Amino Acids DOI 10.1007/s00726-016-2176-5
REVIEW ARTICLE
Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity Clemens Lamberth1
Received: 22 December 2015 / Accepted: 8 January 2016 © Springer-Verlag Wien 2016
Abstract Several naturally occurring amino acid derivatives display significant activities against weeds, fungi and insects: some of them have been even commercialized and are applied as crop protection agents. The 53 most important amino acid natural products with such efficacy are presented in this review together with their natural source, mode of action and biological activity. The diversity of the manifold bacterial, fungal and plantal sources of these compounds is impressive as well as their completely different structural scaffolds, ranging from cyclopeptides via unique non-proteinogenic amino acids to peptidyl nucleosides, the broad range of target enzymes from several different biochemical pathways, which they inhibit and also the plethora of different weeds, fungi and insects they are able to control. Keywords Natural products · Amino acids · Agrochemicals · Crop protection · Herbicides · Fungicides · Insecticides
Introduction Natural products have always played a detrimental role in crop protection chemistry, both as lead compounds and as active ingredients (Cantrell et al. 2012; Dayan et al. 2009; Copping and Duke 2007; Crombie 1999; Pachlatko 1998). Examples of important classes of market products, which have been developed from naturally occurring lead compounds, are Based on a lecture presented at the 14th international congress on amino acids, peptides and proteins, Vienna, 3–7th August 2015. * Clemens Lamberth [email protected] 1
Syngenta Crop Protection AG, Stein, Switzerland
the 4-hydroxyphenylpyruvate dioxygenase inhibiting diketone herbicides inspired by leptospermone (isolated from the red bottlebrush plant Callistemon citrinus) (Beaudegnies et al. 2009), the complex III respiration inhibiting strobilurin fungicides originating from strobilurin A (isolated from the pinecone cap mushroom Strobilurus tenacellus) (Sauter et al. 1999) and the sodium channel blocking pyrethorid insecticides stemming from pyrethin I (isolated from the chrysanthemum flower Tanacetum cinerariaefolium). Natural products, which are successfully sold as crop protection products are the non-selective herbicide bialaphos (isolated from Streptomyces hygroscopicus and Streptomyces viridochromogenes), the fungicide blasticidin S (isolated from Streptomyces griseochromogenes) and the insecticide spinosad (isolated from Saccharopolyspora spinosa) (Copping and Duke 2007). Also naturally occurring amino acid derivatives and their oligo- and polymeric equivalents are more and more in the focus as sources for new agrochemicals. The different features of antifungal peptides and their scope and limitations for agricultural applications have been summarized recently in several reports (Faruck et al. 2016; Lee and Kim 2015; van der Weerden et al. 2013; Everett 1994). Therefore, this review will rather focus on small molecules, specifically naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity, their sources, mode of action and biological activity.
Herbicidally active naturally occurring amino acid derivatives Inhibition of glutamine synthetase The tripeptides bialaphos (1) and phosalacine (2), the tetrapeptide trialaphos (3) as well as their N-terminal amino
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acid l-phosphinotricin (4) are non-selective herbicides. Bialaphos (1), which has been isolated from the fermentation broths of Streptomyces hygroscopicus and Streptomyces viridochromogenes, and trialaphos (3) and phosalacine (2), which both have been isolated from the culture filtrate of Kitasatosporia phosalacinea, are pro-herbicides and only active after their metabolic hydrolysis in the plant to their active principle, the N-terminal amino acid l-phosphinothricin (4) (Dayan and Duke 2014; Duke and Dayan 2011; Dayan et al. 2009; Hoagland 2001; Lamberth 2010; Lydon and Duke 1999). Although only the (S)-enantiomer phosphinothricin is herbicidally active, the ammonium salt of its racemate has been launched in the market and is successfully sold under the common name glufosinate (Basta®, Liberty®) (5). Also bialaphos (1) has been commercialized in Japan and is produced by fermentation. Bialaphos (1) and glufosinate (5) are broad-spectrum post-emergence herbicides which can be used for total vegetation control. As they are non-selective herbicides, especially glufosinate is often marketed along with genetically engineered glufosinate-resistant crops (e.g. corn, cotton and soybean). l-phosphinothricin (4) is a phosphinic acid mimic of (S)glutamic acid, the natural substrate of glutamine synthetase. This target enzyme enables a very rare transformation, the incorporation of inorganic nitrogen into organic forms (e.g. amino acids and nucleobases) by production of glutamine for ammonia detoxification. The inhibition of glutamine synthetase results in the accumulation of ammonia in the plant cells up to toxic levels as well as in inhibition of photorespiration due to reduced levels of amino acid donors (Dayan and Duke 2014; Duke and Dayan 2011; Dayan et al. 2009; Hoagland 2001; Lamberth 2010; Lydon and Duke 1999). Tabtoxin (6), a threonine-based dipeptide from Pseudomonas syringae is another proherbicide. Itself not intrinsically active, it is hydrolyzed in planta to form the potent glutamine synthetase inhibitor tabtoxin-βlactam (Duke and Dayan 2011; Dayan et al. 2009). Also the β-amino acid oxetin (7) from Streptomyces sp. OM-2317 is targeting the same enzyme (Fig. 1) (Duke and Dayan 2011; Dayan et al. 2009).
Inhibition of chloroplastic ATP synthase Also the cyclic tetrapeptide tentoxin (9) is inducing chlorotic plant tissues. It is produced by the plant pathogenic fungus Alternaria alternata and inhibits chloroplast development, herewith directly interacting with CF1 ATPase, the chloroplastic ATP synthase. Tentoxin induces chlorosis on a variety of corn and soybean weeds, such as Ipomoea hederacea (morningglory), Cassia obtusifolia (sicklepod) and Sorghum halepense (Johnsongrass) without affecting the corresponding crops (Fig. 2) (Dayan and Duke 2014; Duke and Dayan 2011; Lamberth 2010; Lax et al. 1988). Inhibition of peptide deformylase The valine derivative actinonin (10) is produced by Actinomyces sp. MG848-hF6. This dipeptide bearing a hydroxamic acid function causes stunting, bleaching and necrosis in a wide range of agriculturally relevant weed species by inhibition of plastid peptide formylase, a critical enzyme required for N-terminal protein processing of plastid-encoded proteins (Fig. 2) (Dayan and Duke 2014; Duke and Dayan 2011; Hou and William 2006). Jasmonic acid analogs Jasmonic acid is a plant hormone derived from linolenic acid. It plays an important role in regulating plant growth and development as well as in responses to both biotic and abiotic stress. Coronatine (11) is a jasmonate mimic produced by Pseudomonas coronafacience. It surpresses natural salicylic acid-dependent plant defense mechanisms, resulting in stunting and chlorosis of developing tissues, which are typical symptoms (Dayan and Duke 2014; Duke and Dayan 2011; Block et al. 2005). The herbicidal activity of the isoleucine derivative cinnacidin (12), a product of the fungus Nectria sp. DA060097, is due to a similar mode of action (Dayan and Duke 2014; Duke and Dayan 2011; Irvine et al. 2008) (Fig. 3). Inhibition of β‑cystathionase
Inhibition of ornithine carbamoyl transferase The non-selective herbicide phaseolotoxin (8) is produced by Pseudomonas syringae pv. phaseolicola. It is another proherbicide and only active after conversion in planta to its N-terminal amino acid octicidine, which is an irreversible inhibitor of Ornithine carbamoyl transferase, a key enzyme in the urea cycle of plants. Phaseolotoxin (8) has been also called the halo-blight toxin because of chlorosis spots on that parts of the leaves where the bacterium has entered (Fig. 2) (Dayan and Duke 2014; Duke and Dayan 2011; Bender et al. 1999).
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Rhizobitoxine (13) has been isolated from Bradyrhizobium japonicum. It inhibits β-cystathionase, an enzyme catalyzing an elimination reaction, wherein l-cystathionine and water are converted to l-homocysteine, ammonia and pyruvare. This reaction is important for several metabolic pathways, e.g. the metabolism of methionine, cysteine, nitrogen and sulfur. Rhizobitoxine (11) is phytotoxic enough to have been considered as a commercial herbicide. It controls Digitaria sanguinalis (large crabgrass) and Brassica japonica (wild mustard) (Dayan and Duke 2014; Duke and Dayan 2011; Owens 1973) (Fig. 3).
Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity Fig. 1 Herbicidally active naturally occurring inhibitors of glutamine synthetase
1 bialaphos
2 phosalacine
3 trialaphos
4 L-phosphinothricin (glufosinate-P)
6 tabtoxin
5 glufosinate (D,L-phosphinothricin)
7 oxetin
Inhibition of photosystem I
Inhibition of ribonucleotide reductase
Photosystem I (PSI) is a key component of the photosynthetic electron transport chain. Pyridazocidin (14), a cationic phytotoxin isolated from Streptomyces sp., blocks PSI by diverting electrons from it, which prevents the conversion of NADP into NADPH and converts the cationic pyridazocidin into a highly reactive free radical, generating reactive oxygen species that cause destructive oxidative processes such as necrosis and chlorosis. Pyridazocidin (14), one of the very rare examples of naturally occurring pyridazine, is highly active against Setaria faberi (giant foxtail), Abutilon theophrasti (velvetleaf) and Ipomoea hederaceae (ivyleaf morningglory) (Duke and Dayan 2011; Hoagland 2001; Gerwick et al. 1997) (Fig. 4).
Mimosine (15), a phytotoxin isolated from the plants Leucaena leucocephala de Wit and Mimosa pudica, inhibits ribonucleotide reductase, an enzyme which catalyzes the formation of deoxyribonucleotides from ribonucleotides. Mimosine (15) displays activity again Bidens pilosa (hairy beggarticks) and Lolium multiflorum (Italian ryegrass) (Williams and Hoagland 2007; Xuan et al. 2006) (Fig. 4). Inhibition of amino acyl tRNA synthetase Ascamycin (16) has been isolated from a Streptomyces sp. fermentation broth. It displays remarkable postemergence activity against different broadleaf weeds. The
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C. Lamberth Fig. 2 Herbicidally active naturally occurring inhibitors of ornithine carbamoyl transferase, chloroplastic ATP synthase and peptide deformylase
8 phaseolotoxin
10 actinonin
9 tentoxin Fig. 3 Herbicidally active naturally occurring analogs of jasmonic acid and inhibitors of β-cystathionase
12 cinnacidin
11 coronatine
13 rhizobitoxine
5-sulfamoylnucleoside ascamycin is a bioisostere of the corresponding nucleotide, the sulfamoyl function mimicking the natural phosphate group. It inhibits protein biosynthesis by blocking amino acyl tRNA synthetase (Lamberth 2005; Beautement et al. 2000) (Fig. 4).
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Inhibition of adenylosuccinate synthetase The isolation of hydantocidin (17) from the fermentation broth of Streptomyces hygroscopicus SANK63584 provided the first example of a naturally occurring
Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity Fig. 4 Herbicidally active naturally occurring inhibitors of photosystem I, ribonucleotide reductase, amino acyl tRNA synthetase and adenylosuccinate synthetase
14 pyridazocidin
15 mimosine
16 ascamycin
H
17 hydantocidin
spironucleoside. It exhibits powerful non-selective postemergence herbicidal activity against a broad range of mono- and dicotyledonous annual, biennial and perennial weeds without showing toxicity to microorganisms and animals. After it has been converted into its active principle 5′-phosphohydantocidin by in vivo phosphorylation within the plant, it acts as an inhibitor of Adenylosuccinate synthetase, an ubiquitous enzyme playing an important role in purine biosynthesis. The hydantoin moiety of hydantocidin (17) can be seen as cyclized derivative of an anomeric ribose amino acid (Lamberth 2005; Pachlatko 1998). The simple glycine derivative hadacidin (18), isolated from Penicillium purpurrescens, is another inhibitor of Adenylosuccinate synthetase. It demonstrates herbicidal activity against Panicum crus-galli (Japanese millet) and Digitaria sanguinalis (large crabgrass) (Lamberth 2010; Kida and Shibai 1985) (Fig. 4).
18 hadacidin
Miscellaneous modes of action The dipeptide l-alanyl-alanine (19) is found in hydrolyzed corn gluten meal, which is a by-product of corn wetmilling. It shows activity against Lolium perenne (perennial ryegrass) (Lamberth 2010; Unruh et al. 1997). The nitrosamine derivative homoalanosine (20), isolated from the culture filtrate of Streptomyces galilaeus, is highly effective against Xanthium strumarium (common cocklebur) and Polygonum persicaria (ladysthumb) (Lamberth 2010; Fushimi et al. 1989). The bis-amino acid N-glucoside ascaulitoxin (21) was isolated from the culture filtrate of Ascochyta caulina. It causes leaf and stem necrosis of Chenopodium album (common lambsquarters) (Lamberth 2010; Bassarello et al. 2001). The peptidyl nucleoside gougerotin (22), which contains a glycinylserine dipeptide unit, has been isolated from Streptomyces gougerotii. It has
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19 L-alanyl-alanine 20 homoalanosine
21 ascaulitoxin
22 gougerotin
Fig. 5 Herbicidally active naturally occurring amino acid derivatives with miscellaneous modes of action
plant-growth inhibitory effect on seedling of Oryza sativa (rice) (Murao and Hayashi 1983) (Fig. 5).
Fungicidally active natural occurring amino acid derivatives
been isolated from Streptomyces kasugaensis. This interesting iminoacetic acid derivative is produced via a fermentation process and commercially used as a potent systemic agent against Magnaporthe grisea (rice blast) (Lamberth 2010; Pachlatko 1998; Yamaguchi 1998) (Fig. 6). Inhibition of chitin synthetase
Inhibition of protein biosynthesis The β-amino acid derivative blasticidin S (23) has been isolated from the soil actinomycete Streptomyces griseochromogenes and was once used commercially on a large scale as a fungicide against Magnaporthe grisea (rice blast). It blocks protein biosynthesis in eukaryotic and prokaryotic cells by interference with peptidyl transferase reactions (Lamberth 2005; Pachlatko 1998; Yamaguchi 1998). The serine derivative mildiomycin (24) from Streptoverticillium rimofaciens combines strong activity against powdery mildew diseases of several different crops, e.g. Blumeria graminis (wheat powdery mildew) and Uncinula necator (grape powdery mildew), with a remarkable low mammalian and fish toxicity (Lamberth 2005, 2010; Yamaguchi 1998). The O-methylated tyrosine derivative puromycin (25), another peptidyl nucleoside inhibiting fungal protein biosynthesis, has been isolated from Streptomyces alboniger and is also effective against various growth stages of Blumeria graminis (barley powdery mildew) (Lamberth 2005, 2010). Another protein biosynthesis inhibitor with an excellent safety profile is kasugamycin (26), which has
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The polyoxin are an important class of peptidyl nucleosides, which were isolated from Streptomyces cacaoi var. asoensis. They interfere with fungal cell wall synthesis by blocking chitin synthetase, the enzyme which facilitates the polymerization of N-acetylglucosamine (GlcNAc) to chitin via the activated precursor UDP-N-acetylglucosamine (UDP-GlcNAc) which is structurally related to the polyoxins. The linear macromolecule chitin is an essential structural component for growth in most fungi, being responsible for shape and rigidity of the cell walls. Both polyoxin B (27) and polyoxin D (28) are commercially produced via fermentation. Polyoxin B (27) found ample application against a number of different fungal pathogens in ornamentals, vegetables and fruits, e.g. Alternaria kikuchiana (pear black spot), while polyoxin D (28) is marketed as Zn salt mainly for the control of Rhizoctonia solani (rice sheath blight). Polyoxin L (30) is also highly active against Alternaria mali (apple cork spot). With neopolyoxin A (31, also called nikkomycin X) and neopolyoxin B (32), two members of the polyoxin family have been isolated with fivemembered imidazolinone nucelobases. Neopolyoxin A (31)
Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity
24 mildiomycin
23 blasticidin S
25 puromycin
26 kasugamycin
Fig. 6 Fungicidally active naturally occurring protein biosynthesis inhibitors
shows excellent activity against Magnaporthe grisea (rice blast), Botroytinia fuckeliana (gray mold) and Cochliobolus miyabeanus (brown spot) (Lamberth 2005, 2010; Isono and Suzuki 1979) (Fig. 7). Inhibition of cytochrome bc1 (mitochondrial complex III) The fungicidal natural products crocacin D (33), antimycin A1 (34) and UK-2A (35) are inhibitors of cytochrome bc1 (mitochondrial complex II in the fungal respiration cycle). Crocacin D (33) is produced by the myxobacterium Chondromyces crocatus and is highly active against Zymoseptoria tritici (wheat leaf blotch), Puccinia recondita (wheat brown rust), Plasmopara viticola (grape downy mildew) and Phytophthora infestans (potato and tomato late blight) (Lamberth 2010; Crowley et al. 2007, 2008). Both antimycin A1 (34) and UK-2A (35) bind specifically to the quinone reduction site at the inner (negative) side of the membrane (Qi site). The cyclic threonine derivative antimycin A1 (34) controls potently Magnaporthe grisea (rice blast), whereas the strength of the cyclized serine derivative UK-2A (35) seems to be powerful activity against Zymoseptoria tritici (wheat leaf blotch) (Lamberth 2010; Owen et al. 2007) (Fig. 8).
27 polyoxin B: R = CH2OH 28 polyoxin D (polyoxorim): R = CO2H 29 polyoxin J: R = CH3 30 polyoxin L: R = H
31 neopolyoxin A (nikkomycin X): R = CHO 32 neopolyoxin B: R = CO2H Fig. 7 Fungicidally active naturally occurring chitin synthetase inhibitors
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33 crocacin D
34 antimycin A 1
36 acivicin
35 UK-2A
37 albizzin
Fig. 8 Fungicidally active naturally occurring inhibitors of cytochrome bc1 and glutamine amidotransferases
Inhibition of glutamine amidotransferases Acivicin (36) and albizzin (37) both block glutamine amidotransferases. The isoxazoline amino acid derivative acivicin (36) has been isolated from the fermentation broths of Streptomyces sviceus and is active against Phytophthora infestans (potato and tomato late blight), Uncinula necator (grape powdery mildew) and Venturia inaequalis (apple scab). The urea derivative albizzin (37) is found in seeds of Albizzia julibrissin and controls Phytophthora infestans (potato and tomato late blight) and Zymoseptoria tritici (wheat leaf blotch) (Lamberth 2010; Brunner et al. 2007) (Fig. 8). Miscellaneous modes of action The dipeptide nitropeptin (38) is produced by Streptomyces xanthochromogenus and displays strong activity against Magnaporthe grisea (rice blast) (Lamberth 2010; Ohba et al. 1987). Rhizocticin A (39) has been isolated from Bacillus subtilis ATCC 6633 and controlled in field trials efficiently Botryotinia fuckeliana (gray mold) on grape (Lamberth 2010; Pachlatko 1998). The alanine derivative
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prumycin (40), isolated from the culture broth of a Streptomyces kagawaensis, posseses strong activity against Sclerotinia sclerotiorum (stem rot) and Botryotinia fuckeliana (gray mold) (Lamberth 2010; Omura et al. 1973). Sinefungin (41) was isolated from Streptomyces griseolus NRRL3739 and is active against foliar diseases like Erysiphe polygoni (pea powdery mildew) and Uromyces phaseoli (bean rust). This unusual adenosine derivative is a competitive inhibitor of different methyltransferases, blocking, for instance, transmethylation reactions of RNA and proteins (Lamberth 2005, 2010) (Fig. 9).
Insecticidally active natural occurring amino acid derivatives Inhibition of chitin synthetase The fact that chitin, which has been discussed already as a structural component of fungal cell walls, forms also the exoskeleton of invertebrates, but does not exist in green plants or vertebrates, makes chitin synthetase, the enzyme responsible for the chitin bioproduction, an ideal target
Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity Fig. 9 Fungicidally active naturally occurring amino acid derivatives with miscellaneous modes of action
_ 38 nitropeptin
39 rhizocticin A
41 sinefungin
40 prumycin
for crop protection. As a result, inhibitors of this enzyme exhibit marked activity against phytopathogenic fungi and insects, but they are not toxic to bacteria, plants or animals. Structurally related to the already-mentioned polyoxins, the nikkomycins are another family of chitin synthetase inhibitors, which have been isolated from Streptomyces tendae. Although nikkomycin Z (42) bears a six-membered uracilbased nucelobase which is also typical for the polyoxins, nikkomycin X (31, also called neopolyoxin A) posseses a formyl-substituted imidazolinone nucleobase, whose biosynthetic source is histidine. Nikkomycin X (31) and Z (42) display, besides fungicidal activity, potent insecticidal and acaricidal efficacy; a mixture of both was once considered for commercial use against Tetranychus urticae (two-spotted spider mite) (Lamberth 2005, 2010; Pachlatko 1998) (Fig. 10). Miscellaneous modes of action The two peptidyl nucelosides bagougeramine A (43) and aspiculamycin (44), which both bear cytosine as nucelobase and a glucopyranosyl sugar moiety, display excellent acaricidal activity against Tetranychus urticae (two-spotted spider mite). Bagougeramine A (43) is produced by Bacillus circulans, whereas aspiculamycin (44) was isolated from the fermentation broth of Streptomyces toyocaensis var. aspiculamyceticus (Lamberth 2005, 2010). The leucine derivative rodaplutin (45) was isolated from Nocardioides albus strains and is active against a broad range of insects
31 nikkomycin X (neopolyoxin A): R =
42 nikkomycin Z:
R=
Fig. 10 Insecticidally active naturally occurring chitin synthetase inhibitors
and mites, such as Phaedon cochlearia (mustard beetle), Plutella maculipennis (diamondback moth), Myzus persicae (peach-potato aphid), Dysdercus intermedius (cotton stainer) and Tetranychus urticae (two-spotted spider mite) (Lamberth 2005, 2010; Dellweg et al. 1988). The phenylalanine derivative ochratoxin A (46), isolated from Aspergillus carbonarius NRRL 369, is highly active against Carpophilus hemipterus (dried fruit beetle) and Helicoverpa
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43 bagougeramine A
44 aspiculamycin
45 rodaplutin
46 ochratoxin A
48 diabroticin A
47 mellamide
Fig. 11 Insecticidally active naturally occurring amino acid derivatives with miscellaneous modes of action
zea (corn earworm) (Lamberth 2010, Wicklow et al. 1996). The valine derivative mellamide (47) from Aspergillus melleus shows good insecticidal efficacy against larvae of Lucilia sericata (sheep blowfly) and Aedes aegypti (yellow fever mosquito) (Lamberth 2010; Ondeyka et al. 2003). The alanine derivative diabroticin A (48) with a pyrazine core is produced by Bacillus subtilis and Bacillus cereus. It is highly active against Diabrotica undecimpunctata (Pachlatko 1998; Stonard et al. 1994) (Fig. 11). Vignatic acid A (49), a cyclotripeptide formed from each one equivalent leucine, phenylalanine and tyrosine, is found in the wild mung bean Vigna radiata var. sublobata and protects it as natural defense agent from Callosobruchus chinensis (azuki bean weevil) (Lamberth 2010; Sugawara et al. 1996). Aspochracin (50), another cyclotripeptide, isolated from the culture filtrate of Aspergillus
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ochraceus, displays strong activity against Hyphantria cunea (fall webworm) (Lamberth 2010; Myokei et al. 1969). The proline derivative domoic acid (51), a member of the kainoid amino acid family which is produced by the red algae Chondria armata shows strong insecticidal activity when injected subcutaneously into the abdomen of Periplaneta americana (American cockroach) (Lamberth 2010; Maeda et al. 1987). The cyclodepsipeptide destruxin A (52) from the culture filtrate of Metarhizium anisopliae controls Heliothis virescens (tobacco budworm) and Spodoptera litura (common cutworm) (Lamberth 2010; Sree et al. 2008). Finally, the tyrosine derivative philanthtoxin 433 (53) is a neurotoxic constituent of the paralytic venom of Philanthus triangulum (digger wasp) and inhibits the glutamate receptor of the muscles of its target insects (Lamberth 2010; Eldefrawi et al. 1993) (Fig. 12).
Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity
50 aspochracin 49 vignatic acid A
52 destruxin A
51 domoic acid
53 philanthotoxin 433
Fig. 12 Insecticidally active naturally occurring amino acid derivatives with miscellaneous modes of action Compliance with ethical standards Conflict of interest The author declares that he has no competing financial interests. Ethical standard This article does not contain any studies with human participants or animals (except insects) performed by the author.
References Bassarello C, Bifulco G, Evidente A, Riccio R, Gomez-Paloma L (2001) Stereochemical studies on ascaulitoxin: a J-based NMR configurational analysis of a nitrogen substituted system. Tetrahedron Lett 42:8611–8613 Beaudegnies R, Edmunds AJF, Fraser TEM, Hall RG, Hawkes TR, Mitchell G, Schaetzer J, Wendeborn S, Wibley J (2009) Herbicidal 4-hydroxyphenylpyruvate dioxygenase inhibitors—a review of the triketone chemistry story from a Syngenta perspective. Bioorg Med Chem 17:4134–4152 Beautement K, Chrystal EJT, Howard J, Ridley SM (2000) N-(αaminoacyl)-5′-O-sulfamoyladenosines: natural product based
inhibitors of amino acyl tRNA synthetases. In: Wrigley SK, Hayes MA, Thomas R, Chrystal EJT, Nicholson N (eds) Biodiversity—new leads for the pharmaceutical and agrochemical industry. Royal Society of Chemistry, London, pp 288–294 Bender CL, Alarcon-Chaidez F, Gross DC (1999) Pseudomonas syringae pytotoxins: mode of action, regulation and biosynthesis by peptide and polyketide synthetases. Micobiol Mol Biol Rev 63:266–292 Block A, Schmelz E, Jones JB, Klee HJ (2005) Coronatine and salicylic acid: the battle between Arabidopsis and Pseudomonas for phytohormone control. Mol Plant Pathol 6:79–83 Brunner H-G, Chemla P, Dobler MR, O’Sullivan AC, Pachlatko P, Pillonel C, Stierli D (2007) Fungicidal properties of acivicin and its derivatives. In: Lyga JW, Theodoridis G (eds) Synthesis and chemistry of agrochemicals VII, ACS symposium series 948. American Chemical Society, Washington, pp 121–135 Cantrell CL, Dayan FE, Duke SO (2012) Natural products as sources for new pesticides. J Nat Prod 75:1231–1242 Copping L, Duke SO (2007) Natural products that have been used commercially as crop protection agents, a review. Pest Manag Sci 63:524–554 Crombie L (1999) Natural product chemistry and its part in the defense against insects and fungi in agriculture. Pestic Sci 55:761–774
13
C. Lamberth Crowley PJ, Godfrey CRA, Viner R (2007) The crocacins A and D: novel natural products as leads for agrochemicals. In: Lyga JW, Theodoridis G (eds) Synthesis and chemistry of agrochemicals VII, ACS Symposium Series 948. American Chemical Society, Washington, pp 93–103 Crowley PJ, Berry EA, Cromartie T, Daldal F, Godfrey CRA, Lee D-W, Phillips JE, Taylor A, Viner R (2008) The role of molecular modeling in the design of analogues of the fungicidal products crocacins A and D. Bioorg Med Chem 16:10345–10355 Dayan FE, Duke SO (2014) Natural compounds as next generation herbicides. Plant Physiol 166:1090–1105 Dayan FE, Cantrell CL, Duke SO (2009) Natural products in crop protection. Bioorg Med Chem 17:4022–4034 Dellweg H, Kurz J, Pflüger W, Schedel M, Vobis G, Wünsche C (1988) Rodaplutin, a new peptidylnucleoside from Nocardioides albus. J Antibiot 41:1145–1147 Duke SO, Dayan FE (2011) Modes of action of microbially-produced phytotoxins. Toxins 3:1038–1064 Eldefrawi ME, Anis NA, Eldefrawi AT (1993) Glutamate receptor inhibitors as potential insecticides. Arch Insect Biochem Physiol 22:25–39 Everett NP (1994) Design of antifungal peptides for agricultural applications. “Natural and engineered pest management agents” ACS symposium series, vol 551. American Chemical Society, Washington, pp 278–291 Faruck MO, Yusof F, Chowdhury S (2016) An overview of antifungal peptides derived from insect. Peptides 76 [Epub ahead of print] Fushimi S, Nishikawa S, Mito N, Ikemoto M, Sasaki M, Seto H (1989) Studies on a new herbicidal antibiotic homoalanosine. J Antibiot 42:1370–1378 Gerwick BC, Fields SS, Graupner PR, Gray JA, Chapin EL, Cleveland JA, Heim DR (1997) Pyridazocidin, a new microbial phytotoxin with activity in the Mehler reaction. Weed Sci 45:654–657 Hoagland RE (2001) Bioherbicides: phytotoxic natural products. In: Baker DR, Umetsu NK (eds) Agrochemical discovery, ACS Symposium Series, vol 774. American Chemical Society, Washington, pp 72–90 Hou C-X, William M (2006) Actinonin-induced inhibition of plant peptide formylase: a paradigm for the design of novel broadspectrum herbicides. In: Rimando AM, Duke SO (eds) Natural products for pest management, ACS Symposium Series, vol 927. American Chemical Society, Washington, pp 243–254 Irvine NM, Yerkes CN, Graupner PR, Roberts RE, Hahn DR, Pearce C, Gerwick BC (2008) Synthesis and characterization of synthetic analogs of cinnacidin, a novel phytotoxin from Nectria sp. Pest Manag Sci 64:891–899 Isono K, Suzuki S (1979) The polyoxins: pyrimidine nucleoside peptide antibiotics inhibiting fungal cell wall biosynthesis. Heterocycles 13:333–351 Kida T, Shibai H (1985) Inhibition by hadacidin, duazomycin A and other amino acid derivatives of de novo starch synthesis. Agric Biol Chem 49:3231–3237 Lamberth C (2005) Nucleoside chemistry in crop protection. Heterocycles 65:667–695 Lamberth C (2010) Amino acid chemistry in crop protection. Tetrahedron 66:7239–7256 Lax AR, Shepherd HS, Edwards JV (1988) Tentoxin, a chlorosisinducing toxin from Alternaria as a potential herbicide. Weed Technol 2:540–544 Lee DW, Kim BS (2015) Antimicrobial cyclic peptides for plant disease control. Plant Pathol J 31:1–11 Lydon J, Duke SO (1999) Inhibitors of glutamine biosynthesis. In: Singh BK (ed) Plant amino acids: biochemistry and biotechnology. Marcel Dekker, New York, pp 445–464
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Maeda M, Komada T, Saito M, Tanaka T, Yoshizumi H, Nomoto K, Fujita T (1987) Neuromuscular action of insecticidal domoic acid on the American cockroach. Pestic Biochem Physiol 28:85–92 Murao S, Hayashi H (1983) Gougerotin as a plant growth inhibitor from Streptomyces sp. No. 179. Agric Biol Chem 47:1135–1136 Myokei R, Sakurai A, Chang C-F, Kodaira Y, Takahashi N, Tamura S (1969) Aspochracin, a new insecticidal metabolite of Aspergillus ochraceus. Agric Biol Chem 33:1491–1500 Ohba K, Nakayama H, Furihata K, Shimazu A, Endo T, Seto H, Otake N (1987) Nitropeptin, a new dipeptide antibiotic possessing a nitro group. J Antibiot 40:709–713 Omura S, Katagiri M, Awaya J, Atsumi K, Oiwa R, Hata T, Higashikawa S, Yasui K, Terada H, Kuyama S (1973) Production and isolation of a new antifungal antibiotic, prumycin and taxonomic studies of Streptomyces sp., strain No. F-1028. Agric Biol Chem 37:2805–2812 Ondeyka JG, Dombrowski AW, Polishook JP, Felcetto T, Shoop WL, Guan Z, Singh SB (2003) Isolation and insecticidal activity of mellamide from Aspergillus melleus. J Industr Microbiol Biotechnol 30:220–224 Owen WJ, Adelfinskaya Y, Benko Z, Schobert CT (2007) Factors involved in the field translation of a class of mitochondrial Qi inhibitor fungicides. In: Lyga JW, Theodoridis G (eds) Synthesis and chemistry of agrochemicals VII, ACS Symposium Series 948. American Chemical Society, Washington, pp 137–152 Owens LD (1973) Herbicidal potential of rhizobitoxine. Weed Sci 21:63–66 Pachlatko JP (1998) Natural products in crop protection. Chimia 52:29–47 Sauter H, Steglich W, Anke T (1999) Strobilurins: evolution of a new class of active substances. Angew Chem Int Ed 38:1328–1349 Sree KS, Padmaja V, Murthy YLN (2008) Insecticidal activity of destruxin, a mycotoxin from Metarhizium anisopliae against Spodoptera litura larval stages. Pest Manag Sci 64:119–125 Stonard RJ, Ayer S, Kotyk JJ, Letendre LJ, McGary CI, Nickson TE, Le-Van N, Lavrik P (1994) Microbial secondary metabolites as a source of agrochemicals. In: Hedin PA, Menn JJ, Hollingworth RM (eds) Natural and engineered pest management agents, ACS Symposium Series, vol 551. American Chemical Society, Washington, pp 25–36 Sugawara F, Ishimoto M, Le-Van N, Koshino H, Uzawa J, Yoshida S, Kitamura K (1996) Insecticidal peptide from mungbean: a resistant factor against infestation with azuki bean weevil. J Agric Food Chem 44:3360–3364 Unruh JB, Christians NE, Horner HT (1997) Herbicidal effects of the dipeptide alaninyl-alanine on perennial rhygrass (Lolium perenne) seedlings. Crop Sci 37:208–212 van der Weerden NL, Bleackley MR, Anderson MA (2013) Properties and mechanisms of action of naturally occurring antifungal peptides. Cell Mol Life Sci 70:3545–3570 Wicklow DT, Dowd PF, Alfatafta AA, Gloer JB (1996) Ochratoxin A: an antiinsectan metabolite from the sclerotia of Aspergillus carbonarius NRRL 369. Can J Microbiol 42:1100–1103 Williams RD, Hoagland RE (2007) Phytotoxicity of mimosine and albizziine on seed germination and seedling growth of crops and weeds. Allelo J 19:423–430 Xuan TD, Elzaawely AA, Deba F, Fukuta M, Tawata S (2006) Mimosine in leucaena as a potent bio-herbicide. Agron Sustain Dev 26:89–97 Yamaguchi I (1998) Natural product derived fungicides as exemplified by the antibiotics. In: Hutson D, Miyamoto J (eds) Fungicidal activity. Wiley, Chichester, pp 57–85
REVIEW ARTICLE
Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity Clemens Lamberth1
Received: 22 December 2015 / Accepted: 8 January 2016 © Springer-Verlag Wien 2016
Abstract Several naturally occurring amino acid derivatives display significant activities against weeds, fungi and insects: some of them have been even commercialized and are applied as crop protection agents. The 53 most important amino acid natural products with such efficacy are presented in this review together with their natural source, mode of action and biological activity. The diversity of the manifold bacterial, fungal and plantal sources of these compounds is impressive as well as their completely different structural scaffolds, ranging from cyclopeptides via unique non-proteinogenic amino acids to peptidyl nucleosides, the broad range of target enzymes from several different biochemical pathways, which they inhibit and also the plethora of different weeds, fungi and insects they are able to control. Keywords Natural products · Amino acids · Agrochemicals · Crop protection · Herbicides · Fungicides · Insecticides
Introduction Natural products have always played a detrimental role in crop protection chemistry, both as lead compounds and as active ingredients (Cantrell et al. 2012; Dayan et al. 2009; Copping and Duke 2007; Crombie 1999; Pachlatko 1998). Examples of important classes of market products, which have been developed from naturally occurring lead compounds, are Based on a lecture presented at the 14th international congress on amino acids, peptides and proteins, Vienna, 3–7th August 2015. * Clemens Lamberth [email protected] 1
Syngenta Crop Protection AG, Stein, Switzerland
the 4-hydroxyphenylpyruvate dioxygenase inhibiting diketone herbicides inspired by leptospermone (isolated from the red bottlebrush plant Callistemon citrinus) (Beaudegnies et al. 2009), the complex III respiration inhibiting strobilurin fungicides originating from strobilurin A (isolated from the pinecone cap mushroom Strobilurus tenacellus) (Sauter et al. 1999) and the sodium channel blocking pyrethorid insecticides stemming from pyrethin I (isolated from the chrysanthemum flower Tanacetum cinerariaefolium). Natural products, which are successfully sold as crop protection products are the non-selective herbicide bialaphos (isolated from Streptomyces hygroscopicus and Streptomyces viridochromogenes), the fungicide blasticidin S (isolated from Streptomyces griseochromogenes) and the insecticide spinosad (isolated from Saccharopolyspora spinosa) (Copping and Duke 2007). Also naturally occurring amino acid derivatives and their oligo- and polymeric equivalents are more and more in the focus as sources for new agrochemicals. The different features of antifungal peptides and their scope and limitations for agricultural applications have been summarized recently in several reports (Faruck et al. 2016; Lee and Kim 2015; van der Weerden et al. 2013; Everett 1994). Therefore, this review will rather focus on small molecules, specifically naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity, their sources, mode of action and biological activity.
Herbicidally active naturally occurring amino acid derivatives Inhibition of glutamine synthetase The tripeptides bialaphos (1) and phosalacine (2), the tetrapeptide trialaphos (3) as well as their N-terminal amino
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acid l-phosphinotricin (4) are non-selective herbicides. Bialaphos (1), which has been isolated from the fermentation broths of Streptomyces hygroscopicus and Streptomyces viridochromogenes, and trialaphos (3) and phosalacine (2), which both have been isolated from the culture filtrate of Kitasatosporia phosalacinea, are pro-herbicides and only active after their metabolic hydrolysis in the plant to their active principle, the N-terminal amino acid l-phosphinothricin (4) (Dayan and Duke 2014; Duke and Dayan 2011; Dayan et al. 2009; Hoagland 2001; Lamberth 2010; Lydon and Duke 1999). Although only the (S)-enantiomer phosphinothricin is herbicidally active, the ammonium salt of its racemate has been launched in the market and is successfully sold under the common name glufosinate (Basta®, Liberty®) (5). Also bialaphos (1) has been commercialized in Japan and is produced by fermentation. Bialaphos (1) and glufosinate (5) are broad-spectrum post-emergence herbicides which can be used for total vegetation control. As they are non-selective herbicides, especially glufosinate is often marketed along with genetically engineered glufosinate-resistant crops (e.g. corn, cotton and soybean). l-phosphinothricin (4) is a phosphinic acid mimic of (S)glutamic acid, the natural substrate of glutamine synthetase. This target enzyme enables a very rare transformation, the incorporation of inorganic nitrogen into organic forms (e.g. amino acids and nucleobases) by production of glutamine for ammonia detoxification. The inhibition of glutamine synthetase results in the accumulation of ammonia in the plant cells up to toxic levels as well as in inhibition of photorespiration due to reduced levels of amino acid donors (Dayan and Duke 2014; Duke and Dayan 2011; Dayan et al. 2009; Hoagland 2001; Lamberth 2010; Lydon and Duke 1999). Tabtoxin (6), a threonine-based dipeptide from Pseudomonas syringae is another proherbicide. Itself not intrinsically active, it is hydrolyzed in planta to form the potent glutamine synthetase inhibitor tabtoxin-βlactam (Duke and Dayan 2011; Dayan et al. 2009). Also the β-amino acid oxetin (7) from Streptomyces sp. OM-2317 is targeting the same enzyme (Fig. 1) (Duke and Dayan 2011; Dayan et al. 2009).
Inhibition of chloroplastic ATP synthase Also the cyclic tetrapeptide tentoxin (9) is inducing chlorotic plant tissues. It is produced by the plant pathogenic fungus Alternaria alternata and inhibits chloroplast development, herewith directly interacting with CF1 ATPase, the chloroplastic ATP synthase. Tentoxin induces chlorosis on a variety of corn and soybean weeds, such as Ipomoea hederacea (morningglory), Cassia obtusifolia (sicklepod) and Sorghum halepense (Johnsongrass) without affecting the corresponding crops (Fig. 2) (Dayan and Duke 2014; Duke and Dayan 2011; Lamberth 2010; Lax et al. 1988). Inhibition of peptide deformylase The valine derivative actinonin (10) is produced by Actinomyces sp. MG848-hF6. This dipeptide bearing a hydroxamic acid function causes stunting, bleaching and necrosis in a wide range of agriculturally relevant weed species by inhibition of plastid peptide formylase, a critical enzyme required for N-terminal protein processing of plastid-encoded proteins (Fig. 2) (Dayan and Duke 2014; Duke and Dayan 2011; Hou and William 2006). Jasmonic acid analogs Jasmonic acid is a plant hormone derived from linolenic acid. It plays an important role in regulating plant growth and development as well as in responses to both biotic and abiotic stress. Coronatine (11) is a jasmonate mimic produced by Pseudomonas coronafacience. It surpresses natural salicylic acid-dependent plant defense mechanisms, resulting in stunting and chlorosis of developing tissues, which are typical symptoms (Dayan and Duke 2014; Duke and Dayan 2011; Block et al. 2005). The herbicidal activity of the isoleucine derivative cinnacidin (12), a product of the fungus Nectria sp. DA060097, is due to a similar mode of action (Dayan and Duke 2014; Duke and Dayan 2011; Irvine et al. 2008) (Fig. 3). Inhibition of β‑cystathionase
Inhibition of ornithine carbamoyl transferase The non-selective herbicide phaseolotoxin (8) is produced by Pseudomonas syringae pv. phaseolicola. It is another proherbicide and only active after conversion in planta to its N-terminal amino acid octicidine, which is an irreversible inhibitor of Ornithine carbamoyl transferase, a key enzyme in the urea cycle of plants. Phaseolotoxin (8) has been also called the halo-blight toxin because of chlorosis spots on that parts of the leaves where the bacterium has entered (Fig. 2) (Dayan and Duke 2014; Duke and Dayan 2011; Bender et al. 1999).
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Rhizobitoxine (13) has been isolated from Bradyrhizobium japonicum. It inhibits β-cystathionase, an enzyme catalyzing an elimination reaction, wherein l-cystathionine and water are converted to l-homocysteine, ammonia and pyruvare. This reaction is important for several metabolic pathways, e.g. the metabolism of methionine, cysteine, nitrogen and sulfur. Rhizobitoxine (11) is phytotoxic enough to have been considered as a commercial herbicide. It controls Digitaria sanguinalis (large crabgrass) and Brassica japonica (wild mustard) (Dayan and Duke 2014; Duke and Dayan 2011; Owens 1973) (Fig. 3).
Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity Fig. 1 Herbicidally active naturally occurring inhibitors of glutamine synthetase
1 bialaphos
2 phosalacine
3 trialaphos
4 L-phosphinothricin (glufosinate-P)
6 tabtoxin
5 glufosinate (D,L-phosphinothricin)
7 oxetin
Inhibition of photosystem I
Inhibition of ribonucleotide reductase
Photosystem I (PSI) is a key component of the photosynthetic electron transport chain. Pyridazocidin (14), a cationic phytotoxin isolated from Streptomyces sp., blocks PSI by diverting electrons from it, which prevents the conversion of NADP into NADPH and converts the cationic pyridazocidin into a highly reactive free radical, generating reactive oxygen species that cause destructive oxidative processes such as necrosis and chlorosis. Pyridazocidin (14), one of the very rare examples of naturally occurring pyridazine, is highly active against Setaria faberi (giant foxtail), Abutilon theophrasti (velvetleaf) and Ipomoea hederaceae (ivyleaf morningglory) (Duke and Dayan 2011; Hoagland 2001; Gerwick et al. 1997) (Fig. 4).
Mimosine (15), a phytotoxin isolated from the plants Leucaena leucocephala de Wit and Mimosa pudica, inhibits ribonucleotide reductase, an enzyme which catalyzes the formation of deoxyribonucleotides from ribonucleotides. Mimosine (15) displays activity again Bidens pilosa (hairy beggarticks) and Lolium multiflorum (Italian ryegrass) (Williams and Hoagland 2007; Xuan et al. 2006) (Fig. 4). Inhibition of amino acyl tRNA synthetase Ascamycin (16) has been isolated from a Streptomyces sp. fermentation broth. It displays remarkable postemergence activity against different broadleaf weeds. The
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C. Lamberth Fig. 2 Herbicidally active naturally occurring inhibitors of ornithine carbamoyl transferase, chloroplastic ATP synthase and peptide deformylase
8 phaseolotoxin
10 actinonin
9 tentoxin Fig. 3 Herbicidally active naturally occurring analogs of jasmonic acid and inhibitors of β-cystathionase
12 cinnacidin
11 coronatine
13 rhizobitoxine
5-sulfamoylnucleoside ascamycin is a bioisostere of the corresponding nucleotide, the sulfamoyl function mimicking the natural phosphate group. It inhibits protein biosynthesis by blocking amino acyl tRNA synthetase (Lamberth 2005; Beautement et al. 2000) (Fig. 4).
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Inhibition of adenylosuccinate synthetase The isolation of hydantocidin (17) from the fermentation broth of Streptomyces hygroscopicus SANK63584 provided the first example of a naturally occurring
Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity Fig. 4 Herbicidally active naturally occurring inhibitors of photosystem I, ribonucleotide reductase, amino acyl tRNA synthetase and adenylosuccinate synthetase
14 pyridazocidin
15 mimosine
16 ascamycin
H
17 hydantocidin
spironucleoside. It exhibits powerful non-selective postemergence herbicidal activity against a broad range of mono- and dicotyledonous annual, biennial and perennial weeds without showing toxicity to microorganisms and animals. After it has been converted into its active principle 5′-phosphohydantocidin by in vivo phosphorylation within the plant, it acts as an inhibitor of Adenylosuccinate synthetase, an ubiquitous enzyme playing an important role in purine biosynthesis. The hydantoin moiety of hydantocidin (17) can be seen as cyclized derivative of an anomeric ribose amino acid (Lamberth 2005; Pachlatko 1998). The simple glycine derivative hadacidin (18), isolated from Penicillium purpurrescens, is another inhibitor of Adenylosuccinate synthetase. It demonstrates herbicidal activity against Panicum crus-galli (Japanese millet) and Digitaria sanguinalis (large crabgrass) (Lamberth 2010; Kida and Shibai 1985) (Fig. 4).
18 hadacidin
Miscellaneous modes of action The dipeptide l-alanyl-alanine (19) is found in hydrolyzed corn gluten meal, which is a by-product of corn wetmilling. It shows activity against Lolium perenne (perennial ryegrass) (Lamberth 2010; Unruh et al. 1997). The nitrosamine derivative homoalanosine (20), isolated from the culture filtrate of Streptomyces galilaeus, is highly effective against Xanthium strumarium (common cocklebur) and Polygonum persicaria (ladysthumb) (Lamberth 2010; Fushimi et al. 1989). The bis-amino acid N-glucoside ascaulitoxin (21) was isolated from the culture filtrate of Ascochyta caulina. It causes leaf and stem necrosis of Chenopodium album (common lambsquarters) (Lamberth 2010; Bassarello et al. 2001). The peptidyl nucleoside gougerotin (22), which contains a glycinylserine dipeptide unit, has been isolated from Streptomyces gougerotii. It has
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19 L-alanyl-alanine 20 homoalanosine
21 ascaulitoxin
22 gougerotin
Fig. 5 Herbicidally active naturally occurring amino acid derivatives with miscellaneous modes of action
plant-growth inhibitory effect on seedling of Oryza sativa (rice) (Murao and Hayashi 1983) (Fig. 5).
Fungicidally active natural occurring amino acid derivatives
been isolated from Streptomyces kasugaensis. This interesting iminoacetic acid derivative is produced via a fermentation process and commercially used as a potent systemic agent against Magnaporthe grisea (rice blast) (Lamberth 2010; Pachlatko 1998; Yamaguchi 1998) (Fig. 6). Inhibition of chitin synthetase
Inhibition of protein biosynthesis The β-amino acid derivative blasticidin S (23) has been isolated from the soil actinomycete Streptomyces griseochromogenes and was once used commercially on a large scale as a fungicide against Magnaporthe grisea (rice blast). It blocks protein biosynthesis in eukaryotic and prokaryotic cells by interference with peptidyl transferase reactions (Lamberth 2005; Pachlatko 1998; Yamaguchi 1998). The serine derivative mildiomycin (24) from Streptoverticillium rimofaciens combines strong activity against powdery mildew diseases of several different crops, e.g. Blumeria graminis (wheat powdery mildew) and Uncinula necator (grape powdery mildew), with a remarkable low mammalian and fish toxicity (Lamberth 2005, 2010; Yamaguchi 1998). The O-methylated tyrosine derivative puromycin (25), another peptidyl nucleoside inhibiting fungal protein biosynthesis, has been isolated from Streptomyces alboniger and is also effective against various growth stages of Blumeria graminis (barley powdery mildew) (Lamberth 2005, 2010). Another protein biosynthesis inhibitor with an excellent safety profile is kasugamycin (26), which has
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The polyoxin are an important class of peptidyl nucleosides, which were isolated from Streptomyces cacaoi var. asoensis. They interfere with fungal cell wall synthesis by blocking chitin synthetase, the enzyme which facilitates the polymerization of N-acetylglucosamine (GlcNAc) to chitin via the activated precursor UDP-N-acetylglucosamine (UDP-GlcNAc) which is structurally related to the polyoxins. The linear macromolecule chitin is an essential structural component for growth in most fungi, being responsible for shape and rigidity of the cell walls. Both polyoxin B (27) and polyoxin D (28) are commercially produced via fermentation. Polyoxin B (27) found ample application against a number of different fungal pathogens in ornamentals, vegetables and fruits, e.g. Alternaria kikuchiana (pear black spot), while polyoxin D (28) is marketed as Zn salt mainly for the control of Rhizoctonia solani (rice sheath blight). Polyoxin L (30) is also highly active against Alternaria mali (apple cork spot). With neopolyoxin A (31, also called nikkomycin X) and neopolyoxin B (32), two members of the polyoxin family have been isolated with fivemembered imidazolinone nucelobases. Neopolyoxin A (31)
Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity
24 mildiomycin
23 blasticidin S
25 puromycin
26 kasugamycin
Fig. 6 Fungicidally active naturally occurring protein biosynthesis inhibitors
shows excellent activity against Magnaporthe grisea (rice blast), Botroytinia fuckeliana (gray mold) and Cochliobolus miyabeanus (brown spot) (Lamberth 2005, 2010; Isono and Suzuki 1979) (Fig. 7). Inhibition of cytochrome bc1 (mitochondrial complex III) The fungicidal natural products crocacin D (33), antimycin A1 (34) and UK-2A (35) are inhibitors of cytochrome bc1 (mitochondrial complex II in the fungal respiration cycle). Crocacin D (33) is produced by the myxobacterium Chondromyces crocatus and is highly active against Zymoseptoria tritici (wheat leaf blotch), Puccinia recondita (wheat brown rust), Plasmopara viticola (grape downy mildew) and Phytophthora infestans (potato and tomato late blight) (Lamberth 2010; Crowley et al. 2007, 2008). Both antimycin A1 (34) and UK-2A (35) bind specifically to the quinone reduction site at the inner (negative) side of the membrane (Qi site). The cyclic threonine derivative antimycin A1 (34) controls potently Magnaporthe grisea (rice blast), whereas the strength of the cyclized serine derivative UK-2A (35) seems to be powerful activity against Zymoseptoria tritici (wheat leaf blotch) (Lamberth 2010; Owen et al. 2007) (Fig. 8).
27 polyoxin B: R = CH2OH 28 polyoxin D (polyoxorim): R = CO2H 29 polyoxin J: R = CH3 30 polyoxin L: R = H
31 neopolyoxin A (nikkomycin X): R = CHO 32 neopolyoxin B: R = CO2H Fig. 7 Fungicidally active naturally occurring chitin synthetase inhibitors
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33 crocacin D
34 antimycin A 1
36 acivicin
35 UK-2A
37 albizzin
Fig. 8 Fungicidally active naturally occurring inhibitors of cytochrome bc1 and glutamine amidotransferases
Inhibition of glutamine amidotransferases Acivicin (36) and albizzin (37) both block glutamine amidotransferases. The isoxazoline amino acid derivative acivicin (36) has been isolated from the fermentation broths of Streptomyces sviceus and is active against Phytophthora infestans (potato and tomato late blight), Uncinula necator (grape powdery mildew) and Venturia inaequalis (apple scab). The urea derivative albizzin (37) is found in seeds of Albizzia julibrissin and controls Phytophthora infestans (potato and tomato late blight) and Zymoseptoria tritici (wheat leaf blotch) (Lamberth 2010; Brunner et al. 2007) (Fig. 8). Miscellaneous modes of action The dipeptide nitropeptin (38) is produced by Streptomyces xanthochromogenus and displays strong activity against Magnaporthe grisea (rice blast) (Lamberth 2010; Ohba et al. 1987). Rhizocticin A (39) has been isolated from Bacillus subtilis ATCC 6633 and controlled in field trials efficiently Botryotinia fuckeliana (gray mold) on grape (Lamberth 2010; Pachlatko 1998). The alanine derivative
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prumycin (40), isolated from the culture broth of a Streptomyces kagawaensis, posseses strong activity against Sclerotinia sclerotiorum (stem rot) and Botryotinia fuckeliana (gray mold) (Lamberth 2010; Omura et al. 1973). Sinefungin (41) was isolated from Streptomyces griseolus NRRL3739 and is active against foliar diseases like Erysiphe polygoni (pea powdery mildew) and Uromyces phaseoli (bean rust). This unusual adenosine derivative is a competitive inhibitor of different methyltransferases, blocking, for instance, transmethylation reactions of RNA and proteins (Lamberth 2005, 2010) (Fig. 9).
Insecticidally active natural occurring amino acid derivatives Inhibition of chitin synthetase The fact that chitin, which has been discussed already as a structural component of fungal cell walls, forms also the exoskeleton of invertebrates, but does not exist in green plants or vertebrates, makes chitin synthetase, the enzyme responsible for the chitin bioproduction, an ideal target
Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity Fig. 9 Fungicidally active naturally occurring amino acid derivatives with miscellaneous modes of action
_ 38 nitropeptin
39 rhizocticin A
41 sinefungin
40 prumycin
for crop protection. As a result, inhibitors of this enzyme exhibit marked activity against phytopathogenic fungi and insects, but they are not toxic to bacteria, plants or animals. Structurally related to the already-mentioned polyoxins, the nikkomycins are another family of chitin synthetase inhibitors, which have been isolated from Streptomyces tendae. Although nikkomycin Z (42) bears a six-membered uracilbased nucelobase which is also typical for the polyoxins, nikkomycin X (31, also called neopolyoxin A) posseses a formyl-substituted imidazolinone nucleobase, whose biosynthetic source is histidine. Nikkomycin X (31) and Z (42) display, besides fungicidal activity, potent insecticidal and acaricidal efficacy; a mixture of both was once considered for commercial use against Tetranychus urticae (two-spotted spider mite) (Lamberth 2005, 2010; Pachlatko 1998) (Fig. 10). Miscellaneous modes of action The two peptidyl nucelosides bagougeramine A (43) and aspiculamycin (44), which both bear cytosine as nucelobase and a glucopyranosyl sugar moiety, display excellent acaricidal activity against Tetranychus urticae (two-spotted spider mite). Bagougeramine A (43) is produced by Bacillus circulans, whereas aspiculamycin (44) was isolated from the fermentation broth of Streptomyces toyocaensis var. aspiculamyceticus (Lamberth 2005, 2010). The leucine derivative rodaplutin (45) was isolated from Nocardioides albus strains and is active against a broad range of insects
31 nikkomycin X (neopolyoxin A): R =
42 nikkomycin Z:
R=
Fig. 10 Insecticidally active naturally occurring chitin synthetase inhibitors
and mites, such as Phaedon cochlearia (mustard beetle), Plutella maculipennis (diamondback moth), Myzus persicae (peach-potato aphid), Dysdercus intermedius (cotton stainer) and Tetranychus urticae (two-spotted spider mite) (Lamberth 2005, 2010; Dellweg et al. 1988). The phenylalanine derivative ochratoxin A (46), isolated from Aspergillus carbonarius NRRL 369, is highly active against Carpophilus hemipterus (dried fruit beetle) and Helicoverpa
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43 bagougeramine A
44 aspiculamycin
45 rodaplutin
46 ochratoxin A
48 diabroticin A
47 mellamide
Fig. 11 Insecticidally active naturally occurring amino acid derivatives with miscellaneous modes of action
zea (corn earworm) (Lamberth 2010, Wicklow et al. 1996). The valine derivative mellamide (47) from Aspergillus melleus shows good insecticidal efficacy against larvae of Lucilia sericata (sheep blowfly) and Aedes aegypti (yellow fever mosquito) (Lamberth 2010; Ondeyka et al. 2003). The alanine derivative diabroticin A (48) with a pyrazine core is produced by Bacillus subtilis and Bacillus cereus. It is highly active against Diabrotica undecimpunctata (Pachlatko 1998; Stonard et al. 1994) (Fig. 11). Vignatic acid A (49), a cyclotripeptide formed from each one equivalent leucine, phenylalanine and tyrosine, is found in the wild mung bean Vigna radiata var. sublobata and protects it as natural defense agent from Callosobruchus chinensis (azuki bean weevil) (Lamberth 2010; Sugawara et al. 1996). Aspochracin (50), another cyclotripeptide, isolated from the culture filtrate of Aspergillus
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ochraceus, displays strong activity against Hyphantria cunea (fall webworm) (Lamberth 2010; Myokei et al. 1969). The proline derivative domoic acid (51), a member of the kainoid amino acid family which is produced by the red algae Chondria armata shows strong insecticidal activity when injected subcutaneously into the abdomen of Periplaneta americana (American cockroach) (Lamberth 2010; Maeda et al. 1987). The cyclodepsipeptide destruxin A (52) from the culture filtrate of Metarhizium anisopliae controls Heliothis virescens (tobacco budworm) and Spodoptera litura (common cutworm) (Lamberth 2010; Sree et al. 2008). Finally, the tyrosine derivative philanthtoxin 433 (53) is a neurotoxic constituent of the paralytic venom of Philanthus triangulum (digger wasp) and inhibits the glutamate receptor of the muscles of its target insects (Lamberth 2010; Eldefrawi et al. 1993) (Fig. 12).
Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity
50 aspochracin 49 vignatic acid A
52 destruxin A
51 domoic acid
53 philanthotoxin 433
Fig. 12 Insecticidally active naturally occurring amino acid derivatives with miscellaneous modes of action Compliance with ethical standards Conflict of interest The author declares that he has no competing financial interests. Ethical standard This article does not contain any studies with human participants or animals (except insects) performed by the author.
References Bassarello C, Bifulco G, Evidente A, Riccio R, Gomez-Paloma L (2001) Stereochemical studies on ascaulitoxin: a J-based NMR configurational analysis of a nitrogen substituted system. Tetrahedron Lett 42:8611–8613 Beaudegnies R, Edmunds AJF, Fraser TEM, Hall RG, Hawkes TR, Mitchell G, Schaetzer J, Wendeborn S, Wibley J (2009) Herbicidal 4-hydroxyphenylpyruvate dioxygenase inhibitors—a review of the triketone chemistry story from a Syngenta perspective. Bioorg Med Chem 17:4134–4152 Beautement K, Chrystal EJT, Howard J, Ridley SM (2000) N-(αaminoacyl)-5′-O-sulfamoyladenosines: natural product based
inhibitors of amino acyl tRNA synthetases. In: Wrigley SK, Hayes MA, Thomas R, Chrystal EJT, Nicholson N (eds) Biodiversity—new leads for the pharmaceutical and agrochemical industry. Royal Society of Chemistry, London, pp 288–294 Bender CL, Alarcon-Chaidez F, Gross DC (1999) Pseudomonas syringae pytotoxins: mode of action, regulation and biosynthesis by peptide and polyketide synthetases. Micobiol Mol Biol Rev 63:266–292 Block A, Schmelz E, Jones JB, Klee HJ (2005) Coronatine and salicylic acid: the battle between Arabidopsis and Pseudomonas for phytohormone control. Mol Plant Pathol 6:79–83 Brunner H-G, Chemla P, Dobler MR, O’Sullivan AC, Pachlatko P, Pillonel C, Stierli D (2007) Fungicidal properties of acivicin and its derivatives. In: Lyga JW, Theodoridis G (eds) Synthesis and chemistry of agrochemicals VII, ACS symposium series 948. American Chemical Society, Washington, pp 121–135 Cantrell CL, Dayan FE, Duke SO (2012) Natural products as sources for new pesticides. J Nat Prod 75:1231–1242 Copping L, Duke SO (2007) Natural products that have been used commercially as crop protection agents, a review. Pest Manag Sci 63:524–554 Crombie L (1999) Natural product chemistry and its part in the defense against insects and fungi in agriculture. Pestic Sci 55:761–774
13
C. Lamberth Crowley PJ, Godfrey CRA, Viner R (2007) The crocacins A and D: novel natural products as leads for agrochemicals. In: Lyga JW, Theodoridis G (eds) Synthesis and chemistry of agrochemicals VII, ACS Symposium Series 948. American Chemical Society, Washington, pp 93–103 Crowley PJ, Berry EA, Cromartie T, Daldal F, Godfrey CRA, Lee D-W, Phillips JE, Taylor A, Viner R (2008) The role of molecular modeling in the design of analogues of the fungicidal products crocacins A and D. Bioorg Med Chem 16:10345–10355 Dayan FE, Duke SO (2014) Natural compounds as next generation herbicides. Plant Physiol 166:1090–1105 Dayan FE, Cantrell CL, Duke SO (2009) Natural products in crop protection. Bioorg Med Chem 17:4022–4034 Dellweg H, Kurz J, Pflüger W, Schedel M, Vobis G, Wünsche C (1988) Rodaplutin, a new peptidylnucleoside from Nocardioides albus. J Antibiot 41:1145–1147 Duke SO, Dayan FE (2011) Modes of action of microbially-produced phytotoxins. Toxins 3:1038–1064 Eldefrawi ME, Anis NA, Eldefrawi AT (1993) Glutamate receptor inhibitors as potential insecticides. Arch Insect Biochem Physiol 22:25–39 Everett NP (1994) Design of antifungal peptides for agricultural applications. “Natural and engineered pest management agents” ACS symposium series, vol 551. American Chemical Society, Washington, pp 278–291 Faruck MO, Yusof F, Chowdhury S (2016) An overview of antifungal peptides derived from insect. Peptides 76 [Epub ahead of print] Fushimi S, Nishikawa S, Mito N, Ikemoto M, Sasaki M, Seto H (1989) Studies on a new herbicidal antibiotic homoalanosine. J Antibiot 42:1370–1378 Gerwick BC, Fields SS, Graupner PR, Gray JA, Chapin EL, Cleveland JA, Heim DR (1997) Pyridazocidin, a new microbial phytotoxin with activity in the Mehler reaction. Weed Sci 45:654–657 Hoagland RE (2001) Bioherbicides: phytotoxic natural products. In: Baker DR, Umetsu NK (eds) Agrochemical discovery, ACS Symposium Series, vol 774. American Chemical Society, Washington, pp 72–90 Hou C-X, William M (2006) Actinonin-induced inhibition of plant peptide formylase: a paradigm for the design of novel broadspectrum herbicides. In: Rimando AM, Duke SO (eds) Natural products for pest management, ACS Symposium Series, vol 927. American Chemical Society, Washington, pp 243–254 Irvine NM, Yerkes CN, Graupner PR, Roberts RE, Hahn DR, Pearce C, Gerwick BC (2008) Synthesis and characterization of synthetic analogs of cinnacidin, a novel phytotoxin from Nectria sp. Pest Manag Sci 64:891–899 Isono K, Suzuki S (1979) The polyoxins: pyrimidine nucleoside peptide antibiotics inhibiting fungal cell wall biosynthesis. Heterocycles 13:333–351 Kida T, Shibai H (1985) Inhibition by hadacidin, duazomycin A and other amino acid derivatives of de novo starch synthesis. Agric Biol Chem 49:3231–3237 Lamberth C (2005) Nucleoside chemistry in crop protection. Heterocycles 65:667–695 Lamberth C (2010) Amino acid chemistry in crop protection. Tetrahedron 66:7239–7256 Lax AR, Shepherd HS, Edwards JV (1988) Tentoxin, a chlorosisinducing toxin from Alternaria as a potential herbicide. Weed Technol 2:540–544 Lee DW, Kim BS (2015) Antimicrobial cyclic peptides for plant disease control. Plant Pathol J 31:1–11 Lydon J, Duke SO (1999) Inhibitors of glutamine biosynthesis. In: Singh BK (ed) Plant amino acids: biochemistry and biotechnology. Marcel Dekker, New York, pp 445–464
13
Maeda M, Komada T, Saito M, Tanaka T, Yoshizumi H, Nomoto K, Fujita T (1987) Neuromuscular action of insecticidal domoic acid on the American cockroach. Pestic Biochem Physiol 28:85–92 Murao S, Hayashi H (1983) Gougerotin as a plant growth inhibitor from Streptomyces sp. No. 179. Agric Biol Chem 47:1135–1136 Myokei R, Sakurai A, Chang C-F, Kodaira Y, Takahashi N, Tamura S (1969) Aspochracin, a new insecticidal metabolite of Aspergillus ochraceus. Agric Biol Chem 33:1491–1500 Ohba K, Nakayama H, Furihata K, Shimazu A, Endo T, Seto H, Otake N (1987) Nitropeptin, a new dipeptide antibiotic possessing a nitro group. J Antibiot 40:709–713 Omura S, Katagiri M, Awaya J, Atsumi K, Oiwa R, Hata T, Higashikawa S, Yasui K, Terada H, Kuyama S (1973) Production and isolation of a new antifungal antibiotic, prumycin and taxonomic studies of Streptomyces sp., strain No. F-1028. Agric Biol Chem 37:2805–2812 Ondeyka JG, Dombrowski AW, Polishook JP, Felcetto T, Shoop WL, Guan Z, Singh SB (2003) Isolation and insecticidal activity of mellamide from Aspergillus melleus. J Industr Microbiol Biotechnol 30:220–224 Owen WJ, Adelfinskaya Y, Benko Z, Schobert CT (2007) Factors involved in the field translation of a class of mitochondrial Qi inhibitor fungicides. In: Lyga JW, Theodoridis G (eds) Synthesis and chemistry of agrochemicals VII, ACS Symposium Series 948. American Chemical Society, Washington, pp 137–152 Owens LD (1973) Herbicidal potential of rhizobitoxine. Weed Sci 21:63–66 Pachlatko JP (1998) Natural products in crop protection. Chimia 52:29–47 Sauter H, Steglich W, Anke T (1999) Strobilurins: evolution of a new class of active substances. Angew Chem Int Ed 38:1328–1349 Sree KS, Padmaja V, Murthy YLN (2008) Insecticidal activity of destruxin, a mycotoxin from Metarhizium anisopliae against Spodoptera litura larval stages. Pest Manag Sci 64:119–125 Stonard RJ, Ayer S, Kotyk JJ, Letendre LJ, McGary CI, Nickson TE, Le-Van N, Lavrik P (1994) Microbial secondary metabolites as a source of agrochemicals. In: Hedin PA, Menn JJ, Hollingworth RM (eds) Natural and engineered pest management agents, ACS Symposium Series, vol 551. American Chemical Society, Washington, pp 25–36 Sugawara F, Ishimoto M, Le-Van N, Koshino H, Uzawa J, Yoshida S, Kitamura K (1996) Insecticidal peptide from mungbean: a resistant factor against infestation with azuki bean weevil. J Agric Food Chem 44:3360–3364 Unruh JB, Christians NE, Horner HT (1997) Herbicidal effects of the dipeptide alaninyl-alanine on perennial rhygrass (Lolium perenne) seedlings. Crop Sci 37:208–212 van der Weerden NL, Bleackley MR, Anderson MA (2013) Properties and mechanisms of action of naturally occurring antifungal peptides. Cell Mol Life Sci 70:3545–3570 Wicklow DT, Dowd PF, Alfatafta AA, Gloer JB (1996) Ochratoxin A: an antiinsectan metabolite from the sclerotia of Aspergillus carbonarius NRRL 369. Can J Microbiol 42:1100–1103 Williams RD, Hoagland RE (2007) Phytotoxicity of mimosine and albizziine on seed germination and seedling growth of crops and weeds. Allelo J 19:423–430 Xuan TD, Elzaawely AA, Deba F, Fukuta M, Tawata S (2006) Mimosine in leucaena as a potent bio-herbicide. Agron Sustain Dev 26:89–97 Yamaguchi I (1998) Natural product derived fungicides as exemplified by the antibiotics. In: Hutson D, Miyamoto J (eds) Fungicidal activity. Wiley, Chichester, pp 57–85
