Prenylated indole derivatives from fungi: structure diversity, biological activities, biosynthesis and chemoenzymatic synthesis

Contents

• 1 Introduction

• 2 Diverse structures of prenylated indole derivatives from fungi with significant pharmacological and biological activities
  • 2.1 Prenylated derivatives of the cyclic dipeptide consisting of l-tryptophan and l-proline.
  • 2.2 Prenylated derivatives of the cyclic dipeptide consisting of two l-tryptophan molecules
  • 2.3 Prenylated derivatives of cyclic dipeptides consisting of l-tryptophan and a second aromatic amino acid
  • 2.4 Prenylated peptide derivatives containing l-tryptophan and aliphatic amino acids
  • 2.5 Prenylated bis(indolyl) benzoquinone derivatives
  • 2.6 Ergot alkaloids and other C4-prenylated indole alkaloids
  • 2.7 Prenylated indole-diterpenes

• 3 Biosynthesis
  • 3.1 Feeding experiments and investigations with crude enzyme extracts
  • 3.2 Identification of the biosynthetic gene clusters by genome mining and molecular biological and biochemical investigations on the biosynthesis of prenylated indole alkaloids

• 4 Production of prenylated indole derivatives by chemoenzymatic synthesis

• 5 Prenylated indole alkaloids from other sources

• 6 Conclusions

• Acknowledgements

• References

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Abstract

Covering: up to mid-2009

Prenylated indole alkaloids are hybrid natural products derived from prenyl diphosphates and tryptophan or its precursors and widely distributed in filamentous fungi, especially in the genera Penicillium and Aspergillus of ascomycota. These compounds represent a group of natural products with diverse chemical structures and biological activities. Significant progress on their biosynthesis has been achieved in recent years by identification of biosynthetic gene clusters from genome sequences and by molecular biological and biochemical investigations. In addition, a series of prenylated indole derivatives have been produced by chemoenzymatic synthesis using overproduced and purified enzymes.

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Shu-Ming Li

Shu-Ming Li is full professor of Pharmaceutical Biology at the Philipps-University in Marburg, Germany. He received his Ph.D. in 1992 from the Rheinische Friedrich-Wilhelms-University in Bonn, Germany. He has served as associate professor for Pharmaceutical Biology at the Heinrich-Heine-University in Düsseldorf. His research interests focus on the genomics of the biosynthesis of secondary metabolites in fungi, especially of prenylated indole alkaloids.

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1 Introduction

Prenylated indole alkaloids are hybrid natural products containing indole/indoline and isoprenoid moieties or structures derived thereof. They are widely distributed in terrestrial and marine organisms, especially in the genera Penicillium and Aspergillus of ascomycota, and display broad structure diversity. These compounds often carry biological and pharmacological activities distinct from their non-prenylated aromatic precursors.^1–3

The availability of the genome sequences of bacteria and fungi, which has increased tremendously in recent years,^4,5 has accelerated the identification of genes involved in the biosynthesis of secondary metabolites by genome mining.^6–8 By using this strategy, biosynthetic genes of several prenylated indole derivatives were identified in the genome sequences of ascomycetes.^9–11 The functions of these genes have been proven by molecular biological and biochemical approaches.^9,10 Additionally, a number of prenylated simple indole derivatives or tryptophan-containing diketopiperazines were synthesised by using overproduced and purified indole prenyltransferases.¹² The aim of this review is to give an overview on the structural characteristics of the main classes of prenylated indole derivatives from fungi, without listing all the structures of known natural products. In addition, this review summarizes briefly the considerable progress on the molecular biological and biochemical investigations on the biosynthesis of prenylated indole alkaloids in recent years and the application of the recombinant proteins for the production of prenylated indole derivatives.

2 Diverse structures of prenylated indole derivatives from fungi with significant pharmacological and biological activities

Prenylated indole alkaloids show diverse chemical structures and a wide range of biological and pharmacological activities. With the exception of indole-diterpenes, tryptophan from primary metabolism is a key precursor and acts as the biogenetic origin of indole or indoline rings.^3,13,14 Besides L-tryptophan, most of these substances contain a second amino acid and form cyclic dipeptides with a diketopiperazine structure or a derivative thereof. In most cases, the second amino acid is L-proline, L-tryptophan, L-histidine, L-phenylalanine or L-alanine. A further large group within the prenylated indole alkaloids are asterriquinones containing two tryptophan moieties with a bis(indolyl) benzoquinone structure.¹⁵

In the structures of prenylated indole alkaloids, the prenyl moieties can be connected via its C1 or C3 to an aromatic nucleus, which are referred to as regular or reverse prenyl moieties, respectively (Fig. 1). In prenylated cyclic dipeptides and bis(indolyl) benzoquinones, reverse prenyl moieties are usually attached to position N1, C2 or C3 of the indole or indoline ring, while the regular moieties are normally connected to position N1, C2, C5, C6 or C7, but not C3 of the indole or indoline rings (Fig. 1). Interestingly, prenylation at position C4 was only found in structural skeletons derived exclusively from only one L-tryptophan molecule such as in ergot alkaloids and cyclopiazonic acid or indole-diterpenes, but not in peptides or benzoquinones.

Fig. 1 Numbering of prenyl and indole/indoline moieties.

2.1 Prenylated derivatives of the cyclic dipeptide consisting of L-tryptophan and L-proline.

Fungal natural products derived from L-tryptophan and L-proline represent a large group within the prenylated indole alkaloids.³ The common precursor of these compounds is the cyclic dipeptide brevianamide F (1), which is converted to tryprostatin B (2) by attaching a regular prenyl moiety at position C2 or to deoxybrevianamide E (3) by a reverse one. Tryprostatin B (2) is a key intermediate in the biosynthesis of diverse structures such as tryprostatin A (4), spirotryprostatin A (5), fumitremorgins (6–8) and verruculogen (9), while deoxybrevianamide E (3) serves as precursor for brevianamides, e.g. brevianamide A (10), austamide (11) and notoamides (12–14).^3,16–18

Fumitremorgin B (7) and verruculogen (9), which contain two prenyl moieties at positions N1 and C2 of the indole ring, are mycotoxins from a number of Aspergillus and Penicillium strains.^19–23 Verruculogen (9), associated with Aspergillus fumigatus hyphae and conidia, was reported to be able to modify the electrophysiological properties of human nasal epithelial cells and could be involved in the pathogenesis of this fungus.²⁴ Fumitremorgin A (8) is also a mycotoxin from Aspergillus and Penicillium strains^20,25 and contains an additional prenyl moiety, in comparison to the structure of verruculogen (9). The biosynthetic intermediates of these compounds containing one prenyl moiety attached to position C2, such as tryprostatin B (2) and its methoxylated derivative tryprostatin A (4) as well as fumitremorgin C (6), showed biological activities of pharmaceutical interest. For example, tryprostatins A (4) and B (2) as well as their diastereomeres were found to exhibit cytotoxicity towards various cancer cell lines, even more potent than etoposide.^26–28 Fumitremorgin C (6) is a specific inhibitor of the breast cancer resistance protein and could reverse the resistance of some tumour cell lines.^29–31 Tryprostatin A (4) was also able to inhibit the ABC transporter of the resistant tumour cell lines.^32,33

Brevianamides and austamides, e.g. brevianamide A (10) and austamide (11), constitute a small group of cyclo-L-Trp-L-Pro derivatives and contain only one reverse prenyl moiety at position C2 of the indole ring or a structure derived thereof. These compounds are produced by Penicillium brevicompactum and Aspergillus ustus, respectively.^34–36 The dimeric cyclic dipeptide brevianamide J (15), containing one reverse prenyl moiety at position C2 of the indole ring in each unit, was recently isolated from cultures of Aspergillus versicolor.³⁷

Notoamides (12–14) and related compounds such as aspergamides, staphacidins and (−)-versicolamide B (16–18) are diprenylated derivatives of cyclo-L-Trp-L-Pro. One of the prenyl residues forms a fused dimethyldihydropyran ring via positions C6 and C7 of the indole ring. The second one was found as an intact reverse prenyl moiety at position C2 (notoamide D 12), C3 (notoamide M 13) or as strongly modified structure elements (notoamide A (14), stephacidin A (16), aspergamide A (17) and (−)-versicolamide (18), which could be considered as rearrangement results of the prenyl moiety at position C2 of the indole ring.³⁸ Stephacidin B (19), a dimeric derivative of stephacidin A (16), has also been described.³⁹ Notoamides, (−)-versicolamide and stephacidins are isolated from different Aspergillus strains.^{17,18,38–40} Notoamide A (14) showed moderate cytotoxicity against HeLa and L1210 cells.¹⁷

2.2 Prenylated derivatives of the cyclic dipeptide consisting of two L-tryptophan molecules

Fellutanines are reversely C2-prenylated derivatives of cyclo-L-Trp-L-Trp. Fellutanines B (20) and C (21) from Penicillium fellutanum are mono- and diprenylated derivatives with an intact diketopiperazine ring,⁴¹ while this ring system is fused with the indoline ring in fellutanine D (22) from Penicillium fellutanum and its diastereomer gypsetin (23) from Nannizzia gypsea.⁴² Amauromine (24) from Amauroascus sp.⁴³ and epiamauromine (25) from Aspergillus ochraceus⁴⁴ represent reversely C3-prenylated indolines. Okaramines (26–29) from Penicillium simplicissimum and Aspergillus aculeatus consist of at least 18 congeners.^45–49 In the structures of the most okaramines, e.g. A (26) and C (27), one reverse prenyl moiety is found at position C2 and a second one at position N1 of another tryptophan unit. These okaramines very likely are derived from cyclo-L-N1-DMAT-L-C2-DMAT (30), which was also isolated from Penicillium simplicissimum.⁴⁸ In the structure of okaramine L (28), position N1 is regularly prenylated instead. In some cases, the second prenyl residue can also be found at other positions than N1, e.g. in okaramine J (29) at position C7.⁴⁸

Fellutanine D (22) was reported to be cytotoxic against several cell lines,⁴¹ while its diastereomer gypsetin (23) showed cholesterol acyltransferase inhibiting activity.⁵⁰ Amauromine (24) was reported to have a vasodilating activity.⁵¹ Its stereoisomer epiamauromine (25) showed, on the other hand, insecticidal activity.⁴⁴ Insecticidal activity against silkworms has also been observed with several okaramines.⁵²

2.3 Prenylated derivatives of cyclic dipeptides consisting of L-tryptophan and a second aromatic amino acid

All members of this group are derived from cyclic dipeptides containing an indoline ring, which is fused with a diketopiperazine or benzodiazepindinone ring. In addition, they carry reverse prenyl moieties at position C3 of the indoline ring. A prominent example is roquefortine C (31, also called roquefortine) derived from L-tryptophan and L-histidine. This compound was firstly isolated from Penicillium roqueforti⁵³ and identified later in a number of Penicillium strains,^54–57 including P. roqueforti strains used for cheese production.^53,55 Roquefortine C (31) is also the precursor of several prenylated indole alkaloids such as roquefortine E (32), glandicoline B (33),⁵⁸ meleagrin (34)⁵⁸ and oxaline (35).^58–60 Roquefortine E (32), containing an additional reverse prenyl moiety attached to the imidazole ring, was isolated from Gymnoascus reessii.⁶¹ A meleagrin derivative (36) carrying a modified prenyl moiety at the imidazole ring was recently isolated from a deep ocean sediment derived Penicillium sp.⁶²

A second example from this group is the mycotoxin acetylaszonalenin (37) (called also LL-S490β) derived from the amino acids L-tryptophan and anthranilic acid. Acetylaszonalenin (37) was isolated initially from an unidentified Aspergillus species,⁶³ Together with its non-acetylated form aszonalenin (38), it was also identified in various fungal strains, e.g. Aspergillus zonatus,⁶⁴A. fumigatus,⁶⁵A. carneus⁶⁶ and Neosartorya fischeri.^67,68 Their stereoisomers epi-aszonalenins A (39) and C (40) were isolated from Aspergillus novofumigatus.⁶⁹

Fructigenine A (41) from Penicillium fructigenum,⁷⁰ which was also identified as rugulosuvine B in Penicillium regulosum⁷¹ is a cyclic dipeptide derivative of L-tryptophan and L-phenylalanine. This compound was reported to be a plant growing inhibitor.⁷⁰ Until now, no prenylated diketopiperazine derivatives containing tryptophan and tyrosine were isolated from the natural sources.

2.4 Prenylated peptide derivatives containing L-tryptophan and aliphatic amino acids

Prenylated indole alkaloids in this category are mainly derived from L-tryptophan and L-alanine or L-tryptophan and L-isoleucine. Prenylated cyclo-L-Trp-L-Ala derivatives including echinulin (42) or its analogues constitute a large group of fungal metabolites. They carry up to three prenyl moieties with a reverse one at position C2 of the indole ring. Echinulin (42), bearing prenyl moieties at positions C2, C5 and C7, was initially isolated from Aspergillus amstelodami⁷² and then from different Aspergillus strains.^73–76 It should be mentioned that echinulin (42) was also identified in different plants of Anacardiaceae, Cucurbitaceae and Orchidaceae.^77,78 Diverse echinulin analogues with different prenylation positions at the benzene ring and modifications, e.g. hydroxylation, oxidation and cyclisation of prenyl moieties were described in literature.⁷⁴ Examples of such structures are variecolorin L (43) from Aspergillus variecolor with prenyl moieties at positions C2, C4 and C5⁷⁴ or arestrictin B (44) from Aspergillus penicilloides with prenyl moieties at positions C2, C6 and C7.⁷⁹ A number of mono- and diprenylated cyclo-L-Trp-L-Ala derivatives were also isolated from various fungal strains,^73–75e.g. preechinulin (45),^73,74 terezine D (46),⁸⁰ tardioxopiperazines A (47) and B (48).^74,81 In the structure of cycloechinulin (49), the prenyl moiety at position C2 is connected to the diketopiperazine ring.⁸²

Astechrome (50) from Aspergillus terreus represents a rare iron-containing prenylated cyclo-Trp-Ala derivative.⁸³ In the structure of 5-N-acetylardeemin (51), which was identified in Neosartorya fischeri var. brasiliensis,⁸⁴ an anthranilic acid moiety is connected to the diketopiperazine ring consisting of tryptophan and alanine. Variecoloritide B (52) from Aspergillus variecolor contains a prenylated cyclo-Trp-Ala residue, which is condensed with an anthraquinone molecule.⁸⁵ Fructigenine B (53) from Penicillium fructigenum,⁷⁰ which was also identified as verrucofortine in Penicillium verucosum var. cyclopium,⁸⁶ is a prenylated cyclic dipeptide of tryptophan and leucine. Together with fructigenine B (53), five new C3-prenylated derivatives including brevicompanine G (54) were isolated from a deep ocean sediment derived Penicillium sp.⁸⁷ Brevicompanine G (54) is likely derived from tryptophan and valine. Both amino acids are also found in the structures of the prenylated linear peptides mellamide (55) and terpeptin (56), which were isolated from Aspergillus melleus⁸⁸ and Aspergillus terreus,⁸⁹ respectively.

Paraherquamides (57 and 58) and related compounds marcfortines (59 and 60) are a structurally complex family of indole alkaloids. Many members of this group show potent anthelmintic and antinematodal activities and have been under intensive investigation for use in veterinary medicine to treat various intestinal parasites.³ The members of this group are derived from L-tryptophan and β-methylproline, which is in turn formed from L-isoleucine.³ These compounds were identified in early 1980s in Penicillium and Aspergillus strains, especially in Penicillium paraherquei.^3,34

Most of the paraherquamides and analogues are diprenylated indole alkaloids. One prenyl moiety is found at position C3 or a structure derived thereof. The second one is connected to positions C6 and C7 of the indole ring via two oxygen atoms forming a seven-membered ring, as in the case of paraherquamide A (57) and macfortine A (59). This prenyl moiety exists also as a dimethyldihydropyran structure, as in the case of paraherquamide F (58) and macfortine C (60).

2.5 Prenylated bis(indolyl) benzoquinone derivatives

Asterriquinone (61), a symmetrical benzoquinone containing two reversely N1-penylated tryptophanyl moieties, was isolated from Aspergillus terreus⁹⁰ and demonstrated to be active against tumour cells.⁹¹ Later on, a series of bis(indolyl) benzoquinones carrying one or two regular or reverse prenyl moieties was identified in A. terreus,^15,92–94Chaetomium sp.⁹⁵ and other fungi.^96–100 Isoasterriquinone (62) from Aspergillus terreus contains reversely N1-prenylated and regularly C2-prenylated tryptophanyl moieties.⁹⁴ Hinnuliquinone (63) from Nodulisporium hinnuleum¹⁰¹ is a symmetrical dimer of reversely C2-prenylated tryptophan components. Further examples of symmetrical dimers are asterriquinones CT5 (64) and CT3 (65), isocochliodinol (66) and asterriquinone CT4 (67), with regular prenylation at positions of C2, C5, C6 and C7, respectively. Asterriquinones CT3 (65), CT4 (67) and CT5 (64) were isolated from Humicola grisea, Humicola fuscoatra and Aspergillus terreus, respectively.^94,99 Together with isocochliodinol (66), asterriquinones CT3 (65) and CT4 (67), termed cochliodinol and neocochliodinol, respectively, were also identified in a Chaetomium sp.⁹⁵

In addition to diprenylated derivatives, diverse monoprenylated indolyl benzoquinones were also reported, e.g. semicochliodinols A (68) and B (69) from Chrysophorium merdarium.¹⁰⁰ In ochrindole D (70) from Aspergillus ochraceus, the prenyl moiety is not attached to the indole, but to the benzoquinone ring.¹⁰² Terrequinone A (71) from Aspergillus terreus and A. nidulans is a bis(indolyl) benzoquinone with a reverse prenyl moiety at position C2 of the indole and a regular one at the quinone ring.^97,103 As in the cases of prenylated peptides, no C4-prenylated derivatives were found within the bis(indolyl) benzoquinones.

A number of asterrequinone derivatives showed cytotoxicity.^104–107 Investigation on the structure–activity relationship showed that the indole ring is important for the effect.¹⁰⁷ Hinnuliquinone (63), semicochliodinols A (68) and B (69) were reported to be active as inhibitors of HIV-1 protease.^100,108

2.6 Ergot alkaloids and other C4-prenylated indole alkaloids

Ergot alkaloids are a complex family of toxins and important pharmaceuticals with diverse structures and biological activities.^1,109 They are produced by fungi of two orders and plants of three families.¹¹⁰ The important producers are fungi of the genera Claviceps, Penicillium and Aspergillus.^1,109 Both natural ergot alkaloids and their semi-synthetic derivatives are in widespread use in modern medicine.^1,110 Chemically, ergot alkaloids are characterised by the presence of the tetracyclic ergoline ring (72) and can be divided into two classes according to their structural features, i.e. amide derivatives of D-lysergic acid (73) and the clavine alkaloids.^109,111 The members of the first group are usually composed of lysergic acid (73) and an amino alcohol, e.g. ergometrine (74), or a peptide moiety, e.g. ergotamine (75). The clavines like agroclavine (76), festuclavine (77) and fumigaclavine C (78) or their precursors like chanoclavine-I (79) merely consist of a tetracyclic or even tricyclic ring system lacking an amide or a peptide moiety. Ergotamine (75) was described as the first ergot alkaloid in 1920. Since then about 50 different ergot alkaloids of both classes have been found in nature.^109,111,112 Due to their significant importance as toxins and drugs, ergot alkaloids have been an important research field in secondary metabolism.¹¹¹ Results on biology, chemistry, molecular biology and biotechnology have been reviewed extensively.^1,109–113

Biogenetically, the ergoline ring (72) is derived from the C4-prenylated tryptophan 4-DMAT (80). This building block was not found in tryptophan-containing diketopiperazine or bis(indolyl) benzoquinone alkaloids discussed above, but in the structures of α-cyclopiazonic acid (81) and rugulovasines (82 and 83). The fungal neurotoxin α-cyclopiazonic acid (CPA) (81), a nanomolar inhibitor of Ca²⁺-ATPase,¹¹⁴ has a pentacyclic indole tetramic acid scaffold and was firstly isolated from Penicillium cyclopium¹¹⁵ and followed by a large number of Penicillium and Aspergillus strains.^57,116–119 α-Cyclopiazonic acid (81) was often found as a contaminant in food and feeds^117,119,120 Rugulovasines A (82) and B (83) and their chlorinated derivatives were identified as a small group of C4-prenylated tryptophan derivatives in several Penicillium strains.^121–123

2.7 Prenylated indole-diterpenes

Indole-diterpenes with a minimal structure (84) are a large, structurally and functionally diverse group of secondary metabolites produced by filamentous fungi with a common cyclic diterpen backbone and an indole residue.² The first reported structure of this group, paspalitrem A (85), was isolated from Claviceps paspali in 1977.¹²⁴ Two years later, the tremorgenic mycotoxin aflatrem (86) was identified in Aspergillus flavus.^125,126 These mycotoxins are monoprenylated derivatives of paspalinine (87), which could also be isolated from various fungal strains.^124,126 The structures of penitrem A (88) and analogues, a group of tremorgenic mycotoxins identified in several Penicillium strains, including P. crustosum,^127–130 were determined in 1981.¹³¹ Lolilline (89) and the tremorgenic lolitrems A (90) and B (91) were identified in Neotyphodium-infected plants Lolium perenne and Festuca sp.^11,132,133 In the structures of the mentioned compounds, a C19 skeleton derived from a geranylgeranyl moiety is fused to positions C2 and C3 of the indole ring.

Similar structural features were also found in shearinines, e.g. shearinine D (92) from Penicillium strains.^134,135 In comparison, indole-diterpenes with a C20 residue attached to indole moiety were also identified, e.g. emindoles PA (93) and PB (94).¹³⁶ As paspalitrem A (85) and aflatrem (86), the other mentioned structures also carry additional intact or modified prenyl moieties at the indole rings. For example, emindoles PA (93) and PB (94) carry one prenyl moiety at N1 and C2, respectively, while two prenyl residues were found in lolilline (89), and lolitrems A (90) and B (91) at positions C4 and C5. Shearinine D (92) is diprenylated at C5 and C6. In the structures of lolitrem A (90) and B (91), an additional C5 unit is attached to the C19 residue.

In 1997, a potent insecticidal agent nodulisporic acid A (95) was identified in an endophytic fungus Nodulispororium sp. by bioassay-guided isolation.¹³⁷ Its structure was determined as an indole-diterpene derivative carrying three modified dimethylallyl moieties at position C5, C6 and C7 of the indole ring.^137,138 Since then, eighteen nontremorgenic nodulisporic acid derivatives have been isolated from Nodulispororium including the biosynthetic precursors of nodulisporic acid A such as nodulisporic acids B (96), C (97), D (98) and E (99).^139–141 All of these compounds are potent anti-flea agents.¹⁴¹ Nodulisporic acids lack the tertiary hydroxyl group at C-9 of the structure (84) that is implicated in the tremorgenic properties of the related alkaloids.¹⁴²

3 Biosynthesis

3.1 Feeding experiments and investigations with crude enzyme extracts

A large variety of feeding experiments with isotope-labelled precursors were carried out for ergot alkaloids in Claviceps,^1,111 roquefortine C (31) in Penicillium roquerforti,¹⁴³ aszonalenin (38) in Aspergillus zonatus,¹⁴³ echinulin (42) in Aspergillus amstelodami,¹⁴⁴ brevianamide A (10) in Penicillium brevicompactum, paraherquamide A (57) in Penicillium fellutanum^3,34 and α-cyclopiazonic acid (81) in Penicillium cyclopium.^145,146 The results of these experiments showed clearly that tryptophan and dimethylallyl diphosphate (DMAPP) serve as biosynthetic precursors of indole or indoline and prenyl moieties of these compounds, respectively.³ The prenyl moieties are derived from the acetate–mevalonate pathway. Incorporation of tryptophan and mevalonolactone into the alkaloid molecules has been clearly demonstrated. Furthermore, additional precursors such as S-adenosylmethionine for methyl groups or a second amino acid for diketopiperazine derivatives were also proven by feeding experiments. In addition, enzyme activities for a number of biosynthetic reactions were demonstrated with crude extracts or partially purified protein fractions. Several excellent reviews have summarized the results of feeding experiments on prenylated indole alkaloids and enzymatic characterisation of certain reactions.^{1,3,34,111,147} This work will therefore not be repeated in this review.

It is worth mentioning the controversial discussion on the role of tryptophan as a biosynthetic precursor for indole-diterpenes.¹⁴⁸ Feeding experiments in washed cells of a Nodulisporium mutant MF6244 showed clear incorporation of 2-¹³C-acetate and 2-¹³C-mevalonolactone into the indole-diterpene derivative nodulisporic acid A (95) and demonstrated the isoprene formation via the classical acetate–mevalonate pathway.¹⁴² Differing from the most prenylated indole alkaloids mentioned previously, the indole moiety of nodulisporic acid A (95) is most likely not derived from tryptophan, but from its precursor indole-3-glycerol phosphate (100). Incubations of Nodulisporium MF6244 with ¹⁴C- and ¹³C-tryptophan showed no incorporation of label into nodulisporic acid A (95). However, high levels of incorporation into nodulisporic acid A (95) were obtained with known tryptophan precursors such as ¹⁴C-, ¹³C-, and ¹⁵N-anthranilic acid as well as ¹⁴C- and ¹³C-ribose.^142,148 These results are in contrast to those obtained for penitrem A (88) in Penicillium crustosum, which demonstrated a low incorporation of tryptophan into penitrem A (88).¹⁴⁹

3.2 Identification of the biosynthetic gene clusters by genome mining and molecular biological and biochemical investigations on the biosynthesis of prenylated indole alkaloids

Significant progress has been achieved in the molecular biological and biochemical investigations on the biosynthesis of prenylated indole alkaloids in the last five years. In most cases, the biosynthetic genes were identified as a cluster in the genome sequences by bioinformatic approaches. Comparison of the orthologous gene clusters in different strains helps to identify a candidate gene for an enzymatic reaction, which can then be proven by molecular biological and biochemical characterisation.

3.2.1 Fumigaclavine biosynthesis in Aspergillus fumigatus. Fumigaclavine C (78) is an ergot alkaloid of the clavine-type and carries no peptidyl moiety, in comparison to ergopeptines from Claviceps purpurea.¹⁰⁹ This compound is produced by Penicillium and Aspergillus strains, e.g. A. fumigatus,¹⁰⁹ but not by the fungal family of the Clavicipitaceae, e.g. C. purpurea.¹⁰⁹ Conversely, ergopeptines are produced by C. purpurea, but not by A. fumigatus.¹⁰⁹ In contrast, chanoclavine-I (79) was identified in both fungal groups.¹⁰⁹ Therefore, we have proposed that the early stages of the biosynthetic pathway of ergot alkaloids are very likely shared by A. fumigatus and C. purpurea, whereas later steps in the pathway differ in the two fungi.¹⁵⁰ A gene cluster for the biosynthesis of fumigaclavine C (78) (Fig. 2A) was identified on chromosome 2 of A. fumigatus Af293 and A1163 by bioinformatic approaches.^9,151,152 This cluster consists probably of 11 putative genes and spans bp 2907012 to 2929163 of AAHF01000001 in Af293 (GenBank). Seven homologous genes were identified in both fumigaclavine clusters of A. fumigatus and the ergopeptine cluster of C. purpurea.⁹ The identification of the fumigaclavine cluster for a clavine-type ergot alkaloid lacking the peptidyl moiety provided a convenient way to identify candidate genes, which are involved in the common steps of the biosynthesis of ergot alkaloids by comparison of the two clusters in C. purpurea and A. fumigatus. Successful application of this strategy was clearly demonstrated by the identification of the dimethylallyltryptophan synthase FgaPT2¹⁵¹ and the N-methyltransferase FgaMT.¹⁵⁰ FgaPT2 catalyses the first pathway-specific step of the ergot alkaloid biosynthesis, i.e. the C4-prenylation of L-tryptophan, resulting in formation of 4-dimethylallyl-L-tryptophan (4-DMAT (80)) (Scheme 1).¹⁵¹ The structure of FgaPT2 was recently solved with a resolution of 1.76 Å and showed significant similarity to bacterial prenyltransferases of the ABBA family,¹⁵³ although no sequence similarity on the amino acid level could be detected for these enzymes.^9,10 The availability of FgaPT2 structure provided a basis for understanding of the reaction mechanism of this important enzyme.¹⁵³ FgaMT shared no significant sequence similarity with known proteins in databases and was found in both clusters, indicating its role in the early stage of the biosynthesis. By gene cloning and biochemical characterisation, it could be indeed shown that FgaMT catalysed the second step of the biosynthesis, i.e. the N-methylation of 4-DMAT (80), resulting in the formation of 4-DMA-L-abrine (101) (Scheme 1).¹⁵⁰ Comparison of both gene clusters also helps to find candidate genes, which are involved in the later steps of the biosynthesis. This approach was demonstrated by the identification of the fumigaclavine B acetyltransferase FgaAT¹⁵⁴ and fumigaclavine A prenyltransferase FgaPT1 in A. fumigatus.¹⁵⁵ Both fgaAT and fgaPT1 were only found in the gene cluster of fumigaclavine C in A. fumigatus, but not in C. purpurea.¹⁵¹ This finding corresponded well to the structural differences of the ergot alkaloids in the two strains, i.e. the presence of an acetoxyl and a reverse prenyl moiety in the structure of fumigaclavine C (78) and absence of these groups in ergopeptines. Biochemical investigations demonstrated that FgaAT catalyses the acetylation of fumigaclavine B (102) resulting in the formation of fumigaclavine A (103), which is then converted to fumigaclavine C (78) by FgaPT1 (Scheme 1).^154,155

Scheme 1 Proposed biosynthetic pathway for fumigaclavine C in Aspergillus fumigatus.

Fig. 2 Biosynthetic gene clusters from different sources. A: fumigaclavine C cluster in Aspergillus fumigatus; B: fumitremorgin/verruculogen cluster in Aspergillus fumigatus; C: acetylaszonalenin cluster in Neosartorya fischeri; D: terrequinone A cluster in Aspergillus nidulans; E: α-cyclopiazonic acid cluster in Aspergillus flavus; F: paxilline cluster in Penicillium paxilli; G: lyngbyatoxin cluster in Lyngbya majuscula.

3.2.2 Fumitremorgin/verruculogen biosynthesis in Aspergillus fumigatus. From the genome sequence of Aspergillus fumigatus Af293, a cluster containing nine putative biosynthetic genes (Fig. 2B) was identified on chromosome 8 by using bioinformatic approaches.¹⁶ Homologous gene clusters could also be identified in the genome sequences of Aspergillus fumigatus A1163 and Neosartorya fischeri NRRL181, with sequence identities of the gene products between 82–100% to those of Af293.⁹ The end product of this cluster could be verruculogen (9),¹⁵⁶ but it could not be excluded that fumitremorgin A (8) is the true end product instead. The fumitremorgin/verruculogen cluster was very likely not expressed in A. fumigatus Af293, therefore, no secondary metabolites of this cluster could be detected in this strain.¹⁵⁷ In contrast, a number of intermediates including tryprostatins A (4) and B (2), fumitremorgin C (6), 12,13-dihydroxyfumitremorgin C (104), fumitremorgin B (7) as well as verruculogen (9) were isolated from A. fumigatus BM 939.¹⁵⁸ The function of seven genes from this cluster was proven experimentally in recent years. The biosynthesis of fumitremorgin/verruculogen begins with the condensation of the two amino acids L-tryptophan and L-proline catalysed by the nonribosomal peptide synthetase FtmPS (also termed FtmA) (Scheme 2). Expression of ftmPS in A. fumigatus resulted in the accumulation of the cyclic dipeptide brevianamide F (1),¹⁵⁷ which is then converted to tryprostatin B (2) by the prenyltransferase FtmPT1/FtmB in the presence of dimethylallyl diphosphate.¹⁶ Conversion of tryprostatin B (2) to tryprostatin A (4) needs two steps, i.e. hydroxylation to 6-hydroxytryprostatin B (105) by the cytochrome P450 FtmP450-1/FtmC and methylation by the putative methyltransferase FtmMT/FtmD. The two other cytochrome P450s, i.e. FtmP450-2/FtmE and FtmP450-3/FtmG catalyse the conversion of tryprostatin A (4) to fumitremorgin C (6) by connection of the prenyl moiety to the diketopiperazine ring as well as fumitremorgin C (6) to 12,13-dihydroxyfumitremorgin C (104) by two hydroxylation steps, respectively (Scheme 2). The function of the three cytochrome P450 enzymes in the biosynthesis was proven by Kato et al.¹⁵⁹ We have shown that the second prenyltransferase FtmPT2/FtmH in the cluster catalyses the conversion of 12,13-dihydroxyfumitremorgin C (104) to fumitremorgin B (7).¹⁶⁰ Very recently, we have demonstrated that the non-heme Fe(II) and α-ketoglutarate-dependent dioxygenase FtmOx1/FtmF is involved in the formation of verruculogen (9) from fumitremorgin B (7).¹⁵⁶ Kato et al.¹⁵⁹ reported that ftmO (AFUA_8G00260) is likely not involved in the biosynthesis of fumitremorgin B (7) or verruculogen (9).

Scheme 2 Biosynthetic pathway for verruculogen or fumitremorgin A in Aspergillus fumigatus.

3.2.3 Acetylaszonalenin biosynthesis in Neosartorya fischeri. Acetylaszonalenin (37) is a mycotoxin carrying a reverse prenyl moiety at position C3 of the indoline ring and a fused ring between the indoline and the benzodiazepine ring system. Acetylaszonalenin (37) was isolated from a two week old culture of the genome reference strain Neosartorya fischeri NRRL181.⁶⁸ Based on its structural feature, we hoped to find the biosynthetic gene cluster in the genome sequence. Acetylaszonalenin (37) is chemically a cyclic dipeptide derivative of tryptophan and anthranilic acid, which is acetylated at position N1 and prenylated at position C3 of the indoline ring. It could be expected that at least three genes/enzymes are involved in the biosynthesis of acetylaszonalenin (37), i.e. a nonribosomal peptide synthethase for the formation of the cyclic dipeptide,^157,161 a prenyltransferase for a prenyl transfer¹⁶² and an acetyltransferase for an acetyl transfer reaction. The formation of the fused ring between the indoline and the benzodiazepine ring system would require an additional enzyme or would be catalysed during the prenylation by the prenyltransferase. Indeed, a 12.8 kb DNA segment consisting of three genes and spanning bp 130 585–143 349 of AAKE03000024.1 was identified in N. fischeri NRRL181 by homologous search and sequence analysis (Fig. 2C). An orthologous cluster was also identified in the genome sequence of Aspergillus terreus NIH2624.⁶⁸ The putative genes anaPS, anaPT and anaAT in this cluster coding for the three putative enzymes mentioned above are likely involved in the biosynthesis of acetylaszonalenin (37).⁶⁸AnaPS is predicted to encode a dimodular nonribosomal peptide synthetase (NRPS) with two adenylation domains (A), two peptidyl carrier domains (P) and two condensation domains (C), which is expected to be responsible for the condensation of the amino acids tryptophan and anthranilic acid (Scheme 3). AnaPT showed clear sequence similarity to indole prenyltransferases and was proven to be responsible for the reverse C3-prenylation of (R)-benzodiazopindinone (106) in the presence of DMAPP, resulting in formation of aszonalenin (38).⁶⁸ These results provided evidence that AnaPT catalyses both the prenyl transfer reaction and the cyclisation between the indoline and the benzodiazepine ring system. By gene cloning and biochemical characterization of the recombinant gene product, it was shown that AnaAT catalyses the acetylation of aszonalenin (38), resulting in the formation of acetylaszonalenin (37) (Scheme 3).⁶⁸ The biosynthetic pathway described for acetylaszonalenin (37) could also be plausible for other dipeptide derivatives with prenyl moieties at position C3 of the indoline rings, e.g. roquerfortine C (31), amauromines (24, 25), fructigenines (41, 53) and brevicompanine (54).^62,68,87 This includes the formation of cyclic dipeptides with a diketopiperazine structure catalysed by NRPS, prenylation and cyclisation catalysed by a prenyltransferase, and acetylation (if necessary) by an acetyltransferase.

Scheme 3 Biosynthetic pathway for acetylaszonalenin in Neosartorya fischeri.

3.2.4 Terrequinone A biosynthesis in Aspergillus nidulans. A cluster consisting of five genes for the biosynthesis of terrequinone A (71) (Fig. 2D) was identified in Aspergillus nidulans during a genome-wide survey for active natural product genes.¹⁰³ All five genes tdiA–tdiE could be characterised by heterologous overexpression.¹⁶³ TdiD is a pyridoxal-5-phosphate-dependent L-tryptophan aminotransferase that generates indole pyruvate (107) for an unusual non-oxidative coupling by the tridomain nonribosomal peptide synthetase TdiA, resulting in the formation of the quinone derivative didemethylasterriquinone D (108) (Scheme 4),¹⁶³ which is then converted to asterriquinone C-1 (110) by the prenyltransferase TdiB.¹⁶⁴ TdiC, an NADH-dependent quinone reductase catalyses the reduction of didemethylasterriquinone D (108) to the nucleophilic hydroquinone (109), which is converted to the end product of the cluster terrequinone A (71) by TdiB in the presence of TdiE (Scheme 4).¹⁶³

Scheme 4 Biosynthetic pathway for terrequinone A in Aspergillus nidulans.

3.2.5 α-Cyclopiazonic acid biosynthesis in Aspergillus oryzae and A. flavus. A gene cluster for the biosynthesis of α-cyclopiazonic acid consisting of three genes (Fig. 2E) was identified in the genome sequences of Aspergillus oryzae and Aspergillus flavus.^165–168 The hybrid two-module polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) CpaS (termed also CpaA) is responsible for the formation of the tetramic acid cyclo-acetoacetyl-L-tryptophan (cAATrp) (111) (Scheme 5), which was proven by gene disruption^165,166 and by functional expression.^167,168 cAATrp (111) should be then prenylated by the putative prenyltransferase CpaD, resulting in the formation of β-cyclopiazonic acid (112). The conversion of β- to α-cyclopiazonic acid (81) would be catalysed by the putative monoamine oxidase CpaO (Scheme 5). Disruption of both genes in Aspergillus flavus, termed dmaT and maoA, respectively, abolished the cyclopiazonic acid production and demonstrated their involvement in the biosynthesis.¹⁶⁶

Scheme 5 Proposed biosynthetic pathway for α-cyclopiazonic acid in Aspergillus flavus and Aspergillus oryzae.

3.2.6 Indole-diterpene biosynthesis in Penicillium, Neotyphodium and Epichloë. Paspaline (113) is proposed to be the first stable indole-diterpene intermediate from which many other metabolites of this class are derived.¹¹ The structural diversity observed within this group of metabolites is achieved by additional prenylations, different ring substitution patterns and stereochemistry.² Considerable progress has been achieved in recent years on understanding indole-diterpene biosynthesis in filamentous fungi.¹¹ A cluster consisting of seven genes (Fig. 2F) necessary for the biosynthesis of paxilline (114) was identified in Penicillium paxilli.¹⁶⁹ By gene deletion and complementation as well as by feeding experiments with proposed precursors, it has been shown that four gene products, i.e. a geranylgeranyl diphosphate synthase PaxG, a FAD-dependent monooxygenase PaxM, a prenyltransferase PaxC and a membrane-associated protein PaxB are required for the formation of paspaline from indole-3-glycerol phosphate (100),^11,170 which is converted to desoxypaxilline (115) by a cytochrome P450 monooxygenase PaxP and then to paxilline (114) by a cytochrome P450 monooxygenase PaxQ (Scheme 6).¹⁷¹ Orthologous gene clusters (ltm cluster) were also found in lolitrem producers Neotyphodium lolii and Epichloë festucae.^11,172,173 Two additional genes, ltmE and ltmJ, coding for a putative prenyltransferase and a cytochrome P450 enzyme, respectively, were also identified in these fungi¹⁷² and proposed to be involved in the conversion of desoxypaxilline (115) to lolitrems (90, 91).¹⁷⁴

Scheme 6 Proposed biosynthetic pathway for paxilline in Penicillium paxilli.

A gene cluster containing homologues of paxG, paxM, and paxC, designated atmG, atmM, and atmC, respectively, was also identified in the aflatrem producer Aspergillus flavus NRRL 6541.¹⁷⁵ Analysis of the genome sequences of A. flavus NRRL 3357 and Aspergillus oryzae RIB40 has revealed the presence of an aflatrem cluster similar to that of A. flavus NRRL 6541 mentioned above.¹¹ These genomes also contain a second gene cluster at a separate chromosomal locus, which includes homologues of paxP, paxQ, paxA, paxB, and paxD.¹¹ Thus, homologues of all seven genes necessary for paxilline (114) production in Penicillium paxilli are present in the genomes of A. flavus and A. oryzae, supporting the proposal that aflatrem production proceeds via paspaline (113) and paxilline (114) intermediates.¹¹

4 Production of prenylated indole derivatives by chemoenzymatic synthesis

As discussed under section 2, many prenylated alkaloids are derived from the same amino acids. For example, tryprostatins (2, 4), fumitremorgins (6–8), brevianamides (10, 15), notoamides (12–14) and stephacidins (16, 19) are derivatives of cyclo-L-Trp-L-Pro. Cyclo-L-Trp-L-Trp is the common precursor of fellutanines (20–22), amauromines (24, 25) and okaramines (26–29). They differ from each other in prenylation position and manner (regular or reverse) as well as by further modifications. It can be expected that the respective cyclic dipeptide is formed by similar nonribosomal peptide synthetases in different producers, but diverse prenyltransferases contribute significantly to the large structure diversity within the prenylated indole alkaloids. The same conclusion is also applicable for asterriquinones and related compounds (61–71), which distinguish from each other by number and position of the prenyl moieties at the indole rings. Therefore, prenyl transfer reactions catalysed by prenyltransferases represent key steps in the biosynthesis of natural products. For this reason, prenyltransferases from different sources are important research topics in the field of secondary metabolism.^9,176

In recent years, ten indole prenyltransferase genes from various fungi were cloned and overexpressed in Escherichia coli or Saccharomyces cerevisiae.^10,12 The overproduced proteins were proven to be soluble proteins and could be purified to near homogeneity by affinity chromatography in good yields.⁹ These prenyltransferases catalyse diverse prenyl transfer reactions onto different indole positions of various substrates.^9,10 Investigations on substrate specificity of the characterised indole prenyltransferases revealed that these enzymes were specific for DMAPP as prenyl donor. Product formation was only observed with DMAPP, but not with geranyl diphosphate under the tested conditions.^{16,68,151,155,160,177,178} In contrast, they showed notable substrate flexibility towards their aromatic substrates.^{16,162,177–179} Diverse simple tryptophan derivatives (116) and tryptophan-containing cyclic dipeptides (117) were accepted by several prenyltransferases as substrates and converted to prenylated derivatives. For example, the two dimethylallyltryptophan synthases FgaPT2 and 7-DMATS, which catalyse the regular prenylation at positions C4 and C7 of the indole ring of L-tryptophan, respectively, accepted a series of simple tryptophan derivatives (116) with modifications at the side chain and at the indole nucleus as substrates.^179,180 Notably, they also accepted tryptophan-containing cyclic dipeptides (117) as aromatic substrates.¹⁸¹ Conversely, the cyclic dipeptide prenyltransferases FtmPT1 and CdpNPT accepted not only tryptophan-containing cyclic dipeptides (117),^16,162 but also simple indole derivatives (116) as substrates.¹⁸² More importantly, the prenyl transfer reactions catalysed by indole prenyltransferases are highly regiospecific.^9,12 These features of substrate flexibility and reaction regiospecificity were successfully used for production of prenylated indole derivatives.¹²

By using chemoenzymatic synthesis with purified enzymes, it was possible to obtain three monoprenylated products from one simple indole derivative (116). The prenyltransferases FtmPT1 or CdpNPT, FgaPT2, and 7-DMATS converted the same substrate to derivatives with a prenyl moiety at position N1 (118), C4 (119) or C7 (120) of the indole ring, respectively (Scheme 7)^179,180,182 By a tandem incubation with FgaPT2 and 7-DMATS, 4,7-diprenylated indole derivatives (121) have also been produced (Scheme 7).¹⁸³

Scheme 7 Chemoenzymatic synthesis of prenylated simple indole derivatives.

By using the same strategy, at least five derivatives with prenyl moieties at N1 (122), C2 (123), C3 (124), C4 (125) and C7 (126) could be obtained from one tryptophan-containing cyclic dipeptide (Scheme 8). CdpNPT prenylates these compounds at position N1 of the indole ring, resulting in the formation of reversely prenylated derivatives (122).¹⁶² FtmPT1 is able to prenylate tryptophan-containing cyclic dipeptides at position C2 of the indole moiety.^16,184 C3, C4 and C7-prenylated derivatives (124–126) could be obtained by using AnaPT, FgaPT2 or 7-DMATS, respectively.¹⁸¹ (Yin and Li, Kremer and Li, unpublished results)

Scheme 8 Chemoenzymatic synthesis of prenylated cyclic dipeptides.

5 Prenylated indole alkaloids from other sources

Prenylated indole alkaloids are mainly, but not exclusively, found in fungi. They exist also in other domains of life such as bacteria, especially in actinomycetes and cyanobacteria, plants, as well as bryozoans.

Lyngbyatoxin A (127) from the cyanobacterium Lyngbya majuscula is a derivative of indolactam-V (128), a cyclic dipeptide consisting of L-valine and L-tryptophan, which is connected via its C7 to a geranyl moiety.¹⁸⁵ Derivatives of indolactam-V (128) such as the tumour promoters teleocidin B-4 (129), olivoretin A (130) and blastmycetin E (131) were identified in various actinomycetes such as Streptomyces mediocidicus, Streptoverticillium olivoreticuli and Streptoverticillium blastmycetium.^186–190

The biosynthesis of lyngbyatoxin A (127) was extensively studied by identification of a biosynthetic gene cluster¹⁹¹ and by biochemical investigation with an overproduced enzyme.¹⁹² The gene cluster (Fig. 2G) consists of four genes ltxABCD, which encode for a nonribosomal peptide synthetase, a cytochrome P450 monooxygenase, a prenyltransferase and an oxidoreductase, respectively.¹⁹¹ LtxA, containing additional N-methylation and reduction domains, catalyses the condensation of the amino acids L-valine and L-tryptophan, resulting in the formation of the linear dipeptide (132), which is then cyclised by LtxB to (−)-indolactam-V (128) (Scheme 9). Conversion of (−)-indolactam (128) to lyngbyatoxin A (127) would be catalysed by LtxC. LtxD would convert lyngbyatoxin A (127) to lyngbyatoxin B (133) (Scheme 9).^191,192 In contrast, little is known about the biosynthesis of teleocidins, olivoretins or blastmycetins in actinomyces on the molecular biological and biochemical level.

Scheme 9 Proposed biosynthetic pathway for lynbyatoxins in Lynbya majuscula.

From the cyanobacterium Fischerella sp., nine antimicrobial isonitrile-containing indole alkaloids were isolated.¹⁹³ These compounds, like ambiguine H isonitrile (134) and ambiguine F isonitrile (135), can be considered as tryptophan derivatives, which are connected to a reverse dimethylallyl and geranyl moiety at positions C2 and C4, respectively. Monoprenylated derivatives like 12-epi-hapalindole H (136) have also been reported.¹⁹³

A number of simple prenylated indole derivatives were identified in the bryozoan Flustra foliacea.^194–196 They are often brominated tryptamine derivatives with prenyl moieties at different positions of the indole ring like flustramines A (137), C (138) and D (139).^197,198

Prenylated indole derivatives occur also in higher plants. A large number of carbazole alkaloids have been isolated from higher plants of the genera Murraya, Glycosmis and Clausena, all belonging to the family Rutaceae.¹⁹⁹ Two examples are mahanimbine (140) and biskoenigine (141) from Murraya koenigii.^200,201

6 Conclusions

A large number of prenylated indole alkaloids with various structural features and important pharmacological activities have been identified in different sources, especially in filamentous fungi. Investigations on their biosynthesis in the last century have been mainly limited to feeding experiments with precursors and biochemical characterisation with crude extracts or partially purified enzymes from producers.^3,111 Molecular biological and biochemical research with structural genes began ten years ago,²⁰² but significant progress was achieved only after sequence release of genome sequencing projects for fungal strains, especially for Aspergillus strains in 2003/2004. The availability of more and more genome sequences provides an enormous chance for the study of secondary metabolites. Meanwhile, this is also a challenge for natural product research. Numerous genes and gene clusters with unknown functions have been identified in genome sequences,²⁰³ and functional proof of these genes and identification of the natural products coded by the gene clusters will be the main challenges for natural product chemists and biologists in the coming years or even decades. Therefore, it can be expected that more and more designed biologically-active substances will be produced by genetic manipulation.

7 Acknowledgements

The work in the author's laboratory was supported by grants from the Deutsche Forschungsgemeinschaft.

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