Nicotinic acid biosynthetic pathways

The rather similar alkaloids anabasine and anatabine come from different biosynthetic pathways. Labelling experiments outlined below show the origin of one carbon atom from lysine and others from nicotinic acid. Suggest detailed pathways. (Hint. Nicotinic acid and the intermediate yoi have been using in Problem 3 in the biosynthesis of the piperidine alkaloid are both electrophilic at position 2. You also need an intermediate derived from nicotinic acid which is nucleophilic at position 3. The biosynthesis involves reduction.)... 

The most accepted biosynthetic pathways for piperidine is lysine via A -piperidine (3973, 17B05). Piperidine can also be formed through decarboxylation and dehydrogenation of nicotinic acid (17B37). 

Pelletierine is biosynthesized through the incorporation of lysine. Among the several types of alkaloid possessing the piperidine nucleus, lobeline involves a similar biosynthetic pathway (Section 4.4) as that of pelletierine, whereas arecoline and coniine are biosynthesized through completely different pathways. The former alkaloid is derived lirom nicotinic acid (Section 10.3), and the latter alkaloid is biosynthesized via the polyketide pathway (Section 15.1). 

Although the chemical structure of (-)-anatabine is quite similar to that of (-)-anabasine, remarkably, the biosynthetic pathways of these alkaloids are considerably different. Thus, (-)-anabasine is biosynthesized from nicotinic acid and lysine as described above, whereas, (-)-anatabine is biosynthesized from two molecules of nicotinic acid [2,3], as described in Chapter 10. 

On the other hand, when [6- H]nicotinic acid was fed to the above system, the total amount of was considerably decreased compared with the result when [2— H], [4- H], or [5- H]nicotinic acid was used as a precursor. This supports the idea that 3,6-dihydronicotinic acid exists as an intermediate in the biosynthetic pathway. The stage at which decarboxylation occurs has not been finally clarified, but it seems that it is in concert with the condensation reaction of 3,6-dihydronicotinic acid with A -pyrroHdine or A -piperidine, because the label from [2— C]nicotinic acid remains at the C-2 of nicotine and is not randomized between C-2 and C-6 through the involvement of a symmetrical intermediate. 

Fig. 1. NAD biosynthetic pathways in enteric bacteria. The genes controlling each metabolic step are indicated. Abbreviations used are ASP, aspartate lA, iminoaspartate QA, quinolinic acid Nm, nicotinamide Na, nicotinic acid NaMN, nicotinic acid mononucleotide NaAD, nicotinic acid adenine dinucleotide.

A scheme in which nicotinamide was used as a precursor of NAD was described before the presently accepted biosynthetic pathway for NAD was elucidated. It is not certain whether nicotinamide can serve as a precursor of NAD. The administration of small amounts of nicotinic acid leads to a marked increase in NAD coenzyme levels in the blood. In contrast, the intake of high doses of nicotinamide has little effect on the blood concentration of NAD. Such results may be interpreted two ways either nicotinic acid is a better precursor for NAD coenzymes than nicotinamide, or the conversion of nicotinamide to the coenzyme is restrained. 

Tropane alkaloids are found mainly in the Solanaceae [14] plant family. First biosynthetic step of tropane alkaloids starts with iV-methylation of putrescine (derived from L-omithine) to form Al-methylputrescine. After the conversion to 1-methyl-Al pyrrolinium cation, its condensation with nicotinic acid gives rise to nicotine synthesis, while other chemical conversions lead to the formation of tropinone, the precursor of many tropane alkaloids through branched pathways (Fig. 8.8a) [15]. 

The piperidine ring - the core of Lobelia alkaloids - is derived generally from lysine but their biosynthetic pathways are depentent on the type (phenolic or aliphatic) of side chains, although the piperidine core seldom could be derived from nicotinic acid (similarly to pyridine alkaloids), e.g., in case of anatabine. 

Simple examples of piperidine alkaloids are iV-methylpelletierine 6.19) and the hemlock alkaloid, coniine 6.14). In these bases the structural relationship is manifestly close. This relationship is similarly apparent between anabasine 6.20) and anatabine 6.7) which are, moreover, found in the same plant. It is however, clear, from biosynthetic experiments, that whilst the piperidine rings of iV-methylpelletierine 6.19) and anabasine 6.20) derive from the amino acid lysine 6.17) those of coniine 6.14) and, most surprisingly, anatabine 6.7) have quite different origins. It is proved that anatabine 6.7) is formed from two molecules of nicotinic acid 6.4) [4] (the labelling results, and a suggested pathway, is illustrated in Scheme 6.4). Only the pyridine ring of anabasine derives from... 

Fig. 5 Biosynthetic pathway of nicotine. Unbroken arrows indicate single enzymatic conversions and broken arrows indicate multiple enzymatic conversions. It is not known whether the 7V-methyl-pyrrolinium cation is coupled to nicotinic acid or a derivative of the latter. PMT putrescine A -methyltransferase...

NAD is biosynthesized via four pathways as shown in Figure 2 (I) nicotinic acid NaMN —> NaAD —> NAD (II) nicotinamide —> NMN — NAD (III) nicotinamide nicotinic acid -> NaMN NaAD -> NAD+ (IV) quinolinic acid — NaMN —> NaAD NAD. In the four NAD biosynthetic pathways, pathways II and IV are physiologically important. Quinolinic acid is synthesized... 

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. 

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