Ornithine putrescine formation

By analogy with the asymmetrical incorporation of [2-14C] ornithine it was proposed (5,116,117) (Scheme 22) that to avoid the formation of putrescine... 

The pivotal role of hygrine in the biosynthesis of cuscohygrine and of the tropane alkaloids has justified numerous investigations. The following scheme represents the now generally admitted pattern of formation of these bases. Ornithine (119) is first converted to putrescine or V-methylputrescine (120)... 

Examples of amines that frequently occur in fish muscle include cadaverine from lysine, putrescine from ornithine and histamine from histidine. Histamine, because of its involvement in Scombroid food poisoning (histamine intoxication), has been extensively studied with respect to factors influencing its formation in many different fish species. Tuna and other fish from the families Scomberesocidae and Scombridae and a non-scombroid fish, mahi-mahi (dolphin fish) have been most... 

The V-methyl -A1 -pyrrol ini um cation is the last common intermediate in both TA and nicotine biosynthesis (Fig.7.4). V-Methy 1-A1 -pyrrolinium cation formation begins with the decarboxylation of ornithine and arginine by ornithine decarboxylase (ODC) and arginine decarboxylase (ADC), respectively. Putrescine is formed... 

The concept of inhibition via p elimination of fluoride ion has now been extended to the irreversible inhibition of a-amino acid decarboxylases. Ornithine decarboxylase (ODC), which catalyzes the decarboxylation of ornithine to putrescine is irreversibly inhibited by a-difluoromethylornithine (IX Fig. 9) (28). In this case, the carbanion formation which precedes P elimination is generated by loss of CO2, and not by proton abstraction (Fig. 9). Similarly, aromatic amino acid decarboxylase is irreversibly inhibited by C-difluoromethyl-3,4-dihydroxyphenylalanine (29) while histidine decarboxylase, ornithine decarboxylase and aromatic amino acid decarboxylase have been inhibited by the corresponding <=d-monof luoromethylanri.no acids, respectively (29). 

The first key step in the biosynthesis of tropane alkaloids is the formation of the intermediate putrescine. Polyamines and, therefore putrescine, are found in plant cells and are implicated in growth, root, fruit and flower development, and in different stress phenomena. It is well known that plants synthesize polyamines from ornithine and arginine, unlike other eukaryotes like mammals, which only synthesize polyamines from ornithine. In plants putrescine is synthesized directly from ornithine, a reaction catalysed by ornithine decarboxylase (ODC, EC 4.1.1.17) and indirectly from arginine via agmatine catalysed by arginine decarboxylase (ADC, EC 4.1.1.19), Fig. (1). In Arabidopsis, it is known that the adc gene is required for the production of polyamines that are essential for normal seed development [103]. 

The urea so formed is distributed throughout the body water and excreted. The renal clearance of urea is less than the glomerular filtration rate because of passive tubular back-diffusion. Diffusion of urea in the intestine leads to formation of ammonia, which enters the portal blood and is converted to urea in liver. Reentry of ornithine into mitochondria initiates the next revolution of the urea cycle. Ornithine can be converted to glutamate-y-semialdehyde (which is in equilibrium with its cyclic form A -pyrroline-5-carboxylate) by ornithine aminotransferase and de-carboxylated to putrescine by ornithine decarboxylase. Ornithine is also produced in the arginine-glycine trans-amidinase reaction. 

Metcalf et al. (23) reported the synthesis of efiornithine (difluoromethyl ornithine [DFMO]) in 1978. Their interest arose from the desire to prepare ornithine decarboxylase (ODC) inhibitors as tools for studying the role of polyamines as regulators of growth processes. Ornithine decarboxylase catalyzes the conversion of ornithine to putrescine (1,4-diaminobutane), which in turn leads to the formation of the polyamines, spermine, and spermidine. It was not until 1980 that Bacchi et al. (24) demonstrated the potential of DFMO in the treatment of trypanosomiasis. 

Pioneering tracer studies carried out in the laboratories of D. J. Robins and I. Spenser had demonstrated that the carbon skeleton of the necine base originates from ornithine or arginine via putrescine. Extension of these studies in the 1980s using precursors labeled with stable isotopes confirmed that retronecine is derived from putrescine via a symmetrical intermediate such as homospermidine [17-19]. The formation of the necic acids is less well understood. Early tracer-studies primarily carried out by D. H. G. Grout and collaborators revealed that the carbon skeletons of all aliphatic necic acids so far studied are derived from branched-chain amino acids, i. e., isoleucine, and less frequently leucine and valine [see 17]. 

Figure 11.6. Formation of histamine and putrescine from the amino acids histidine and ornithine.

In the biosynthesis of nicotine 6.71) in Nicotiana species it has been found [45, 46] that both ornithine 6.60) and putrescine 6.63) are again involved in pyrrolidine-ring formation. For this alkaloid, however, incorporation of the amino acid is through at least one symmetrical intermediate, logically putrescine 6.63), because [2- " C]ornithine gave nicotine 6.71) with label equally spread over C-2 and C-5 additional results were obtained with [ N]ornithines. This symmetrical pathway is supported by experiments with C02, although a few results indicate an unsymmetrical route [47, 48]. 

Ornithine decarboxylase (ODC) and arginine decarboxylase (ADC) are the first enzymes involved in the formation of tropane alkaloids (TPAs) snch as atropine and cocaine (Fig. 3). Decarboxylation of ornithine yields pntrescine, whereas arginine is converted to agmatine, which is metabolized to putrescine via a second rente. ADC is assnmed to play the primary role in TPA synthesis [18]. 

The formation of nicotinic acid—or, more precisely, of quinolinic acid—via two different pathways is an example of biochemical convergence, Now to the biosynthesis of the pyrrolidine ring of nicotine and nornicotine. Ornithine comes into play here. It furnishes the pyrrolidine component by the route already outlined, and this is then combined with nicotinic acid to give nicotine (Fig. 124). It is not known with certainty at what stage the methyl group is introduced. Very probably ornithine or putrescine is methylated and the methylated precursor is then icorporated into nicotine. Nicotine can be converted into nornicotine by demethyla-tion. 

Figure 9.11 The formation of two examples of the tetraponerines from ants. Glutamic acid, ornithine and y-aminobutyric acid uniformly labelled with 0, sodium acetate labelled in C-1 and C-2 with Q and [l,4- C]putrescine were all used to show the synthesis is as shown...

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