Quinolinate from aspartate

An alternative pathway for synthesis of quinoli-nate from aspartate and a triose phosphate exists in bacteria and in plants and provides the major route of nicotinic acid synthesis in nature. In E. coli the reaction is catalyzed by two enzymes, one an FAD-containing L-aspartate oxidase which oxidizes aspartate to a-iminoaspartate.228 The latter condenses with dihydroxyacetone-P to form quinolinate (Eq. 25-13).229 There are at least two other pathways for synthesis of quinolinic acid as well as five or more salvage pathways for resynthesis of degraded pyridine nucleotide coenzymes.224/230/231... 

Feldman, P, L. and Rapoport, H Synthesis of optically pure A -tctrahydroquinolinic acids and hexahydroindolo[2,3-a quinolines from L-aspartic acid. Racemization on the route to vindoline. J. Org. Chem.. 51, 3882,... 

The pyridine moiety of (-)-nicotine is derived biogenetically from nicotinic acid, which is formed in prokaryotes and plants starting from aspartic acid and glyc-eraldehyde-3-phosphate. [533] In this, the aspartic acid is activated by pyridox-al phosphate. After cycHsation and aromatisation, quinolinic acid is formed first, and then decarboxylation leads to nicotinic acid. 

In most bacteria and in higher plants nicotinic acid is formed from aspartic acid and a three carbon unit derived from glycerol, probably D-glyceraldehyde-3-phosphate (D 2). A key intermediate is quinolinic acid, which in animals, however, is derived from l-tryptophan (D 21). Nicotinic acid originates from quinolinic acid via nicotinic acid mononucleotide formed with the participation of 5-phosphoribosyl-l-pyrophosphate. It changes either directly to nicotinic acid or is formed via nicotinamide adenine dinucleotide (NAD+) in the nicotinic acid nucleotide cycle. 

Degradation of L-tryptophan in most organisms proceeds via L-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxyanthranilic acid and quinolinic acid to acetyl Co A and CO2 (Fig. 244). Anthranilic acid formed as an intermediate may be recycled to L-tryptophan (see above). The ring of 3-hydroxyanthranilic acid is cleaved by a dioxygenase (C 2.5). The x-amino-/3-carboxymuconic acid-e-semialdehyde formed either undergoes a cis trans isomerization of the Zl -double bond and cyclization to quinolinic acid, a compound synthesized in microorganisms and plants from aspartic acid and D-glyceraldehyde-3-phosphate (D 16.2). On the other hand o -amino-/3-carboxymuconic acid-e-aldehyde may be de-carboxylated and is then the immediate precursor of NH3, acetic acid and COg. 

Scheme 12.104. A proposed pathway from aspartate (Asp, D) and dihydroxyaetone monophosphate to pyridine-2,3-dicarboxylate (quinolinic acid) (after Sakuraba, H. Tsuge, H. Yoneda, K. Katumuma, N. Ohshima, T. J. Biol. Chem., 2005,280, 26645).

Quinolinic acid is synthesized not only from tryptophan in mammals (50) but also from aspartic acid and dihydroxyacetone phosphate in microorganisms (51). Therefore, quinolinic acid is the key intermediate in the de novo NAD biosyn-thethic pathway. Furthermore, quinolinic acid has been shown to excite nerve cells in rodents and primates on iontophoretic application (52) and intracerebral injection of quinolinic acid in rats results in selective axon-sparing neuronal lesions (53). The quinolinic acid content in biological materials is very low, so its content cannot be measured by the HPLC-UV method described under (28) in Section III.B. Recently, Mawatari et al. (54) found that quinolinic acid induces fluorescence by photoirradiation in the presence of hydrogen peroxide and established a system based on HPLC with detection by the fluorescence reaction. The detection limit was 1.1 pmol. Chromatograms of reference quinolinic acid and of quinolinic acid in urine are shown in Figure 18. 

NAD(P)+ from the diet is first hydrolysed to a mixture of nicotinic acid and nicotinamide. Nicotinic acid can then be transformed into nicotinamide and then to NAD(P)+ in the body. These dinucleotides are de novo synthesised by bacteria and some plants from aspartic acid and 1,3-dihydroxyacetone phosphate (glycerone phosphate). Quinolinic acid is an intermediate. It arises from tryptophan in some microorganisms and in animals. 

Quinolinate ASPOX synthesis from L-aspartate (Asp-DHAP pathway) L-Aspartate oxidase (EC 1.4.3.16) nadB + +... 

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). ... 

As mentioned earlier, A. suaveolens Mar. ex Spreng. (Lamiaceae) is used as an anticonvulsant through the Brazilian Amazon. The EO obtained from A. suaveolens and its main component linalool (3) proved to be anticonvulsant against several types of experimental convulsions, including those induced by PTZ and transcorneal electroshock (Elisabetsky et al. 1995a), intracerebrally injected quinolinic acid, and ip N-methyl aspartate (NMDA) (Elisabetsky et al. 1999). Moreover, psychopharmacological evaluation of linalool (3) showed dose-dependent marked sedative effects. 

The pyridine nucleotide cycle is a series of reactions that are ubiquitous in nature, differing only in the biosynthesis of quinolinic acid. It (quinolinic acid) occurs from tryptophan in animals, fowl, molds, and in certain microorganisms. It may come from either aspartate and glyceraldehyde-3-phosphate in higher plants and bacteria. In other plant systems highly specialized examples exist, such as mimosine, fusaric acid, and actinidine, where other precursors are used. 

Gholson et al. (1976) have studied quinolinic acid (QA) biosynthesis, in a cell-free system prepared from E. coli mutants. In this system QA is synthesized by the condensation of aspartate and a [3- C]dihydroxyacetone phosphate which is incorporated into the C-4 of QA. An FAD-requiring reaction is catalyzed by two partially purified proteins which they call quinolinate synthetase. Quinolinate synthetase is composed of protein A (MW about 35,(X)0) and protein B(MW about 85,000). Preincubation of A and B proteins leads to inactivation of at least the A protein and DHAP prevents this inactivation reaction. Neither the A nor the B protein binds aspartate- C but in the presence of both proteins aspartate is bound to an entity with an apparent MW greater than the B protein. 

---