Histidine pilocarpine

L-histidine Imidazole alkaloids Imidazole Histamine Pilocarpine Pilosine... 

The basic alkaloid in Pilocarpus jaborandi (Rutaceae) is pilocarpine, a molecule of which contains an imidazole nucleus and is also used as a clinical drug. During alkaloid synthesis, L-histidine can produce the manzamine nucleus (Figure 27). These alkaloids are quite widespread, though they were first isolated in the late 1980s in marine sponges. They have an unusual polycyclic system and a very broad range of bioactivities. Common alkaloids with this nucleus include manzamine A, manzamine B, manzamine X, manzamine Y, sextomanzamine A and so on. 

Jaborandi leaves (Pilocarpus microphyllus and P. jaborandi Rutaceae) are also probably derived from histidine, but experimental data are lacking. Jaborandi leaves contain primarily pilocarpine and pilosine (Figure 6.112). Pilocarpine is valuable in... 

A stereoselective synthesis of (+)-pilocarpine (7) starting from L-histidine (2) has been worked out by Noordam et al. (88 - 90). Use was made of the S configuration of the amino acid, which is the same as that of C-3 of the lactone ring in both (+)-pilocarpine and (+)-isopilocarpine. Furthermore, regioselective N-alkylation reactions of the imidazole nucleus of histidine had been developed by Beyerman et al. (29,91). Schemes 3 and 4 depict the different ways of the regioselective alkylations. For the synthesis of pilocarpine, the N7I-methylation has been performed via Nb-protection with the 4-nitrobenzenesulfonyl group, instead of the benzoyl group (29). 

Boit (97) and Leete (98) suggested that in the biogenesis of pilocarpine, the imidazole compound 47 reacts with acetylacetic acid (48). It should be remarked that the phosphate of 47 is assumed to be an intermediate in the biogenesis of histidine. The reaction between the methylene group in 48 and... 

The biosynthesis of pilocarpine in Pilocarpus pennatifolius was studied by the administration of radiolabeled precursors. Radioactive sodium acetate, histidine, histidinol, methionine, and threonine were administered by the cut-stem method. Histidine, methionine, and threonine were administered together by a wick inserted through the stem of an intact plant. Sodium acetate and histidine were fed to root cuttings by suspending the roots in aqueous solutions of the precursors. After 64 - 7 5 h, the roots were harvested and total alkaloid extracts made. These extracts were then fed to stem cuttings. 

Histidine is a precursor of a very limited number of alkaloids. The most well-known is pilocarpine from Pilocarpus jaborandi. The plant was formerly used as a truth serum (diaphoretic activity), and the alkaloid is used to counter the mydriatic effects of atropine. 

This group of alkaloids is an exception in the transformation process of structures, because the imidazole nucleus is already made at the stage of the precursor. The a of these alkaloids is L-histidine, and the first A is developed in a decarboxylation process by histidine decarboxylase (HDC). The histamine is a product of this reaction (Figure 2.38). Other alkaloids from this group include, for example, dolichotheline, pilocarpine, and pilosine. 

Only a very limited number of alkaloids derived from histidine are known. As an example of these alkaloids, (+)-pilocarpine is described in this chapter, as well as histamine. Alkaloids derived from histidine are also called imidazole alkaloids because of the imidazole nucleus in the histidine skeleton. 

Pilocarpine possesses an imidazole nucleus and the biosynthesis of this alkaloid is regarded as beginning with histidine, although the details are lacking. 

Several alkaloids derived from histidine occur in plants. Probably the best known of these is pilocarpine (5), found in species of Pilocarpus (Rutaceae) (Fig. 37.2). This compound is a peripheral stimulant of the parasympathetic system and is used topically as a myotic to counteract the mydriatic effects of atropine and other parasympatholytic drugs. Pilocarpine is used for the treatment of glaucoma (as a 0.5-10% solution). 

Pilocarpine has been suggested to arise from condensation of an alcohol involved in the biosynthesis of histidine (as the phosphate) and acetoacetate (Fig. 37,2). A second path has also been suggested. There is little experimental evidence to establish either pathway (Maat and Beyerman, 1983). 

Imidazole alkaloids alkaloids of sporadic occurrence, possessing the imidazole ring system. Tlieir most important representative is Pilocarpine (see). The biosynthesis of the I. a. is coupled to histidine metabolism. 

Histamine possesses hormone activity in animals (E 3.1) and acts as a neurotransmitter (E 3.2). It is a plant feeding deterrent present, for instance, in nettle toxin (E 5.5.3). Also the alkaloid pilocarpine has strong physiological activity in vertebrates and deters potential predators (E 5.5.3). It is used as a cholinergic drug in medicine (F 2). Urocanic acid, hydantoin propionic acid, imidazoleacetic acid riboside, 1-methylhistidine, 1-methylimidazoleacetic acid and other imidazole derivatives are involved in the removal of L-histidine and histamine residues from the organism of animals. They are found in the urine. Urocanic acid is also a constituent of sweat (E 1). It is involved in the protection of skin to UV radiation (E 2.2). 

L-Histidine derivatives Pilocarpine (D 20) Cholinergic, used in ophthalmo-logy... 

Alkaloids Derived from Histidine Imidazole C (Pilocarpine, Pilosine)... 

This is undoubtedly the most important class of L-histidine derivatives only because of pilocarpine s (27) therapeutic uses [8, 23, 24]. Since Byasson s first report of jaborandi alkaloids isolation from the leaves of Pilocarpus spp. (Rutaceae) [8], in 1875, several other imidazole alkaloids have been reported in this genus. The identification of these was facilitated due to recent advances in hyphenated chromatographic techniques such as HPLC—ESI—MS/MS (high performance liquid chromatography with electrospray ionization tandem mass spectrometry). 

The amino acid L-histidine is the assumed building block in the biosynthesis of pilocarpine (27) and other imidazolic alkaloids due to the presence of glyoxaline ring [8, 23]. First attempts to clarify this pathway were proposed by Boit and Leete that considered the phosphate derivative of 2-oxo-3-(5-imidazofyl)-propanol, also known as imidazole pyruvic acid, as imidazole ring precursor (Scheme 25.1-Pathway 1) [8]. This initial biosynthesis proposal was improved detailing the lactone ring formation by aldol condensation. Another biosynthetic approach suggested condensation of 2-oxobutyric acid (lactone moiety) with urocanic acid (imidazole moiety) (Scheme 25.1- Pathway 2) [8, 39]. 

Isotopic studies with labeled potential precursors such as sodium acetate- " C, threonine- C, histidine- " C, histidinol- " C, and L-methionine-(S-methyl- " C) were carried out with P. pennatifolius in an attempt to prove the proposed pathways [8, 39]. Only the methylation of pilocarpidine, last step in both mechanisms, was attested by significant incorporation of radioactivity in the methyl group attached to the imidazole nucleus. This data confirmed an important assumption, the one that considers methionine the biological source of the A -methyl group of pilocarpine. Also, one should consider that these radiolabeled studies were carried out with stems, no other parts of the plant were analyzed, and thus some other site involved in biosynthesis was not considered in this study. 

The presence of the enzyme histidine aminotransferase, (HT) (EC 2.6.1.38) was reported in P. pennatifolius roots [40], which could link L-histidine to imidazole alkaloids biosynthesis and reinforce the hypothesis of a specific site for pilocarpine production. The enzyme activity was estimated in 46.09 nKat.mg of protein and optimal reaction at pH 8-9. HPLC data from enzymatic reaction indicated the formation of a product with the same retention time of the imidazole pyruvic acid standard obtained by synthesis. Such an enzyme activity could not be detected in P. pennatifolius leaves, reinforcing these organs could be involved only in the later steps of the biosynthesis, such as iV-methylation, or could play a role as accumulation site and not in the productimi. 

In P. microphyllus model, callus were also subjected to conditions and elicitors in an MS-liquid medium supplemented with 2,4-D as growth regulator [54]. Different nutrient concentration, pH value, type/concentration of elicitors (histidine, threonine and methyl jasmonic acid), and osmotic and salt stress (PEG and NaCl) were evaluated. Light incidence influence was also analyzed. Pilocarpine was released in the liquid medium from callus kept in the dark. Detection was carried out using HPLC-MS/MS techniques, and pilocarpine quantification was performed by HPLC. Elicitors induced highest accumulation of the alkaloid in a time/concentration relationship. Light incidence and methyl jasmonic acid inhibited pilocarpine release to the medium. 

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