S-Adenosylhomocysteine hydrolase

Low levels or absence of adenosine deaminase (ADA) is associated with one form of severe combined immunodeficiency disease (SCID) characterized by B-andT-lymphocyte dysfunction due to toxic effects of deoxyadenosine (HI9). Most patients present as infants with failure to thrive, repeated infections, severe lymphopenia, and defective cellular and humoral immunity. Disease severity is correlated with the degree of deoxyadenosine nucleotide pool expansion and inactivation of S-adenosylhomocysteine hydrolase in red blood cells. Up to now, more than 40 mutations have been identified (A4, H20, S5, S6). The majority of the basic molecular defects underlying ADA deficiency of all clinical phenotypes are missense mutations. Nonsense mutations, deletions ranging from very large to single nucleotides, and splicing mutations have also been reported. It is likely that severe... 

A coupled enyzmatic assay makes use of S-adenosylhomocysteine hydrolase (SAHH) which hydrolyzes the methyltransfer product SAH to homocysteine and adenosine. The homocysteine concentration can be determined by conjugation of its free sulfhydryl moiety to a thiol-sensitive fluorophore [61]. This could of course also be used for arginine methyltransferases. 

Dwivedi RS, Wang LJ, Mirkin BL (1999) S-adenosylmethionine synthetase is overexpressed in murine neuroblastoma cells resistant to nudeoside analogue inhibitors of S-adenosylhomocysteine hydrolase a novel mechanism of drug resistance. Cancer Res 56 1852-1856... 

S-adenosylmethionine is also a biological methyl group donor. The product of its methyl transferase reactions is S-adenosylhomocysteine. This product is further degraded by S-adenosylhomocysteine hydrolase, an enzyme that contains tightly bound NAD+, to form homocysteine and adenosine. 

S-Adenosylhomocysteine 592s, 778s S-Adenosylhomocysteine hydrolase 778 S-Adenosylmethionine (AdoMet,... 

One of the major features of solid tumors and even small deposits of tumor tissue is deficiency in the level of oxygen, because of an inadequate vascular supply. The adenosine elevation in response to hypoxia is not exclusive to tumor tissues, but, in this context, the adenosine elevation is localized to the tumor microenvironment, since the surrounding tissue is normally oxygenated. Adenosine is generated mainly by two enzymatic systems intra- or extracellularly localized 5 -nucleoti-dases and cytoplasmic S-adenosylhomocysteine hydrolase. The processes of adenosine elimination in the cell involve reactions catalyzed by adenosine deaminase and adenosine kinase (Shryock and Belardinelli 1997) yielding inosine or 5 -AMP,... 

A number of imidazo[4,5-c]pyridine nucleosides (3-deazapurine nucleosides) are of special interest because of their biological properties. 3-Deazaadenosine (655) inhibits biochemical methylations by acting as either an inhibitor or substrate of (S)-adenosylhomocysteine hydrolase <79BP1897>. Compound (655) has antiviral <78BBR(82)417> and antimalarial activities <80MI 708-01). 3-Deaz-... 

A wide vtiriety of methylation reactions, including developmentedly importtmt methylation of DNA, may be inhibited by S-adenosylhomo-cysteine, which accumulates because homocysteine is a product inhibitor of S-adenosylhomocysteine hydrolase. 

Heim WG, Sykes KA, Hildreth SB, Sun J, Lu RH, Jelesko JG. Cloning and characterization of a Nicotiana tabacum methylpu-trescine oxidase transcript. Phytochemistry 2007 68 454-463. Heim WG, Jelesko JG. Association of diamine oxidase and S-adenosylhomocysteine hydrolase in Nicotiana tabacum extracts. Plant Mol. Biol. 2004 56 299-308. 

Figure 8 Extended folate metabolism, including compartmentation. MTHFR, methylenetetrahydrofolate reductase SHMT, serine hydroxymethyltransferase BHMT, betaine homocysteine methyltransferase, MAT, methionine adenosyltransferase SAH-hydrolase, S-adenosylhomocysteine hydrolase MT, methyltransferase CBS, cystathionine /i-synthase SAM, S-adenosylmethionine SAH, S-aden-osylhomocysteine THF, tetrahydrofolate and 5-MeTHF, 5-methyltetrahydrofolate. (Reproduced from Van der Put etal. (2001) Folate, homocysteine and neural tube defects An overview. Experimental Biology and Medicine 226 243-270.)...

To obtain accurate results, it is recommended that specimens be refrigerated and quickly centrifuged. " If specimens are allowed to stand at room temperature, glycolysis can double homocysteine levels. Addition of fluoride or specific S adenosylhomocysteine hydrolase inhibitors will prevent problems caused by glycolysis. " The short-term and longterm variability of plasma homocysteine measurements has been discussed. "... 

Another nucleoside-derived mechanism-based enzyme inhibitor is Fluoronepla-nocin A [79]. This compound is of interest as a broad-spectrum antiviral drug which acts by irreversible inhibition of S-adenosylhomocystein hydrolase (SAH). In a first enzymatic reaction step the 3 -hydroxy group of the inhibitor is oxidized to the corresponding ketone (Scheme 4.34). This leads to depletion of the biochemical oxidizer nicotinamide adenine dinudeotide (NAD ). In the next step a nucleophilic residue of the enzyme undergoes Michael addition to the /i-fluoro a,/>-unsatu-rated ketone moiety. This is followed by fluoride elimination and thus the inhibitor stays covalently trapped in the active site and disables the enzyme permanently. 

Scheme 4.34 Mechanism of action proposed for the S-adenosylhomocystein hydrolase (SAH) inhibitor Fluoroneplanocin A (Ad = adenine ...

Fig. 2 Transulphuration pathway. Enzymes involved 1 methionine S-adenosyltransferase, Jmethyltransferase, 3 S-adenosylhomocysteine hydrolase, 4 cystathionine -synthase, 5 p-cys-tathionase, 6 methionine synthase...

In this chapter, we discuss the synthetic methodologies used to prepare fluoroolefins and present examples of mechanism-based inhibitors of amine oxidases, r-aminobutyric acid transaminase and S-adenosylhomocysteine hydrolase which incorporate this structural functionality. Ve have restricted our discussion to the syntheses of terminal mono-, di- and trifluoroolefins, omitting the large body of synthetic endeavour directed towards other fluoro olefins (4). 

It was then possible for Yang et al. [52] to make use of the results of Kirby and Walwyn to understand a significant mechanistic feature of the NAD -dependent enzyme S-adenosylhomocysteine hydrolase. 

Porter, D. J. Boyd, F. L. 1992 J. Biol. Chem. 267, 3205-3213 Reduced S-adenosylhomocysteine hydrolase. Kinetics and thermodynamics for binding of 3 -ketoadenosine, adenosine, and adenine. 

Chemical precedent for the nonenzymic elimination of base and inorganic pyrophosphate may be found in the attempted synthesis of 3 -ketothymidine by oxidation of TMP (54), which led instead to the formation of Pj, thymine, and unidentified sugars. Furthermore, Hershfield reported that 2 -deoxyadenosine inactivated S-adenosylhomocysteine hydrolase and that this inactivation was accompanied by adenine release (55). 

Ueland, P. M. (1982) Pharmacological and biochemical aspects of S-adenosylhomocysteine and S-adenosylhomocysteine hydrolase. Pharmacol. Rev. 34, 223-253. 

A second hypothesis suggests that the accumulation of deoxyadenosine in lymphocytes leads to an inhibition of S-adenosylhomocysteine hydrolase, the enzyme that converts S-adenosylhomocysteine to homocysteine and adenosine. This leads... 

Other antiviral compounds, such as rifampin132 and S-adenosylhomocysteine hydrolase inhibitors,133135 have activity against vaccinia, and hence... 

---