Diterpenes Specially Produced by Fungi: Structures, Biological Activities, and Biosynthesis (2010-2020)

Abstract

Fungi have traditionally been a very rewarding source of biologically active natural products, while diterpenoids from fungi, such as the cyathane-type diterpenoids from Cyathus and Hericium sp., the fusicoccane-type diterpenoids from Fusicoccum and Alternaria sp., the guanacastane-type diterpenoids from Coprinus and Cercospora sp., and the harziene-type diterpenoids from Trichoderma sp., often represent unique carbon skeletons as well as diverse biological functions. The abundances of novel skeletons, biological activities, and biosynthetic pathways present new opportunities for drug discovery, genome mining, and enzymology. In addition, diterpenoids peculiar to fungi also reveal the possibility of differing biological evolution, although they have similar biosynthetic pathways. In this review, we provide an overview about the structures, biological activities, evolution, organic synthesis, and biosynthesis of diterpenoids that have been specially produced by fungi from 2010 to 2020. We hope this review provides timely illumination and beneficial guidance for future research works of scholars who are interested in this area.

Keywords: biological activity; biosynthesis; diterpenes; isolation; structure.

Chart 1

Fungal diterpenoids (2010–2020) classified by skeleton.

Chart 2

Source genera of fungal diterpenoids (2010–2020).

Chart 3

The proportion of one activity as compared with the whole occurrence of activities of bioactive fungal diterpenoids (2010–2020).

Figure 1

The evolutionary analysis tree constructed with selected fungi producing cyathane diterpenoids. The evolutionary analysis was reconstructed by the maximum likelihood method from the internal transcribed spacer (ITS) sequences as follows: Cyathus africanus (JX103204.1), C. earlei (KY964272.1), C. gansuensis (KC869661.1), C. helenae (DQ463334.1), C. hookeri (KC005989.1), C. stercoreus (MH543350.1), C. striatus (KU865513.1), C. subglobisporus (MH156046.1), Gerronema albidum (MF318924.1), Hericium erinaceus (KU855351.1), H. flagellum (MG649451.1), H. ramosum (U27043.1), H. sp. WBSP8 (MN243091.1), Hydnum repandum (LC377888.1), Laxitextum incrustatum (KT722621.1), Phellodon niger (MH310794.1), Sarcodon glaucopus (MT955152.1), S. scabrosus (MN992643.1), Strobilurus tenacellus (MF063128.1). Since the ITS sequence of Sarcodon cyrneus was not available, Sarcodon sp. (MK049936.1) was selected, since it is in the same family with S. cyrneus. The evolutionary history was inferred by using the maximum likelihood method and the general time reversible model [62]. The bootstrap consensus tree inferred from 1000 replicates is taken to represent the evolutionary history of the taxa analyzed [63]. Branches corresponding to partitions reproduced in less than 50% bootstrap replicates are collapsed. The percentage of replicate trees in which the associated taxa clustered together in the bootstrap test (1000 replicates) are shown next to the branches [63]. Initial tree(s) for the heuristic search were obtained automatically by applying the Neighbor-Join and BioNJ algorithms to a matrix of pairwise distances estimated using the maximum composite likelihood (MCL) approach, and then selecting the topology with superior log likelihood value. A discrete Gamma distribution was used to model evolutionary rate differences among sites (5 categories (+G, parameter = 1.2219)). The rate variation model allowed for some sites to be evolutionarily invariable ([+I], 0.00% sites). This analysis involved 20 nucleotide sequences. Codon positions included were 1st + 2nd + 3rd + noncoding. There were 924 positions in the final dataset. The evolutionary analysis was conducted in MEGA X (version 10.2.2) [64].

Figure 2

The evolutionary analysis tree constructed with selected fungi producing cyclopiane diterpenoids. The evolutionary analysis was reconstructed by the maximum likelihood method from the ITS sequences as follows: Penicillium commune MCCC 3A00940 (KY978585.1), P. sp. F23-2 (EU770318.1), P. sp. YPGA11 (MG835908.1), P. sp. TJ403-2 (MK613138.1), P. chrysogenum MT-12 (MF765611.1), P. chrysogenum QEN-24S (GU985086.1), P. roqueforti IFM 48062 (AB041202.1), and Leptosphaeria sp. XL026 (MK603060.1). Since the ITS sequence of strain P. cyclopium IMI 229034 was not available, P. cyclopium IFM 41611 (AB041169.1) was selected, since it was in the same family as P. cyclopium. The evolutionary analysis was conducted in MEGA X (version 10.2.2) [64].

Scheme 1

(A) Reaction catalyzed by the prenyltransferase domain of PcCS; (B) reaction catalyzed by the terpene synthase domains of PcCS [69].

Scheme 2

Proposed cyclization mechanism catalyzed by PchDS/PrDS [71].

Figure 3

The evolutionary analysis tree constructed with selected fungi producing fusicoccane diterpenoids. The evolutionary analysis was reconstructed by the maximum likelihood method from the ITS sequences as follows: Alternaria brassicicola XXC (KR779774.1), Penicillium sp. DT10 (MH458525.1), Periconia sp. No. 19-4-2-1 (KP873157.1), Roussoella hysterioides KT1651 (KJ474829.1), Talaromyces stipitatus (MH857968.1), Talaromyces purpurogenus (MH120320.1), and Trichoderma citrinoviride cf-27 (KT259441.1). The evolutionary analysis was conducted in MEGA X (version 10.2.2) [64].

Scheme 3

Proposed biosynthetic pathways of talaronoids A–D 22–25 [80].

Scheme 4

Hypothetical biosynthetic pathways for alterbrassicene A 47 and alterbrassicicene A 48 [78,98].

Scheme 5

(A) Biosynthetic gene clusters of the brassicicenes in P. fijiensis and A. brassicicola; (B) proposed biosynthetic pathway for brassicicenes (dashed arrows are those deduced from expected protein function) [117].

Scheme 6

Mechanistic hypothesis for the cyclization of GGPP to myrothec-15(17)-en-7-ol 86 and myrotheca-7,15(17)-diene 87 [118].

Figure 4

The evolutionary analysis tree constructed with selected fungi producing guanacastane diterpenoids. The evolutionary analysis was reconstructed by the maximum likelihood method from the ITS sequences as follows: Coprinus heptemerus D99052 (JN159553.1), Coprinus radians M65 (HM045514.1), Coprinus plicatilis 82 (Parasola plicatilis) (FM163216.1), Psathyrella candolleana (MF401519.1), Cercospora sp. (KF577929.1), and Verticillium dahlia (HQ839784.1). Since the ITS sequence of Cortinarius pyromyxa was not available, Cortinarius misermontii (NR_130230.1) was selected since their ITS sequences were the most similarly. The evolutionary analysis was conducted in MEGA X (version 10.2.2) [64].

Scheme 7

Biosynthetic mechanism to harziene and taxadiene scaffolds [151,152].

Scheme 8

Proposed biosynthetic pathway of phomopsene 190 and methyl phomopsenonate 191 [164].

Scheme 9

Proposed cyclization mechanism catalyzed by PaPS [165].

Scheme 10

Proposed biosynthetic pathway to pleuromutilin 192 in Clitopilus passeckerianus [180].

Scheme 11

The biosynthetic pathway for sordarin 195 and hypoxysordarin 197 [114].

Scheme 12

Proposed biosynthetic pathway for psathyrins A 216 and B 217 [201].

Scheme 13

Plausible biogenetic origin of eryngiolide A 223 [203].

Scheme 14

Incorporation patterns of [1-¹³C]-, [2-¹³C]-, and [1,2-¹³C₂]-acetates enriched wickerol B 226, and proposed mechanism of cyclization from GGPP to wickerols [206].