Chondramides

Many NRPs such as cyclosporin, complestatin, actinomycin, and chondramide contain N-methyl amides. M-Methyl transferase (N-MT) domains utilize S-adenosylmethionine (SAM) as a cofactor to catalyze the transfer of the methyl group from SAM to the a-amine of an aminoacyl-S-PCP substrate. The presence of M-methylamides in NRPs is believed to protect the peptide from proteolysis. Interestingly, N-MT domains are incorporated into the A domains of C-A-MT-PCP modules, between two of the core motifs (A8 and A9). MT domains contain three sequence motifs important for catalysis. ° 0-Methyl transferase domains are also found in NRPSs and likewise use the SAM cofactor. For instance, cryptophycin and anabaenopeptilide synthetases contain 0-MT domains for the methylation of tyrosine side chains. These 0-MT domains lack one of the three core motifs described for N-MT domains. ... 

Kunze B, Jansen R, Sasse F, Hofle G, Reichenbach (1995) Chondramides A-D, New Antifungal and Cytostatic Depsipeptides from Chondromyces crocatus (Myxobacteria). Production, Physico-Chemical and Biological Properties. J Antibiot 48 1262... 

Sasse F, Kunze B, Gronewold TMA, Reichenbach H (1998) The Chondramides Cytostatic Agents from Myxobacteria Acting on the Actin Cytoskeleton. J Natl Cancer Inst 90 1559... 

Proteobacteria, Myxobacteria Chondromyces crocatus (chondramides A—D) [90]. F Basidiomycota Cortinarius violaceusa [5]. P Acanthaceae Aphelandra spp. (aphel-andrine, orantine [102]) Veronicaceae Chaenorhinum sp. [(S)-/ -Tyr chaenorhine, chaenorpine] [103]. 

Tyr substructures are, moreover, found within several peptidic antibiotics, for example the edeines 57 from Bacillus brevis, or within cyclodepsipeptides that have been isolated from marine sponges, for example jaspamides A-C 59 [106] or geo-diamolides H-I 58 [107] (Scheme 1.5.9). The chondramides 60 are closely related antibiotics that have been obtained from the myxobacterium Chondromyces croca-tus. Within the edeine biosynthesis D-/ -Tyr 9 seems to be a real precursor [89]. The biosynthesis of the jaspamides, the geodiamolides, or the chondramides has not yet been investigated. 

Figure 14 Biosynthesis of PKS-NRPS hybrid compounds in myxobacteria (b). Biosynthesis of chondramide D (34) in Chondromyces crocatus Cm c5. The DH domain from module 1 (marked with an asterisk) is most likely inactive. During the assembly of the chondramide backbone, an unusual extender unit - a /3-amino acid - is incorporated by NRPS module 6. The precursor is generated by the tyrosine amino mutase (TAM) CmdF, which converts L-tyrosine into R-/3-tyrosine (see box). The function of the terminal phosphoenolpyruvate synthase (PEP) domain is still unknown. Macrocyclization catalyzed by the TE domain yields chondramide C (40), which can be further transformed to the chlorinated derivative chondramide D (34). The halogenation process catalyzed by CmdE may also take place on the assembly line intermediate.

Chondramides Cytotoxic, antifungal inhibits actin polymerization... 

Kunze, B., Jansen, R., Reichenbach, H., and Hofle, G. (1996) Chondramides A-D, new cytostatic and antifungal cyclodepsipeptides from Chondromyces crocatus (myxobacteria) Isolation and structure elucidation. Liebigs Ann. Chem., 1996 (2), 285-290. 

Rachid S, Krug D, Kunze B, Kochems I, Scharfe M, Zabriskie TM, Blocker H, Mueller R. Molecular and biochemical studies of chondramide formation-highly cytotoxic natural products from Chondromyces crocatus cm c5. Chem. Biol. 2006 13 667-681. 

Schmauder, A., Muller, S., and Maier, M.E. (2008) Concise route to defined stereoisomers of the hydroxy acid of the chondramides. Tetrahedron, 64, 6263-6269. 

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