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S-adenosyl homocysteine hydrolase

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). [Pg.131]

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). [Pg.148]

The racemic cyclopentenone (17), obtained as a byproduct in a synthesis of neplanocin A, has been used to make ( )-neplanocin F (18). A similar starting material has been used to make 3-deaza-neplanocin A (19), which shows antiviral properties and is a power-ful inhibitor of S-adenosyl-homocysteine hydrolase. This enzyme has been used to oxidize neplanocin A to the corresponding 3 -keto analogue sodium cyanoborohydride reduction of this ketone was... [Pg.196]

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... [Pg.372]

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... [Pg.246]

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. 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.
The 5 -alkynyl(cyano) derivatives of adenosine 274 and its carbocyclic analog derivatives 231 and 232 were examined as inhibitors of S-adenosyl-L-homocysteine and S-adenosyl-L-methionine hydrolase (89EUP334361). [Pg.102]

Robins, M. J., Wnuk, S. F., Mullah, K. B. and Dailey, N. K. (1994) Nucleic Acid related compounds. 80. Synthesis of 5 -5-(alkyl and aryl )-5 -(l uoro-5 -thioadenosi ncs with xenon difluoride or (diethylamido)sulfur trifluoride, hydrolysis in aqueous buffer, and inhibition of S-adenosyl-L-homocysteine hydrolase by derived adenosine 5 -aldehyde species. J. Org. Chem., 59, 544-555. [Pg.460]

Schowen, R. L. 2003 Biochemistry 42, 1900—1909 The catalytic strategy of S-adenosyl-L-homocysteine hydrolase Transition-state stabilization and the avoidance of abortive reactions. [Pg.1076]

S-Adenosyl-L-methionine is the important methyl donor in biological transmethylation to form S-adenosyl-L-homocysteine, which is hydrolyzed to adenosine and homocysteine by S-adenosyl-L-homocysteine hydrolase (E.C. 3.3.1.1) in vivo. However, equilibrium of the S-adenosyl-L-homocysteine hydrolase reaction favors the direction toward synthesis of S-adenosyl-L-homocysteine. Shimizu et al. developed a simple and efficient method for the high yield preparation of S-adenosyl-L-homocysteine with S-adenosyl-L-homocysteine hydrolase of Alcaligenes faecalis, in which the cellular content of S-adenosyl-L-homocysteine hydrolase was about 2.5% of the total soluble protein. S-Adenosyl-r-homocysteine was produced at a concentration of about 80 g I. 1 with a yield of nearly 100% 661. However, when racemic... [Pg.1290]

Figure 17-7. Structures of adenosine and related nucleosides which serve as substrates for S-adenosyl-L-homocysteine hydrolase. 1, Adenosine 2, formycin A 3, neburalin 4, adenosine Af-oxide 5, 2-chloroadenosine 6, tubercidine 7, N6-methyladenosine 8, inosine 9, 1-methyladenosine. Figure 17-7. Structures of adenosine and related nucleosides which serve as substrates for S-adenosyl-L-homocysteine hydrolase. 1, Adenosine 2, formycin A 3, neburalin 4, adenosine Af-oxide 5, 2-chloroadenosine 6, tubercidine 7, N6-methyladenosine 8, inosine 9, 1-methyladenosine.
Using differential screening, Tanaka et al. [34] found cDNAs representing cytokinin-induced mRNAs in the tobacco thin layer system. One cDNA encodes S-adenosyl-L-homocysteine hydrolase (SAH hydrolase), which is involved in regulating intracellular transmethylation reactions. The promoter sequence of the gene was fused to the 3-glucuronidase (GUS) reporter gene and introduced in suspension-cultured cells, which rendered expression of GUS inducible by kinetin. [Pg.467]

S-Adenosyl-L-homocysteine hydrolase as an attractive target for antimicrobial drugs 07YZ977. [Pg.41]

The phosphonic aeid moiety has been shown to be inhibitors of numerous metabolic processes [99,100], In recent years, S-adenosyl-L-homocystein hydrolase(AdoHcy) has become an attractive target for drug design since its inhibitors have been shown to exhibit antiviral [101], antiparasitic [102], antiarthritic [103], and immunosuppressive effects [104], Importantly, a-aminophosphonate diesters are more attractive as intermediates for multistep synthesis than the corresponding phosphonic acids. The insolubility of the latter in both organic and neutral aqueous media complicates derivation of both the amine and acid functionalities. [Pg.144]

Fluoronoraristeromycin (43, Fig. 1) was investigated as an inhibitor of S-adenosyl-L-homocysteine (SAH) hydrolase in Plasmodium falciparum, and showed 100-fold enhanced selectivity for toxicity to the parasite versus mammalian cells when compared to the unfluorinated noraristeromycin [67]. Analogues of SAH inhibit human DNA methyltransferases, which use S-adenosyl-L-methionine as the cofactor to transfer methyl groups to DNA [18]. The addition of a 2-fluoro substituent to SAH was found to confer selectivity for inhibition of the DNMTl isoform of enzyme over the DNMT3b2 subtype, while unfluorinated SAH was a better inhibitor of the DNMT3b2 enzyme. [Pg.729]

KitadeY, KojimaH, ZulfiqurF, Kim HS, WatayaY (2003) Synthesis of 2-fluoronoraristeromycin and its inhibitory activity against Plasmodium falciparum S -adenosyl-L-homocysteine hydrolase. Bioorg Med Chem Lett 13 3963-3965... [Pg.756]

M.S. Wolfe, Y. Lee, W J. Bartlett, D.R. Borcherding, and R.T. Borchardt, 4-Modified analogues of aristeromycin and neplanocin A Synthesis and inhibitory activity toward 5-Adenosyl-L-homocysteine hydrolase, /. Med. Chem. 35 1782 (1992). [Pg.126]


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See also in sourсe #XX -- [ Pg.246 ]




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Homocysteine

Hydrolases adenosyl homocysteine hydrolase

S hydrolase

S-Adenosyl homocysteine

S-adenosyl-L-homocysteine hydrolase

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