User:Ixiaohoui/Brevianamide a and b

h3. Introduction

Brevianamide A/B are non-ribosomal glycopeptides produced as secondary metabolites in the Penicillum and Aspergillus sp. fungi [7]. Structurally similiar to paraherquamides, they encompass a small class of indole alkaloids that ontain a bicyblo[2.2.2]diazoctan ring system [2]. One of the major secondary metabolites in Penicillum spores, they are responsible for inflammatory response in lung cells [4].

h3. Compound Information

1H\- cyclopent(f)indolizine-\- 7 (8H),2'\- (2H)indole)-3',5,10(1'H)\- \\ trione,-2,3,8a,9 - tetrahydro - 8,8 - dimethyl\- ,(2'S,5aR,8aS,9aR)\- \\ | | Systematic (IUPAC name) - Spiro(5H,6H-5a,9a-(iminomethano) \\ 1H\- cyclopent(f)indolizine\- 7(8H),2'\- (2H)indole)\- 3',5,10(1'H)\- \\ trione,\- 2,3,8a,9\- tetrahydro8,8\- dimethyl \-, (2'S,5aR,8aS,9aR)\- |
 * ( + ) Brevianamide A \\ || || ( - ) Brevianamide B ||
 * Systematic (IUPAC name) - Spiro(5H,6H-5a,9a-(iminomethano) \\
 * Chemical Formula: C21H23N3O3   \\ | | Chemical Formula: C21H23N3O3 |
 * Molecular Weight: 365.43 | | Molecular Weight: 365.43 |
 * Elemental Analysis: C, 69.02; H, 6.34; N, 11.50; O, 13.13 \\ | | Elemental Analysis: C, 69.02; H, 6.34; N, 11.50; O, 13.13 |
 * CAS Registry #: 23402-09-7 \\ | | CAS Registry #: 25163-93-6 \\ |

h3. History

Originally isolated from _Pennicillum compactum_ in 1969, Brevianamide A has shown insecticidal activity [6\][7]. Further studies showed that a minor secondary metabolite, Brevianamide B, has an epimeric center at the spiro-y-indoxyl quaternary center. Both were found to fluoresce under long-wave ultraviolet radiation [3]. Furthermore, under irradaton, Brevianamide A has been shown to isomerize to it's B isomer.

h3. Biosynthesis

While the biosynthesis has not been conclusively elucidated, Brevianamide A and B are a group of indole alkaloids that are constructed from tryptophan, proline, and isoprene unit, with the isoprene unit derived from a typical mevalonate pathway [1]. As part of the nonribosomal peptide synthesis (NRPS). Afu8g00170, named ftmA, encodes has been determined to encode the NRPS responsible for formation of the L-Trp-L-Pro product [10].

Through a L-Tryptophan-L-Proline phosphodiester reaction with an isoprene unit, deoxyprevianamide is formed [3]. Subsequent studies have proposed several biosynthetic pathways for Brevianamide A/B formation, with the most accepted shown below. It has been speculated that the formation of the bicyclo\[2.2.2\]diazaoctan ring system is formed by a biosynthetic Diels Alder reaction. It has been supported by several derivations that underwent Diels Alder cycloadditions.

Brevianamide B, a stereoisomer of Brevianamide A, can also be formed formed under irradiation, and it's mechanism proposed below [9].

h3. Activity/Toxicity

Tests for antibiotic effectiveness against E. coli, A. fecalis, B. subtilis, S. aureus, P. aeruginosa, were negative. Also, no inhibitory action was shown against _A. niger, A. flavis, P. crustosum, F. graminearum, F. moniliforme, Alternara sp., and Cladosporium sp_. However, some insectidal activity has been shown in one study, possibly showing some use as a insecticide for food crops [7]. However, in mamamalian (mice lung cell) studies, Brevianamide A has shown to induce cytoxicity in cells [4]. Furthermore, ELISA assays showed elevated levels of tissue necrosis factor A (TNF-A), macrophage inflammatory protein-2 (MIP-2), and interleuken-6 (IL-6). Therefore, Brevianamide A may not be a suitable insecticide in food crops.

h3. References


 * 1) Bringmann G, Lang G, Steffens S, Schaumann K. (2004) Petrosifungins A and B, novel cyclodepsipeptides from a sponge-derived strain of Penicillium brevicompactum .Journal of Natural Products, 67 (3), pp 311-315
 * 2) Williams RM, Cox RJ, (2003) Paraherquamides, brevianamides, and asperparalines: laboratory synthesis and biosynthesis. An interim report, ??Acc. Chem. Res.??, 2003, 36 (2), pp 127-139
 * 3) Production, isolation, and preliminary toxicity studies of brevianamide A from cultures of Penicillium viridicatum.Wilson BJ, Yang DT, Harris TM.
 * 4) Thomas G. Rand,1, S. Giles, J. Flemming, J. David Miller, and Eva Puniani (2005). Inflammatory and Cytotoxic Responses in Mouse Lungs Exposed to Purified Toxins from Building Isolated Penicillium brevicompactum Dierckx and P. chrysogenum Thom. Toxicological Sciences 2005 87(1):213-222
 * 5) Robert Michael Williams (2002), "Total Synthesis and Biosynthesis of the Paraherquamides: An Intriguing Story of the Biological Diels-Alder Construction", _Chem. Pharm. Bull._, Vol. *50*, 711-74 (2002)
 * 6) Birch A. J., Wright J. J., J. Chem (1970) Studies in relation to biosynthesis. XLII. The structural elucidation and some aspects of the biosynthesis of the brevianamides-A and \-E. May;26(10):2329-44. Soc. Chem. Commun., 1969, 644---64
 * 7) Paterson, R. R. M.; Simmonds, M. J. S.; Kemmelmeier, C.; Blaney, W. M. (1990) Effects of Brevianamide A, its photolysis product brevianamide D, and ochratoxin A from two _Penicillium_ strains on the insect pests _Spodoptera_ _frugiperda_ and _Heliothis virescens_. _Mycol. Res._ 1990, _94_, 538-542.
 * 8) Maiya, S., Grundmann, A., Li, S. M. & Turner, G. (2006). The fumitremorgin gene cluster of Aspergillus fumigatus: identification of a gene encoding brevianamide F synthetase. ChemBioChem 7, 1062-1069.
 * 9) Birch, A. J., and Wright, J. J. (1970). Studies in relation to Biosynthesis---XLII. The Structural elucidation and some aspects of the biosynthesis of the Brevianamides-A and \-E. Tetrahedron 26, 2329-2344.
 * 10) Shubha Maiya, Alexander Grundmann, Shu-Ming Li, Geoffrey Turner (2006). The Fumitremorgin Gene Cluster of _Aspergillus fumigatus_: Identification of a Gene Encoding Brevianamide F Synthetase. ChemBioChem, 1062-1069