S-Adenosyl homocysteine

Figure 12.2 Adenosine metabolism. Intracellular adenosine concentrations depend on the balance between energy storage and breakdown. The most important enzymes catalyzing the reactions are indicated. SAH, S-adenosyl-homocysteine ENTs equilibrative nucleoside transporters CNTs, concentrating nucleoside transporters.

The biosynthesis of adenosine is theoretically controlled by several processes namely (1) the biosynthesis of adenosine from AMP by 5 -nucleotidase [EC 3.1.3.5], (2) from S-adenosyl homocysteine by S-adenosyl homocystine hydrolase [EC 3.3.1.1], (3) the metabolism of adenosine to AMP by adenosine kinase [EC 2.7.1.20], and (4) to inosine by adenosine deaminase (ADA) [EC 3.5.4.2], Interestingly, both 5 -nucleotidase and ADA activities were found to be highest in the leptomeninges of rat brain in contrast, the adenosine kinase activity was widely distributed throughout the brain parenchyma, which has negligible ADA activity... 

This enzyme [EC 2.1.1.6] catalyzes the reaction of catechol with 5-adenosylmethionine to produce. S-adenosyl-homocysteine and guaiacol (or, o-methoxyphenol). 

The abnormal T- and B-cell functions in patients with SCID are the result of ADA dehciency. The ADA gene has been mapped to chromosome 20q.l3, and a number of point and deletion mutations have been identihed in SCID patients [5-7]. ADA catalyses the irreversible deamination of adenosine and 2 -deoxyadenosine to inosine and 2 -deoxyi-nosine as a part of purine nucleoside metabolism. Adenosine and deoxyadeno-sine are suicide inachvators of S-adenosyl-homocysteine (SAH) hydrolase, and lead indirectly to intracellular accumulation of SAH, which is a potent inhibitor of methy-lation reactions. Cellular methylation function is essential for detoxihcation of adenosine and deoxyadenosine. As a result ADA dehciency leads to accumulation to... 

Figure 7.64 The role of methionine in methylation reactions and the mechanisms underlying ethionine hepatotoxic-r. ity. After the substrate is methylated, the S-adenosyl homocysteine remaining is broken down into homocysteine and adenine, both of which are reused. When S-adenosyl ethionine is formed, however, this recycling is reduced (=), and a shortage of adenine and hence ATP develops.

S-Adenosyl methionine is the major methyl donor in biological reactions. It is regenerated via the intermediates S-adenosyl homocysteine, homocysteine and methionine in the activated methyl cycle. 

Fig. 3.1 Metabolomics of Hey. During gene and protein methylation, S-adenosyl homocysteine (SAH) is generated by methyl transferase and methionine. SAH hydrolase (SAHH) generates Hey. DZA blocks SAHH, otherwise Hey induces NOS, NADH oxidase and decreases thioredoxin in mitochondria. Hey inhibits DDAH and increases ADMA causing decrease in NO. Deficiency in MTHFR and CBS increases Hey. The decrease in kidney ability to filter increases Hey.

As shown in Figure 10.9, the methyl donor is S-adenosyl methionine, which is demethylated to S-adenosyl homocysteine. After removal of the adenosyl group, homocysteine may undergo one of two metabolic fates remethylation to methionine or condensation with serine to form cystathionine, foUowed by cleavage to yield cysteine - the transulfuration pathway (Section 9.5.5). Cystathionine synthetase has a relatively low Tni compared with normal intra-ceUular concentrations of homocysteine. It functions at a relatively constant rate, and under normal conditions, most homocysteine wUl be remethylated to methionine. 

FIGURE 6.2 Phosphatidylcholine (PC) synthesis by the CDP-ethanolamine pathway. Structures of ethanolamine and choline. The nucleotide moiety S-adenosyl methionine (SAM) is requiivct to transfer the methyl group of methionine to phosphatidylethanolamine (J E) to form PC. In the process, SAM is converted to S-adenosyl homocysteine (SAH). The nitrogen atom of PC has four covalent bonds and is called a quaternary amine. It bears a positive charge that is not influenced by changes in the pH of the suitoimding fluids. The PE methyltran.sferase pathway of I C synthesis occurs only in the liver. 

The methyl group of the methionine unit is activated by the positive charge on the adjacent sulfur atom, which makes the molecule much more reactive than N -methyltetrahydrofolate. The synthesis of S-adcnO Sylmethionine is unusual in that the triphosphate group of ATP is split into pyrophosphate and orthophosphate the pyrophosphate is subsequently hydrolyzed to two molecules of P . S-Adenosylhomocysteine is tormed when the methyl group ot S-adenosylmethionine is transferred to an acceptor. S-Adenosyl homocysteine is then hydrolyzed to homocysteine and adenosine. 

NADP+/ nicotinamide adenine dinucleo- SAH S-adenosyl homocystein... 

Outside of DNA synthesis, folate plays a role in methylation metabolism. The major methyl donor is S-adenosyl methionine (SAM), which is required for many reactions. For example, SAM is needed for the production of norepinephrine from epinephrine and for DNA methylation, which can influence gene transcription. After methyl group transfer, SAM is converted to S-adenosyl homocysteine (SAH), which is hydrolyzed to homocysteine and... 

After the initial discovery that 0-fluoromethylene-substituted amines (e.g., 184, Table 1) were potent, mechanism-based inhibitors of monoamine oxidase (MAO) (41), the concept was successfully broadened to include most of the common amine oxidases (Table 1). This approach was also used to design inhibitors of y-aminobutyric acid transaminase both the a- and 0- substituted amino acids 189 and 190 were found to inactivate this enzyme. Recently, applica-tion of this concept to the design of inhibitors of S-adenosyl-homocysteine hydrolase (SAH) has led to the discovery of very potent inhibitors of this enzyme (e.g., 176, Table 1). 

Capping of eukaryotic mRNA. (a) Enzymatic reactions required for 50 capping SAM is -S -adenosyl methionine and SAC is -S -adenosyl homocysteine, (b) Structure of 7-methylguanosine cap. 

The collaboration between USAMRIID and the NIAID Drug Discovery Program that identified cidofovir as a potential smallpox treatment has also discovered a class of compounds (s-adenosyl homocysteine hydrolase inhibitors) that may be effective against filoviruses, such as Ebola. In a mouse Ebola model that produces 100 percent mortality within 7 days, treatment beginning on the day of exposure provided 100 percent protection, and treatment beginning 4 days after exposure saved 40 percent of infected mice (memo from John Huggins of USAMRIID to F Manning, May 21, 1998). 

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