Biosynthesis Of Alkaloids From Chaetomium Globosum

Microbes and plants produce a multitude of unpredictably structured small organic molecules known as secondary metabolites (natural products), from which more than half of globally marketed drugs has been developed.Chaetomium globosum, an endophyte capable of producing various valuable natural products, has been paid more and more attention since the development of genome mining and combinational biosynthesis.Nine novel halogenated chaetoglobosins were isolated and characterized from endophytic C. globosum 1C51 using precursor-directed biosynthesis. The significant immunosuppressive bioactivities of these "unnatural" alkaloids were also reported. The Pictet-Spengler (PS) reaction constructs a diverse collection of plant alkaloids (such as morphine, camptothecin and reserpine) by condensing β-arylethylamines with aldehydes, but nothing is known concerning the PS reaction in the fungal kingdom. The marine derived fungus C. globosum has a Pictet-Spenglerase (STR) gene which remains silent (produces no PS products). Here,1-methyl-L-tryptophan (1-MT) has been found to be an STR gene up-regulator and STR substrate which condenses with flavipin (fungal aldehyde) in a region-specific manner to form skeletally unprecedented alkaloids.1-MT-fed cultivation of C. globosum afforded fourteen novel indole alkaloids featuring collectively seven unprecedented skeletons. Their structures were elucidated by a combination of spectroscopic methods, isotope-labeling experiments and single crystal X-ray (Cu Ka) diffraction analysis. Compound 5 and 11 were demonstrated to be antibacterial against the clinical strains Veillonella parvula, Streptococcus sp., Bacteroides vulgatus and Peptostreptococcus sp. with MICs ranging from 0.24 to 0.66μM. In addition, compound 11 also inhibited acetylcholinesterase (AChE) with IC50 value of 4.13μM. Biosynthetic pathways of some new compounds were proposed based on 13C-labeling experiments.Furthermore, recent studies of the precursor-directed biosynthesis were reviewed briefly.