Methionine metabolism polyamine biosynthesis

Polyamine biosynthesis is associated with regulation of a number of metabolic functions including growth of cells in most of the living organisms. In mammals, ornithine is the precursor of aliphatic polyamines. Putrescine, formed by decarboxylation of the former by ornithine decarboxylase, is the first amine formed in polyamine biosynthesis. Putrescine gives rise to the other two polyamines, spermine and spermidine by successive addition of 3-aminopropyl residues derived from S-adenosyl-L-methionine (SAM) in the presence of different enzymes [44] (Chart 7). 

The conclusion reached from these findings from the point of view of methionine metabolism in developing brain is that involvement of S-adenosylmethlonlne in methylation reactions is more important than its involvement in synthesis of polyamines. Furthermore, in its role as a methyl donor it is converted to S-adenosylhomocysteine by various methyltransferases, and the carbon skeleton is retained within the methionine-homocysteine cycle. The absence of an active transsulfuratlon pathway at these early stages of development supports the concept that the most important metabolic role of methionine in developing neural tissue is methylation. Thus metabolic pathways which involve loss of the methionine carbon skeleton, polyamine biosynthesis and transsulfuratlon, are minimal or absent in order to promote and conserve this remethylatlon cycle. These alterations in the pathways of methionine metabolism in developing tissue may also be necessary to compensate for the greater utilization of methionine for protein synthesis at this time. 

Fig, 7. Pathways for the metabolism of methionine to 5 -methylthioadenosine (MTA) and recycling of MTA to methionine. Methionine can serve as a carbon source for the synthesis of polyamines and, in some tissues, ethylene. 5 -Methylthioadenosine is a product of both processes. Only the methylthio group of methionine is recycled, the C4 moiety for the resynthesis of methionine being derived from the ribosyl moiety of ATP. The enzymes involved are (1) SAM synthetase, (2) SAM decarboxylase, (3) various C3 transfer enzymes of polyamine biosynthesis, (4) MTA nucleosidase, (5) methylthioribose kinase, (6) three( ) uncharacterized enzymes, (7) aminotransferase, and (8) aminocyciopropane carboxylate synthase. 

Deficiency of either vitamin Bj or folate decreases the synthesis of methionine and SAM, thereby interfering with protein biosynthesis, a number of methylation reactions, and the synthesis of polyamines. In addition, the cell responds to the deficiency by redirecting folate metabolic pathways to supply increasing amounts of methyltetrahydrofolate this tends to preserve essential methylation reactions at the expense of nucleic acid synthesis. With vitamin Bj deficiency, methylenetetrahydro-folate reductase activity increases, directing available intracellular folates into the methyltetrahydrofolate pool (not shown in Figure 53-6). The methyltetrahydrofolate then is trapped by the lack of sufficient vitamin Bj to accept and transfer methyl groups, and subsequent steps in folate metabolism... 

The aminopropyl transfer from dcSAM results in the release of 5 -methylthio-adenosine (MTA), which is rapidly metabolized and recycled to the SAM precursor methionine in a cyclic pathway known as the methionine salvage cycle (Sauter et al. 2013). MTA is also released from SAM in the biosynthesis of ethylene and nicoti-anamine and considered a toxic metabolite because of product inhibition. A study has shown that MTA affects the synthesis of polyamines (Waduwara-Jayabahu et al. 2012). 

---