Pipecolic acid, from lysine

L-Pipecolic acid, a key component of many antibiotic and anticancer biomolecules, serves as an important chiral pharmaceutical intermediate. We have developed an enzyme-coupled system consisting of zl -piperidine-2-carboxylate reductase (Pip2C) from Pseudomonas putida, glucose dehydrogenase (GDH) from Bacillus subtilis, and L-lysine a-oxidase from Trichoderma viride, affording L-pipecolic acid from L-lysine in high yield with an excellent enantioselectivity (Figure 10.2). ... 

Plpecolic Acid. 2-Piperidinecarboxylic acid pipe-colinic acid hexahydropicolinic acid homoproline dihydro-baikiaine. CtH,N02 mol wt 129.16. C 55.79%, H 8.58%, N 10.85%, O 24,78%. The /-form occurs in plants Phillips, Chem. A Ind. (London) 1953, 127. Prepn A. Ladenburg, Ber. 24, 640 (1891) Stevens, Ellman, J. Biol. Chem. 182, 75 (1950) V. Asher et ai, Tetrahedron Letters 22, 141 (1981). Synthesis of E-pipecolic acid from l-lysine Fujii, Miyoshi, Bull. Chem. Soc. Japan 48, 1341 (1975). 

In rat liver preparations no formation of 5-aminovalerate from C -pipecolic acid or lysine-6-C could be detected in the author s laboratory 160). An unknown compound that was difficult to separate chromato-graphically from 5-aminovalerate was observed. The results surest that a pathway of lysine metabolism through 6-aminovaleric acid may occur in certain bacteria but not in the mammalian organism. This has been supported by new data from the laboratory of M. Suda 167a). 

Formation of Pipecolic Acid from o-Lysine.—Gilbertson has compared the... 

The a is L-lysine, as in the case of piperidine, but the f3 is different. The /3 is a-aminoadipic acid 6-semialdehyde. The q> is L-pipecolic acid, which is synthesized in plants from piperideine-6-carboxylic acid. In the case of many other organisms, the obligatory intermedia (q>) is derived from the /3. The

ring structure. The indolizidine nucleus will be formed only in the synthesis of the x- The deep structmal change occms when

Claisen reaction with acetyl or malonyl CoA (Cra/mCoA) and the ring closme process (by amide or imine) to 1-indolizidinone, which is the x- The second obligatory intermedia ( k ) only has the indolizidine nucleus. 

Slaframine.—Slaframine (37) is produced by the phytopathogen Rhizoctonia leguminicola. It has been known for some time that (37) derives in part from lysine via pipecolic acid (33), which is incorporated intact the earliest bicyclic intermediate identified is (38) (c/. Vol. 5, p. 9 and ref. 2). New results have shown that the two skeletal carbons in (37), and also in the metabolite (36), not accounted for by pipecolic acid, derive from malonate (and acetate).13 The labelling of (37) by, in particular, [2-2H2]acetate was deduced to be of C-2 on the basis of mass spectral evidence (which is not entirely convincing). The acyl-CoA derivative (34) has been suggested as an intermediate in the biosynthesis of (37) and also of (36). It is to be noted that condensation between malonyl-CoA and pipecolic acid (33) to give (34) must be simultaneous with decarboxylation of malonyl-CoA, since two deuterium atoms of acetate are retained at C-2 in (37) (later intermediates with a double-bond to C-2 are also excluded by these results). 

The chirality of a precursor product relationship was determined by the use of doubly labeled lysine, in which one enantiomer was labeled only with tritium and the other with tritium and 14C (55). Comparison of the 3H/14C ratios of substrate and products demonstrated that decodine and decinine were derived from L-lysine, whereas pipecolic acid (186) was derived from D-lysine. Thus, pipecolic acid does not serve as a precursor of Lythraceae alkaloids (57). 

The biosynthesis of swainsonine was studied in the fungus Rhizoctonia leguminicola The piperidine ring was shown to be derived from lysine via pipecolic acid. A noteworthy... 

Gatto et al m characterized the mechanism of L-pipecolic acid formation by cyclodeaminase RapL from L-lysine within rapamycin biosynthesis, which is a hybrid NRP—polyketide antibiotic (Figure 25(a)). RapL was characterized by biochemical assays to require cofactor nicotinamide adenine dinucleotide (NAD+) and an oxidative cyclodeamination reaction mechanism corresponding to ornithine cyclodeamination was proposed based on ESI-FTMS analysis of RapL reaction products (Figure 25(b)). 

Figure 25 L-Pipecolic acid formation by cyclodeaminase RapL in rapamycin biosynthesis, (a) Rapamycin and incorporated pipecolic acid moiety, (b) Proposed oxidative cyclodeamination mechanism of pipecolic acid formation from L-lysine. (c) RapL activity assays and exact ESI-FTMS analysis of derivatized reaction products revealing mechanistic insights such as a-H retainment and loss of e-N.

The urinary elimination of glutaric acid increases in rats after administration of L-lysine (T15), a fact which is in accordance with the known metabolic route leading from lysine to glutaric acid via pipecolic acid (R8) (Fig. 5). Another intermediate of that metabolic sequence, a-keto-adipic acid, is foimd in urine after administration of lysine to the rat, the amount representing about 2 % of that of the administered L-lysine... 

Since a-amino-acids serve as starting materials for the synthesis of protein and the elaboration of many plant alkaloids, there must be a sharing of any amino-acid which is required for both of these activities. The extent to which this happens has been the subject of a new study in one particular plant, Lophophora williamsii, which produces isoquinoline and j8-phenethylamine alkaloids. These bases are derived from the a-amino-acid tyrosine and the results from feeding L-[f/- C]tyrosine indicate that this amino-acid is incorporated into the alkaloids approximately three times more efficiently than into protein. Only the L-isomer was examined and one wonders what the results with D-tyrosine would be in the light of the known preference for particular optical isomers of lysine in pipecolic acid and piperidine alkaloid biosynthesis. 

Chemical conversions of marcfortine to paraherquamides have been achieved [415]. Utilising various soil-derived microorganisms, individual hydroxylation at carbon atoms 5, 10, 12, 14, 15, 16 and 27 has been realized [416] but no improvement on the activity of (244) was observed. A study of the biosynthesis of (244) has shown that it is derived from methionine, tryptophan, lysine and two isoprene units, the latter two being derived from acetic acid. The pipecolic acid moiety arises from lysine via a-ketoglutarate [417]. 

L-Pipecolic acid [as (34)] is derived from o-lysine in several higher plants, - - rats," and the bacterium Pseudomonas putida. In contrast, recent evidence indicates that L-pipecolic acid arises from L-lysine in the mould R. leguminicola D-lysine, it appears, is converted into e-AT-acetyl-lysine. Otherwise the evidence... 

Although amino-acids have been administered to plants on occasions legion in number, rarely has attention been paid to the question of whether there is any selectivity for the D- or L-amino-acid in alkaloid biosynthesis. An exception appears in work on the Amaryllidaceae alkaloids where it was shown that d- and L-tyrosine were equally well utilized in lycorine biosynthesis. The question has now been answered in Nicotiana glauca for the biosynthesis of anabasine (118) and pipecolic acid (113) from lysine. Pipecolic acid was found to be derived preferentially from the D-isomer ( 48 times better), in accord with a similar preference in intact rats and corn seedlings, whereas L-lysine was the more effective precursor ( 30 times) for anabasine. 

These results tie in neatly with others obtained for the biosynthesis of sedamine (117), anabasine (118), and N-methylpelletierine (119) where, it was shown, the pathway differs from that which leads to pipecolic acid. In essence the results show that (117), (118), and (119) derive from lysine without loss of the hydrogens from C-2 and C-6, whereas the genesis of pipecolic acid (113) is with retention of the hydrogens from C-6 and loss of the one from C-2. Further, all these piperidine derivatives arise from lysine without the intermediacy of a symmetrical intermediate. The results may be summarized in terms of the... 

The prevalence of isobutylamine, pyrrolidine and piperidine as the amine component of amides from numerous species of Piper has been noted, and is clearly evident in Tables 1 and 2. In a 1973 paper, Bohlmatm [14] speculated on the biosynthetic origins of the amine moieties of some amides belonging to the same class isolated from Achillea spp. (Compositae). He drew attention to the strong probability that the isobutylamine component, where present, would be derived from valine. He proposed, further, that the piperidine portion of the amide 10(n=4), and other piperidyl amides, is biosynthesized via pipecolic acid (now known to be most commonly derived from D-lysine [13]), and that lysine (configuration unspecified) is the progenitor of the piperideine ring embodied in 14 and 18 [14]. 

Competitive incorporation studies with radiolabeled precursors proved that the pipecolate ring is derived from lysine via free pipecolic acid [244]. 

Nonprotein Amino Acids Derived from Aspartic Acid Lysine-Derived Nonprotein Amino Acids Pipecolic Acid and Related Compounds L-Mimosine Homoserine L-Canavanine Canaline... 

Homoserine (13), threonine (14), isoleucine (15), methionine (16), and cysteine (12) are all derived from aspartic acid (22). Lysine (23) (Fig. 13.1) is derived via 3-aspar-tylsemialdehyde and is, in turn, involved in formation of many nonprotein amino acids such as pipecolic acid (17) and mimosine (18) (Figs. 13.5 and 13.6) (Rosenthal, 1982). D-Lysine is a precursor of L-pipecolic acid in many plants... 

Pipecolic acid (17) can arise from lysine via two distinct mechanisms (Fig. 13.6). This synthesis can occur by a trans-... 

The biosynthesis of slaframine (38) and swainsonine (35) in Rhizoctonia leguminicola involves lysine and proceeds via the intermediacy of pipecolic acid. Carbon atoms 2 and 3 have been demonstrated to come from acetate via malonate (Fig. 30.14). The biosynthesis of swainsonine and related compounds in plants does not appear to have been investigated (Elbein and Molyneux, 1987 Harris et al, 1987 Howard and Michael, 1986). 

L-PIpecolic acid piperidine-2-carboxylic acid, a nonproteogenic amino acid. It is formed from L-ly-sine, either by a-deamination followed by cyclization and reduction, or as a normal intermediate in the degradation of lysine to a-aminoadipic acid. The 4- and 5-hydroxy derivatives of L-P.a. are found especially in mimosas and palms. 

The biosynthesis of marcfortine has been investigated at the Pharmada and Upjohn company [37]. Industrial interest in the biosynthesis of marcfortine A, which does not display the potency that paraherquamide A possesses, is presumably due to the report from the Pharmada and Upjohn group demonstrating that marcfortine A can be semi-synthetically converted into paraherquamide A [38]. Kuo et al. found that marcfortine is derived fi-om L-tryptophan (oxindole moiety), L-methionine (via SAM methylation at the y-N C29), L-lysine (pipecolic acid residue), and acetate (isoprene imits) (Scheme 16) [37]. 

These results clearly demonstrate that the isoprene moieties are of mevalo-nate origin. The pipecolic acid moiety, being derived from L-lysine, can arise via two biochemical pathways as shown in Scheme 17. In order to discriminate between these pathways (A andB),Kuo etal.fed individually [a- N]- or [c- N]-L-lysine to a marcfortine A-producing Penicillium strain UC7780 and foimd that... 

Scheme 17. Possible biosynthetic pathways from L-lysine to pipecolic acid [37b]...

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