Adda, -3 amino-9 methoxy

ADDA = 3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid... 

These two families of toxins are both eyclic peptides (Figure 27.1 A and B), with the same basie eyclic structure involving an amino acid known as ADDA (3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid), and four (nodularins) or six (microcystins) other amino acids (Chorus and Bartram, 1999). Only six nodularins have so far been identified. In eontrast, mieroeystins have two variable amino acids (X and Z), two groups (Rl, R2) and two demethylated positions (3 and 7), and as a result there are more than 80 known mieroeystins, ranging in molecular weight from 800 to 1,100 daltons. 

Microcystins have a cyclic heptapeptide structure (Figure 31.1). More than 80 naturally occurring structural variants have been described (Welker and Von Dohren, 2006). Six amino acids, including four nonprotein amino acids and two protein amino acids, form a ring structure. One nonprotein amino acid, referred to as ADDA (3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca 4,6-dienoic acid), forms a side chain. The ADDA side chain... 

Figure 7.26 The structure of the hepatotoxic cyclic heptapeptide microcystin LR. L-Arginine and L-leucine are variable amino acids. The reactive unsaturated group is indicated by the star. Abbreviations Adda, amino-methoxy-trimethyl-phenyl-decadienoic acid Mdha, methyldehydro-alanine Masp, methyl D-/so-aspartate D-Glu, D-/soglutamate D-Ala, D-alanine.

These natural toxins are heptapeptides produced by cyanobacteria, which are associated with algal blooms. These substances are a hazard to wild and farm animals and sometimes humans who come in contact with contaminated water. There are a number of these toxins, some of which such as microcystin LR are hepatotoxic, causing damage to both hepatocytes and endothelial cells. The toxins have some unusual structural features, incorporating three D-amino acids and two very unusual ones, namely, methyldehydro alanine (Mdha) and amino-methoxy-trimethyl-phenyl-decadi-enoic acid (Adda) (Fig. 7.26). 

S,4S,5 E,7E)-3-Amino-4-hydroxy-6-methyl-8-(4-bromophenyl)-octa-5,7-dienoic acid [Aboa = Br-Ahmp, Br-Apoa], (2S,3S,8S,9S)-3-Amino-9-methoxy-2,6,8-trimethyl-10-phenyl-deca-4,6-dienoic acid (Adda). 3-Amino-2,4-dimethylpentanoic acid (Admpa). (2S,3R,5S)-3-amino-2,5,9-trihydroxy-10-phenyldecanoic acid (Ahda). j3-Aminoisobutyric acid (jS-AiB). (3S,4S,5E,7E)-3-Amino-4-hydroxy-6-methyl-8-phenylocta-5,7-dienoic acid [Ahmp (Faulkner) or Apoa (Fusetani)]. (2S,3R,5R)-3-Amino-2,5-dihydroxy-8-phenyloctanoic acid (Ahoa). 3-Aminopentanoic acid (Apa /5-Apa). (2R,3R)-3-Amino-2-methylbutanoic add (Amba). 3-Amino-2-methylhexanoic acid (Amha). 3-Amino-2-methyl-7-octynoic add (Amoa, Amoya). 3-Amino-7-octynoic add (Aoya). (2S,3R)-3-Amino-2-methylpentanoic acid (Map). http // www.ncbi.nlm.nih.gov/ Taxonomy/ tax.html... 

The C20 amino acid (2.V,3.S, 8.S, 9.S, 4/ , 6 )-3-amino-9-methoxy-2,6,8-tri-methyl-10-phenyldeca-4,6-dienoic acid (Adda 19) is a molecule of interest to biologists and organic chemists as a component of the hepatotoxic cyclic peptides called microcystins. Kim and Toogood used Ireland-Claisen rearrangement in their successful synthesis of Adda8 (Scheme 1.3h). The ester 20 underwent highly diastereoselective Ireland-Claisen rearrangement to provide the acid 21. Conversion of this acid to the phosphonium bromide 22 was achieved in nine... 

One of the invariant amino acids is a unique P-amino acid called Adda (2S,3S,8S,9S)-3 amino-9 methoxy-2,6,8-trimethyl-10-phei5fldeca-4,6-dienoic acid is the most unusual structure in this group of cyanobacterial cyclic peptide toxins). A two-letter suffix (XY) is ascribed to each individual toxin to denote the two variant amino acids (Carmichael 1988). X is commonly leucine, arginine, or tyrosine. Y is arginine, alanine, or methionine. Variants of all the invarianf amino acids have now been reported, e.g., desmethyl amino acids and/or replacement of the 9-methoxy group of Adda by an acetyl moiety. Currently there are in excess of 60 variants of microcystin that have been characterized (Rinehart 1994 Sivonen and Jones 1999). Of these 60 compounds, microcystin-LR would appear to be the microcystin most commonly found in cyanobacteria. It is also common for more than one microcystin to be found in a particular strain of cyanobacterium (Namikoshi 1992 Lawton 1995). The microcystin variants may also differ in toxicity (Carmichael 1993). The literature indicates that hepatotoxic blooms ofM aeruginosa containing microcystins occur commonly worldwide. 

The most important of the peptidic phosphatase inhibitors are the microcystins and nodularin. Mycrocystins are heptapeptides characterised by the sequence cyclo(D-Ala-X-D-e/7t/i/ o-P-methylisoAsp-Y-Adda-D-isoGlu-iV-methyldehydroAla), where X and Y are different L-aminoacids, and Adda is the abbreviation of the P-aminoacid [25,35,85,95]-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4(E),6(E)-dienoic acid. In the most common microcystin, namely microcystin-LR, X is Leu and Y is Arg. This kind of compounds was considered to be the highly hepatotoxic principle of the cyanobacteria genera Microcystis, Artabaena and Oscillatoria. Apart Jfrom the variations represented by X and Y, other differences arising jfrom the demethylation of aminoacids, lead to the existence to more than fifty microcystins. The rare acid Adda is also... 

Adda — (2 5, 35, 85, 95)-3-Amino-9-methoxy-trimethyl- 10-phenyl-4,6-decadienoic acid... 

Figure 39.1a shows the generic structure of microcystins (MC), with the two most variable positions marked by X and Z. The numbering of the individual positions was done before the elucidation of the biosynthetical pathway and is arbitrary (see below). MCs are cyclic heptapeptides with several structural peculiarities. The moiety characteristic of microcystins and nodularins is the Adda, abbreviated for 3-amino-9-methoxy-2,6,8,-trimethyl-10-phenyl-4,6-decadienoic acid, a P-amino acid that is not known from other natural products. Further peculiarities of the molecule are o-amino acids. These stereoisomers of commonly occurring L-amino acids are not found in ribosomally synthesized proteins and peptides and are therefore called nonproteinogenic amino acids. A-methyl-dehydroalanine (Mdha) in position 7 also is a nonproteinogenic amino acid as it is the case with o-erythro-P-methyl-iso-aspartate (o-MeAsp). 

The first chemical stractures of cyanobacterial cyclic peptide toxins were identified in the early 1980s and the number of fully characterized toxin variants has greatly increased since the 1990s. To-date there are 77 different microcystins isolated from cyanobacteria (Table 40.3). The first such compounds found in freshwater cyanobacteria were cyclic heptapeptides with the general stracture of cyclo-(D-alanine -X -D-MeAsp -Z" -Adda -D-Glutamate -Mdha ) in which X and Z are variable amino acids, o-MeAsp is D-eryt/jro-p-methylaspartic acid, and Mdha is A-methyldehydroalanine (Eigure 40.1a). The amino acid Adda, (2S, 3S, 8S, 9S)-3-amino-9-methoxy-2,6,8- trimethyl-10-phenyldeca-4,6-dienoic acid, is the most unusual structural moiety in... 

Figure 1. Structure of the blue-green algal toxin microcystin-LR. Besides the two variable L-amino acids, leucine and arginine, the microcystin contains three D-amino acids (glutamic acid, alanine and methylaspartic acid) and two unusual amino acids, N-methyl-dehydroalanine (Mdha) and 3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-deca-4,6-dienoic acid (Adda) (see Ref. 4).

Ala), where X and Z represent two variable L-amino acids, and Adda stands for 3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid. The main differences in variants are based on different variable amino acids in positions 2 and 4 of heptapeptide. Most commonly occurring MC contain leucine (L) and arginine (R) or tyrosine (Y), and their names are abbreviated as MC-LR, MC-RR, and MC-YR, respectively. Microcystins with different stmcture of Adda (in position 5), such as stereoisomers or 9-(9-desmethyl-Adda, were also identified. Production of MC by cyanobacteria depends on different factors such as intensity and wavelength of light, temperature, pH, concentration of nutrients such as phosphoms and nitrogen. Their synthesis is an energy (ATP)-dependent process that can be also affected by the presence of some trace metals. Reported occurrences of most common MC in different environmental samples, where different MC are produced by different cyanobacteria are shown in Table 1. ... 

Microcystins are cyclic heptapeptides that share a general structure, as shown in Fig. 1 and Table 1, containing g-hnked D-glutamicacid (d-G1u), D-alanine (d-Ala), p-linked D-erythro-b-methylaspartic acid (d-MeAsp), iV-methyldehydroalanine (Mdha), and a unique C20 p-amino acid, (25,35, 85, 95)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4( ), 6( )-dienoic acid (Adda). The other two t. -amino acids are variable (denoted X and Z) and are found in positions 2 and 4 of the cyclic structure. The single-letter abbreviation of the variable amino acids is used to distinguish different microcystins for example, the most commonly occurring microcystin... 

The part of the molecule inside the dotted box, which is common to all of the microcystins, is 3(S)-amino-9(S)-methoxy-2(S),6,8(S)-trimethyl-10-phenyl-4,6-decadienoic acid, usually known as Adda. The most widespread microcystins are as follows microcystin-LA, -LR, -RR, -YA, -YM, and -YR, but there are many others (Namikoshi et al, 1995). An article on the toxicology of microcystins was published by Dawson in 1998, and some microcystins have been characterized from Antarctic cyanobacterial mats (Jungblut et al, 2006). For the detection of microcystins in cells and water, see Lawton, Edwards, and Codd, 1994 Lawton and Edwards, 2008 Lawton et al, 2010. 

Beatty, M.F., Jennings-White, C., and Avery, MA. (1992) Stereo-controlled synthesis of (2S,3S,8S,9S,4E,6 )-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic add (Adda), the amino add characteristic of microcystins and nodularin. J. Chem. Soc. Perkin Trans. 1,1637-1641. 

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