Nicotinic acid ricinine

Experiments performed on the nicotinic acid-ricinine relationship in sterile cultures of R, communis established clearly that (1) the relationship exists, and (2) the metabolism of ricinine can be spared by the presence of higher concentrations of nicotinic acid than normally found in the tissue (Waller and Nakazawa, 1963). This sparing action of nicotinic acid on ricinine utilization suggests a vitamin-alkaloid metabolic relationship not previously found in a plant system. 

Waller, G.R., Nakazawa, K., 1963. Nicotinic acid-ricinine relationship in sterile cultures of Ricinus... 

The pyridine alkaloids anabasine (1), nicotine (2), ricinine (3), nomicotine (4) and trigonelline (5) form an important group of natural products. Thus anabasine (1) is extracted on a large scale in the Soviet Union (56MI20900) and functions as an insecticide with acute and subacute toxicity. Nicotine (2) has been used as an anthelmintic but more widely as an agricultural insecticide, functioning as a contact poison when combined with oleic acid... 

Nicotinic acid undoubtedly provides the basic skeleton for some other alkaloids. Ricinine (Figure 6.35) is a 2-pyridone structure and contains a nitrile grouping, probably formed by dehydration of a nicotinamide derivative. This alkaloid is a toxic constituent of castor oil seeds (Ricinus communis Euphorbiaceae), though the toxicity of the seeds results mainly from the polypeptide ricin (see page 434). Arecoline (Figure 6.36) is found in Betel nuts (Areca catechu Palmae/Arecaceae) and is a tetrahydronicotinic acid derivative. Betel nuts are chewed in India and Asia for the stimulant effect of arecoline. 

The cyanogenic glucoside, acalyphin (Fig. 3.1), found in Acalypha indica, appears to be derived from nicotinic acid metabolism (Nahrstedt et al, 1982). Acalyphin is homologous to four non-cyanogenic 3-cyanopyridones, including ricinine, that have also been isolated from various Acalypheae (Nahrstedt, 1987). 

Azaserine, a glutamine antagonist," is known to inhibit the NAD synthetase reaction in which nicotinic acid adenine dinucleotide is converted into NAD with glutamine or ammonia as the nitrogen donor. ° When azaserine or azaleucine was fed to Ricinus communis plants followed by [6- C]quinolinic acid, a marked decrease in incorporation of radioactivity into ricinine was observed with azaleucine, less so with azaserine." Both azaserine and azaleucine were found also to inhibit the incorporation of [6- " C]quinolinic acid into pyridine nucleotide cycle intermediates [in the case of azaserine the conversion of nicotinic acid dinucleotide into nicotinamide adenine dinucleotide (NAD ) was apparently inhibited]. 

Nicotinic acid is also a biogenetic precursor of ricinine (XCV) 143). By the use of tritiated nicotinic acid-7-i C and tritiated nicotinamide in... 

Ricinine.—Ricinine (49), the alkaloid of castor bean plants, is derived from nicotinic acid (28) and quinolinic acid (48), and its formation is intimately associated with the pyridine nucleotide cycle cf. ref. 6. Quinolinic acid is built from a C3 fragment that is formed from glycerol via glyceraldehyde and a C4 unit that is related to succinic or aspartic acids. A recent investigation has confirmed this pathway for ricinine (49) and indicated that dihydroxyacetone phosphate lies between glycerol and glyceraldehyde (loss of tritium from C-2 of labelled glycerol). ... 

Plants produce various pyridine alkaloids derived from nicotinic acid. Trigonelline, the major component in coffee seeds, and ricinine, the toxic alkaloid produced by Ricinus communis, are formed from nicotinic acid originating from the NAD catabolism [20, 25, 26], Quinolinic acid was found to be an efficient precursor in the biosynthesis of nicotine [27]. 

It was shown that nicotinamide was derived from nicotinic acid, and that nicotinic acid was biosynthesized from aspartic acid and glycerol, as described at the beginning of this chapter. Therefore, ricinine, as in the case of arecoline and nicotinic acid, is also an alkaloid derived from aspartic acid. 

A series of compounds that appear to be derived from nicotinic acid is found in a number of euphorbiaceous plants. Ricinine (49), an alkaloid from Ricinus communis, is derived from nicotinic acid via nicotinamide (50). This alkaloid may occur in quantities as great as 1% of the plant dry weight. A crude enzyme preparation has been isolated that will convert a series of pyridinium salts into ricinine and related compounds (Fig. 28.20) (Fodor and Colasanti, 1985). This alkaloid disappears completely from senescent leaves. Ricinine (49) has an LD50 p.o. of 42 mg/kg in Agelaius (Wink, 1993). 

Ricinin a poisonous pyridine alkaloid from seeds of Ricinus communis. M, 164.17, m.p. 201 °C, b.p.20 170-180°C.R. is an exceptional alkaloid, in that it occurs in only one type of plant and is not accompanied by other alkaloids. It is biosynthesized from nicotinic add biosynthetic precursors of nicotinic acid are as-... 

Succinic acid is incorporated into the 2-, 3- and 7-carbon atoms of ricinine (3-cyano-4-methoxy-l-methyl-2-pyridone). Carbon 1 of succinic acid becomes the nitrUe carbon of ricinine. " Nicotinic acid and nicotinamide are highly incorporated into ricinine, which suggests that these two compounds are closer to ricinine than is succinic acid. Ricinine and nicotine show labeling patterns that are consistent with a pathway where succinic acid or a related dicarboxylic acid is a precursor to nicotinic acid, which is an intermediate in the formation of nicotine and ricinine. The a-carbon of lysine is incorporated into carbon 6 of ricinine and the e-carbon of a-aminoadipic acid is incorporated into carbons 2 and b. " ... 

Figure 4.4a. Specific activity of ricinine in rootless plants fed with [7- K]]nicotinic acid ST—stems ...

In a preliminary experiment, it was shown that [7- C] nicotinic acid was significantly incorporated into both ricinine and N-demethylricinine during the first day of germination, which indicated that alkaloid biosynthesis is one of the earliest metabolic processes initiated with growth and differentiation in R. communis. 

Figure 6.20. Rate of disappearance of [ HJricinine and [8- C]ricinine in castor plants. They were 26 days of age and were at the fifth to sixth nodal stage when the labeled compounds were injected. [ Hjricinine, 9.7 /Ltc/mmol, was dissolved in 200 ix of distilled water and injected in a single plant. [7- K ]Nicotinic acid, 0.108 jumol, with a specific activity of 9.2 mc/mmol was dissolved in 10 of distilled water and injected in a different single plant, o—pHJricinine, —[ Cjricinine, A—ricinine content per plant. The entire plant was used for ricinine isolation (Waller et ai, 1965). Courtesy of the American Society of Plant Physiology.

Figure 6.37. A metabolic grid proposed for the biosynthesis and control of metabolism of ricinine. A1—quinolinic acid A2—nicotinic acid mononucleotide A3—nicotinic acid adenine dinucleotide A4—nicotinamide adenine dinucleotide A5—nicotinamide A6—nicotinic acid A7—nicotinamide mononucleotide B1— AT-demethjiiicinine B2— ricinine Cl— N-methylnicotinic acid and C2— AT-methylnicotinamide. pyridine nucleotide cycle and postulated reaction sequence (Nowacki and Waller 1975a). Courtesy of Pergamon Press, Ltd., copyright 1975.

Ricinus communis.—The specific intermediates between nicotinic acid and ricinine are unknown a reasonable biosynthetic pathway is illustrated in Scheme 10. Robinson and co-workers have obtained a crude enzyme from R. communis seedlings, and resolved it by chromatography on DEAE-cellulose into three components, all of which catalysed the oxidation of 3-cyano-l-methylpyridinium perchlorate (43) to the pyridones (46) and (47). The optimum activity for ail these fractions was between pH 9.S and 10.S. The enzymes were relatively non-specific. All the following pyridinium salts were oxidized 3-formyl-l-methylpyridinium iodide, 3-nitro-l-methylpyridinium iodide, 3-acetyl-l-methylpyridinium iodide, 3-cyano-l-ethylpyridinium iodide, and l-benzyl-3-cyanopyridinium chloride. N-Methylnicotinamide, trigonelline sulphate, 1-methylpyridinium iodide, nicotinic acid, 1-methylquinolinium iodide, and 3-cyanopyridine, were not oxidized to any appreciable extent. 

A second route to ricinine was suggested by the observation that ethyl 2 4-dihydroxy-6-methyl-nicotinate is obtained from the condensation of ethyl malonate and ethyl /3-aminocrotonate in the presence of sodium ethylate (59). This substituted ethyl nicotinate when converted to the amide by means of alcoholic ammonia and dehydrated with phosphorus oxychloride gives rise to 2 4-dichloro-3-cyano-6-methylpyridine (LXXXYIII). Condensation of LXXXVIII with benzaldehyde followed by oxidation yields the acid (LXXXIX) and this on treatment with sodium methylate... 

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