Trichoderma viride, gliotoxin

Gliotoxiii.—In contrast to the recent report that the cyclic dipeptide (121) is not incorporated into gliotoxin (123) in Penicillium terlikowskii, it has recently been found that this cyclic dipeptide, with both constituent amino-acids labelled, is efficiently incorporated into gliotoxin (123) in Trichoderma viride and without alteration in isotope ratio. Thus, (123), like brevianamide A and echinulin, originates from a cyclic dipeptide. The difference in the two results could be due to the different organisms used in the two experiments, but is was suggested that the probable reason was associated with the large excess of (121) used in the first experiment. 

Several naturally occurring organosulfur compounds show pesticidal activity examples include nereistoxin (77), isolated from the marine worm Lumbriconereis heteropoda, which is insecticidal, and the antifungal antibiotic gliotoxin (78) (Figure 10), produced by the soil fungus Trichoderma viride. 

Gliotoxin (6) is present in the metabolites of many fungi, such as Trichoderma viride, Gliocladium flbriatum, Aspergillus fumigatus an several Penicillium spp. (Brian and Hemming, 1946). It is a fairly stable compound of composition, 2,3,5a,6-tetrahydro-6-hydroxy-3-hydroxymethyl-2-methyI- lOH-3,1 Oa-epidithiopyrazino-[l,2-a]-indoI-l,4-dion (Bell et al., 1958). 

We have therefore focussed our attention on Trichoderma viride. When someone discovers a better source or a superior cellulase, we will gladly transfer our allegiance. The results reported in this paper were obtained with the Army Quartermaster Strain QM 6a. This strain does not produce gliotoxin (38). We have tested over one hundred other strains of Trichoderma viride and closely related organisms. Most appear to produce a similar cellulase complex (Table III), but in lesser amounts. 

Gliotoxin.—Gliotoxin (46) is a metabolite of Trichoderma viride and Penicillium terlikowskii. Recently, phenylalanine but not w-tyrosine (in contrast to earlier work ) or o-tyrosine or 2,3-dihydroxyphenylalanine has been shown to be incorporated. The incorporation was sufficiently high to allow the use of... 

Fur Gliotoxin (CVIII) ist in Trichoderma viride der in Schema 17 wiedergegebene Biosyntheseweg bewiesen worden (316, 350. ... 

Gliotoxin.—cyc/o-(L-Phenylalanyl-L-seryl) (121) has been observed to be an intact and efficient precursor for gliotoxin (122) in Trichoderma viride. This has been confirmed in further experiments with (121) and its three stereoisomers. Only (121) was incorporated at all efficiently (at least forty times better than the others) it was also proved to be utilized intact. Moreover, (121) was formed from labelled phenylalanine in growing cultures. It follows that (121) is either an intermediate in gliotoxin biosynthesis, or is reversibly converted into an intermediate on the pathway. The biosynthesis of gliotoxin has been reviewed. 

In addition to the penicillins, a number of antibiotics produced by fungi have structures that could arise from the condensation of two or three amino acids. For example, gliotoxin, which is formed by Trichoderma viride and Aspergillus fumigatus, may be regarded as an anhydrodipeptide containing the skeletons of phenylalanine and serine, as shown by the broken line in XXXII. 

Suhadolnik and Chenoweth (1958) were the first to demonstrate that phenylalanine (4 R = H), rather than tryptophan (5), provides the reduced indole nucleus of gliotoxin (1). Both dl- I- C]- and DL-[2- C]phenyla-lanine were incorporated efficiently (4-12%) into gliotoxin in cultures of Trichoderma viride. In contrast, no incorporation of DL-[7a- " C]tryptophan was observed, although this amino acid was taken up from the culture medium and radioactivity appeared in the mycelium. Degradation (Fig. 1) of gliotoxin derived from DL-[l- C]phenylalanine showed that radioactivity resided largely (82%) at position 1, suggesting that the carbon skeleton of the amino acid had been incorporated intact this conclusion has been amply confirmed by later work (see below). 

Gliotoxin is a highly anti-fungal and anti-bacterial metabolite of several Glio-cladium and Trichoderma species such as T. viride as well as Aspergillus... 

---