased to accumulate as TAG in oilbodies. While acyl redistribution is known to occur through the interplay of pathways shown, identification of the specific factors controling unusual fatty acid accumulation is an area of active investigation. Each type of lipid conjugate can provides a specific entry point for the elaboration of C8–C18 acetylenic natural products. Both fatty acid and PK-derived secondary metabolism appear to be active in marine organisms.
Fig. 4
Fig. 4
Acetylenic fatty acids derived from the crepenynate pathway. Primary metabolism provides the pool of fatty acid precursors for 2E. Fatty acids central to the crepenynate pathway and their most commonly employed acyl conjugates for enzymatic conversions to subsequent products are shown connected by heavy arrows. Pathways to products from other diverged desaturase activities and branches from the crepenynate pathway are shown with light arrows.
Fig. 5
Fig. 5
Natural products produced through the crepenynate pathway.
Fig. 6
Fig. 6
Falcarinol and related metabolites are widespread amongst Apiaceae and Araliaceae species. A. The metabolic web to falcarindiol and falcarinone commences from crepenynic acid, where favored metabolic pathways are depicted with solid arrows. The ubiquitous enzymatic transformations that provide alterative routes to many of the natural products remain largely unexplored (one subset described in the text is marked with dashed lines). B. Accessing polyacetylenic metabolites with unsaturation patterns rarely encountered in other fatty acids occurs through combinations of novel desaturation and hydrogenation processes. Hydroxylation/dehydration processes remain viable hypotheses for many unsaturated metabolite pairs. C. Species from fatty acid catabolism, such as 3-hydroxyoleic acid, have been found to be metabolic precursors to falcarinol derivatives [54].
Fig. 7
Fig. 7
Acetylenic fatty acids derived from the stearolic and tariric acid pathways. A. Stearolic acid metabolites relies on a Δ9-acetylenase activity and their structures are distinguished by the presences of uniformly trans-alkenes. B. The formation of the (E)-alkenes has been proposed by El-Jaber to pass through an allylic cationic rearrangement [67], although other dehydration or trans-desaturation routes are plausible. C. Cyclopropenyl fatty acids, originally postulated to rise from acetylenic fatty acids, are created stepwise by an sn-1-selective cyclopropane synthase followed by an uncharacterized desaturation activity (X = PC). The coexistence of cyclopropenyl and acetylenic fatty acids may indicate a common mode of desaturation. D. A plant Δ6-acetylenase is believed to catalyze the formation of tariric acid and related compounds.
Fig. 7
Fig. 7
Acetylenic fatty acids derived from the stearolic and tariric acid pathways. A. Stearolic acid metabolites relies on a Δ9-acetylenase activity and their structures are distinguished by the presences of uniformly trans-alkenes. B. The formation of the (E)-alkenes has been proposed by El-Jaber to pass through an allylic cationic rearrangement [67], although other dehydration or trans-desaturation routes are plausible. C. Cyclopropenyl fatty acids, originally postulated to rise from acetylenic fatty acids, are created stepwise by an sn-1-selective cyclopropane synthase followed by an uncharacterized desaturation activity (X = PC). The coexistence of cyclopropenyl and acetylenic fatty acids may indicate a common mode of desaturation. D. A plant Δ6-acetylenase is believed to catalyze the formation of tariric acid and related compounds.
Fig. 8
Fig. 8
Acetylenic fatty acid biosynthesis in moss. Conversions of common bryophyte precursors are shown and the favored pathway in C. purpureus is marked with heavy arrows.
Fig. 9
Fig. 9
Acetylenic pheromone biosynthesis in insects. In T. pityocampa, the transformation of the acetylenic fatty acid to the pheromone 7B is blocked in the absence of the hormone PBAN [91].
Fig. 10
Fig. 10
Stereochemistry of acetylenase/desaturase activities. An acetylenase, such as Crep1, forms both (9Z,12E)- and (9Z,12Z)-isomers of linoleate. A. For the normal (12Z)-isomer, an alkyl chain eclipsed to the carboxylate-bearing chain allows the abstraction of the pro-(R) hydrogens from C-12 and C-13. B. During the formation of the (12E)-isomer, a diastereomeric conformation with eclipsing alkyl-hydrogen interactions is proposed to place the alkyl chain in a broadened, or second distinct, binding pocket. In this model, the binding pockets for acetylenases and trans-desaturases are similar and allow for the linearization of the nascent acetylenic lipid. For the bifunctional Δ1110,12-desaturase from the insect Spodoptera littoralis, a two binding pocket model has been developed to accommodate the observed stereoselectivity [124]. RS is a smaller ethyl segment in tetradecenoyl substrates and RL is a longer butyl projection for hexadecenoyl substrates. C. For (11Z)-hexadecenoate, only the binding conformation leading to (10E,12Z)-hexadecadienoate is sterically allowed. D. In the case of (11Z)-tetradecenoate, both conformations shown in figure panels C and D are possible resulting in a mixture of (10E,12E)- and (10E,12Z)-tetradecadienoate. The stereochemical outcomes with myristate and palmitate are modeled by a similar sterically limiting binding pocket model where a large pocket produces the (11Z)-C14 and C16 isomers and a smaller pocket produces solely (11E)-tetradecenoate.
Fig. 11
Fig. 11
Carboxy-terminal chain-shortening pathways for fatty acids. A. Important C13 and C14 fatty acids and alcohols result from apparent combinations of α- and β-oxidation pathways. B. Aldehyde, alkene, and methyl ketone chain termini are directly formed through α-oxidation chemistry, although the latter two are proposed to arise through fragmentation of β-oxidation intermediates 8K and 8M, respectively. X’ is an undefined group, such as phosphate or pyrophosphate, that may assist in elimination.
Fig. 12
Fig. 12
Intra-chain cleavage pathways. Two processes may be relevant to the insertion of oxygen into an acetylenic fatty acid chain: A. Bayer-Villiger oxidation to C10 polyacetylenes [12]and B. Hock rearrangement of a bis-allylic hydroperoxide leading to maracin A (9D) and maracen A (9E) [167]. The labeling pattern for 9D is shown in the lower right.
Fig. 13
Fig. 13
Modifications to acetylenic fatty acids distal to the carboxyl group. A metabolic grid is presumed to generate a variety of ω-oxidized polyacetylenes, and the functionalization is necessary for their biological functions. For falcarinol, accumulated incorporation data and the recent identification of a terminal desaturation activity support the outlined proposal that many of the metabolic steps occur as acylglycerolipids; however, many details of these reactions remain to be ascertained.
Fig. 14
Fig. 14
Sulfur addition to polyacetylenes. A. Sulfur addition to a diyne unit leads to a thiophene through a stepwise process. Formal addition of H2S produces vinyl thiols that are intercepted in certain Asteraceae species to produce thioethers (11A). Ring closure results in thiophenes (11B) and bithienes (11C) and oxidative formation of disulfide linkages produces dithienes (11D). Combinations of substituent R1 and R2 described in the text are tabulated and designated by a suffix. B. Acetate incorporation patterns for dithienyl 11Ca and its precursors tridecenepentayne (11E) and octadecenetriynoic acid (2M) determined through [13C]glucose feedings of T. patula [189]. C. The summarized incorporation experiments indicate that methyl cleavage reactions occur prior to the formation of the second heterocycle creating two distinct reaction manifolds [190].
Fig. 15
Fig. 15
Proposed biosynthesis of alkamides. The ligation of an alkyl or aryl amine with a polyalkenyl or acetylenic fatty acid produces the alkamides. The progression from 2A to 12B has been verified in Echinaceae pupurea by radiotracer studies with [10-14C] methyl oleate, [16-14-C] methyl enediynoate, and [12-14C]anacyclin, however, the enzymatic participants have not been identified [194].
Fig. 16
Fig. 16
Nine-membered ring cycloenediynes. A. Cyclization commonly occurs by nucleophilic attack on a diacetylenic chromophore yielding a strained cumulene-ene-yne (shown) or by perturbing a moiety stabilizing an enediyne. B. Structures of C9 cycloenediyne natural products.
Fig. 17
Fig. 17
Ten-membered ring cycloenediynes. A. The calicheamicin-like metabolites cyclize through a thiol-activated Michael addition activating the subsequent Bergman cyclization. B. Structures of the C10 cycloenediyne natural products.
Fig. 18
Fig. 18
Biosynthesis of the enediynes. A. Incorporation patterns have been ascertained for three of the enediyne natural products [–210]. B. Crepenynate was originally suggested as a progenitor, which was cleaved to a C14 species. In this model, the ab fragment leads to 13A; either ac or b fragments provide the labeling pattern for 14A–F [209]. C. The organization of SgcE, the PKS for C-1027 biosynthesis, is consistent with an iterative PKS enzyme and includes an ORF for a specialized PPTE domain and several ORFs of unknown function [214]. PKS subdomains are: ACP, acyl carrier protein; AT, acyltransferase; DH, dehydratase; KR, β-ketoacyl reductase; KS, β-ketoacyl synthase; PPTE, phosphopantetheinyl thioesterase; and UNK, domain of unknown function.
Fig. 19
Fig. 19
Metabolites produced via haloenediyne cyclizations. A. 15B and 15C originate from the mixed PK enediyne presporolide, which undergoes a haloenediyne cyclization to produce the aromatic core [220]. B. Halide accelerations of enediyne cycloaromatization had been recently shown with for the cyanosporasides 15D–E [221].
Fig. 20
Fig. 20
Jamaicamides and their biosynthesis [223]. A. Structures of jamaicamides A-C (16A–C). B. Analysis of isotopic incorporation studies for jamaicamide B. ωAcetylenic fatty acids, which have been previously reported and may be formed through acetylenase action (e.g., 16D to 16E), are potential starter units for these PKS-NRPS metabolites. C. The jamaicamide biosynthetic gene cluster. JamB bears resemblence to a fatty acid desaturase. A portion of JamE is of unknown function, possessing weak similarity to the Fe2+/α-ketoglutarate-dependent dioxygenases. Open-reading frames are shown as arrows. The color of an arrow indicates its assigned pathway: blue, NRPS; red, PKS; yellow, other assigned function; black, function not annotated. Boxes provide the order of the subdomains for the multifunctional polypeptides: A, adenylation domain; ACP, acyl carrier protein; AS, acyl-ACP synthetase; AT, acyltransferase; C, condensation domain; CM, C-methyltransferase; CYC, cyclase; DC, decarboxylase; DH, dehydratase; ECH, enoyl-CoA hydratase/isomerase; ER, enoyl reductase; HMG, 3-hydroxy-3-methylglutaryl-CoA synthase; KR, β-ketoacyl reductase; KS, β-ketoacyl synthase; KSD, β-ketoacyl synthase/dehydratase; OM, O-methyltransferase; PCP, peptidyl carrier protein; and TE thioesterase.
Fig. 21
Fig. 21
Marine terpenoids. A. Incorporation studies of caulerpenyne have clearly shown this metabolite to arise from the MEP pathway [233]. A diverse set of acylated metabolites has been identified. B. The order of lipase reactions leading to the highly toxic secretion oxytoxin-2 are believed to follow the upper path in vivo [236]. Other cyclized species, such as 17F–H, are known in this metabolic family.
Fig. 22
Fig. 22
A. Structures of acetylenic sterols from marine sources. B. Biosynthesis of C23-alkynyl steroids from 24-methylenecholesterol [241].
Fig. 23
Fig. 23
Structures of quinoid natural products with acetylenic substituents and related aromatic heterocycles.
Fig. 24
Fig. 24
Biosynthesis of polyacetylenes via the shikimate pathway. While it is rare that acetylenic metabolites result from only shikimate intermediates, the aryl ethers 20A–C have been proposed to arise from two such fragments via the hypothetical cyclic ether 20D [261, 262].
Fig. 25
Fig. 25
Acetylenic alkaloids from amphibians. A. Structures of well known acetylenic polycyclic amines isolated from ants and/or frogs and their precursors. B. Enamine cyclizations are believed to expand the ring systems, and subsequent dehydrogenations occur to form acetylenic and allenic derivatives.
Fig. 26
Fig. 26
Acetylenic secondary metabolites from the Campanulaceae family.
Fig. 27
Fig. 27
Proposed biosynthesis of acetylenic spiroketals found in Asteraceae species.
Fig. 28
Fig. 28
Acetylenic natural products from the Asteraceae species include thiophenes, polyols, glycosides, and coumarins.
Fig. 29
Fig. 29
Polyacetylenes from the plant families Apiaceae and Araliaceae.
Fig. 30
Fig. 30
Acetylenic secondary metabolites from the families Annonaceae and Lauraceae.
Fig. 31
Fig. 31
A. Brominated acetylenic and allenic fatty acids from lichen. B. Hypothetical biosynthetic pathway to 1-haloacetylenic fatty acids in these organisms [319].
Fig. 32
Fig. 32
Polyacetylenes including the phomallenic acids, 07F275 and the xerulins have been recently identified from fungi.
Fig. 33
Fig. 33
The petroformyne family of sponge secondary metabolites.
Fig. 34
Fig. 34
The petrocortynes family of sponge natural products and other Petrosia ssp. polyacetylenic alcohols.
Fig. 35
Fig. 35
Very long-chain acetylenic acids, including the corticatic acids (31A–E) and nepheliosyne A (31I), have structural similarities suggesting the involvement of common biochemical activities, including terminal oxidases. The size and symmetrical nature of di- and tetrahydroxyacetylenes 31Q and 31R support the involvement of hypothetical condensation reactions of long-chain fatty acid precursors.
Fig. 36
Fig. 36
A. Mycolic acid biosynthesis involves a specialized condensing enzyme system initially furnishes a 2-alkyl-3-ketoacid [350, 352, 353]. B. Expanding upon the Fleming-Harley-Mason hypothesis, the carboxylation of a C16–C18 acetylenic fatty acid may be coupled with an acceptor acyl derivative to assemble the marine PKs.
Fig. 37
Fig. 37
Other very-long chain marine polyacetylenic alcohols and acids.
Fig. 38
Fig. 38
Marine organisms occasionally accumulate relatively short-chain acetylenic metabolites. The strongylodiols are novel, as they are produced as epimeric mixtures at C-6, and the peroxyacarnoic acids contain a distinctive 1,2-dioxane.
Fig. 39
Fig. 39
A wide array of bromoacetylenic acids have be uncovered in marine sponges.
Fig. 40
Fig. 40
Chlorinated polyacetylenic acids produced by Haliclona lunisimilis may be consumed and modified by the nudibranch D. sandiegensis to augment defensive secretions.
Fig. 41
Fig. 41
A. The diacetylenic montiporic acids appear to be formed by a series of α- and ω-oxidations analogous to terrestrial plants and fungi. The timing of the chain modifications is indeterminate.
Fig. 42
Fig. 42
A. Alkaloids from the genera Xestospongia, Amphimedon, Niphates, and Clathrina. B. The biosynthesis of the acetylenic 3-alkylpyridines can be rationalized by a Mannich reaction involving a formaldehyde-derived iminium ion. The hydroxylamino termini are presumed to have origins similar to plant glycosinolates.
Fig. 43
Fig. 43
A. α-Methoxy fatty acids found in sponge species. B. Acetylenic 1-alkenylglycerols are likely furnished either by the exchange of acetylenic alcohols into 1-acyl DHAPs by alkyl dihydroxyacetonephosphate synthase or the direct desaturation of ether lipids. C. In terrestrial organisms, the desaturation to 2-acyl-1-alkylphosphatidylethanolamines involves the action of a Δ1-desaturase [396]. An analogous dehydrogenating system is expected in marine sponges. It has been demonstrated that 1-alkylglycerol derivatives can be cleaved by triplet oxygen producing toxic α, β-acetylenic aldehydes [394].
Fig. 44
Fig. 44
Callyspongia and Diplastrella spp. produce acetylenic alcohols and sulfates absent the 1,4-pentadiyn-3-ol core of the petroformyne and petrocortyne metabolites.
Fig. 45
Fig. 45
Marine diacetylenic propargyl alcohols and alkamides.
Fig. 46
Fig. 46
Certain chlorinated natural products result from the free-radical halogenation of methyl groups. The acetylenic acetamides are presumed to arise by a similar path followed by the elimination of HCl.
Fig. 47
Fig. 47
Structurally novel marine PKs (43A–E) expand the distribution of glycosylated acetylenic metabolites from terrestrial to marine organisms. Other PK motifs, shown in 43F–G appear to be rare [425].
Fig. 48
Fig. 48
A wide array of lipopeptides and cyclodepsipeptides containing terminal acetylenic branches are known. The acetylenic units and their more saturated congeners may arise from fatty acyl starter units that undergo stepwise desaturation. It remains to be determined which marine invertebrates accomplish aspects of acetylene biosynthesis and which compounds may be dietarily acquired from cyanobacteria.
Fig. 48
Fig. 48
A wide array of lipopeptides and cyclodepsipeptides containing terminal acetylenic branches are known. The acetylenic units and their more saturated congeners may arise from fatty acyl starter units that undergo stepwise desaturation. It remains to be determined which marine invertebrates accomplish aspects of acetylene biosynthesis and which compounds may be dietarily acquired from cyanobacteria.
Fig. 49
Fig. 49
Acetylenic modification of the terpenoids appears to occur on assembled metabolites. Acetylenases acting upon this class of substrates remain to be discovered.
Fig. 50
Fig. 50
Selected acetylenic compounds for which ecological and ethnopharmacological roles have been described.
Fig. 51
Fig. 51. Legend for Biosynthesis
Key to the experimentally determined isotopic labeling patterns that are superimposed on structures found in Figures (e.g., Fig. 5, 12, etc.). (Place unnumbered Figure, “Legend for Biosynthesis”)

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