Disease relevance of S-adenosylhomocysteine

• Impaired ability to catabolize AdoHcy may have contributed to the cytolytic responses to dCF and ara-A, as well as to hepatic and central nervous system toxicity associated with their combined use [1].
• The crystal structures of Escherichia coli MTA/AdoHcy nucleosidase complexed with the transition state analog, formycin A (FMA), and the nonhydrolyzable substrate analog, 5'-methylthiotubercidin (MTT) have been solved to 2.2- and 2.0-A resolution, respectively [2].
• When the methylation of VSV mRNA was measured in assays carried out with permeabilized virions at the AdoHcy and AdoMet concentrations found in interferon-treated cells, a preferential inhibition of the viral (guanine-7-)methyltransferase activity was observed [3].
• Accumulation of adenosylhomocysteine results in a fall in the adenosylmethionine:adenosylhomocysteine methylation ratio, and this change is believed to cause defective methylation and demyelination in the nervous system [4].
• In the present study, we have investigated the influence of hypoxia and inhibition of AdoHcy hydrolase on MP in HepG2 cells [5].

High impact information on S-adenosylhomocysteine

• Our findings show an impairment of this posttranslational modification of proteins, associated with high AdoHcy intracellular concentration in CRF [6].
• Here we describe the crystal structure of the rat PRMT3 catalytic core in complex with reaction product AdoHcy, determined at 2.0 A resolution [7].
• S-Adenosylhomocysteine hydrolase (AdoHcyase) controls intracellular levels of S-adenosylhomocysteine (AdoHcy) [8].
• Activity of AdoHcy hydrolase was approximately equal to 3% of control in liver and was 5-10% of the control values in red blood cells and cultured fibroblasts [9].
• Furthermore, AdoHcy does not inhibit transcription by purified HeLa RNA polymerase II [10].

Chemical compound and disease context of S-adenosylhomocysteine

• An increased AdoHcy/AdoMet ratio was also found in HeLa cells treated with pure alpha 2 interferon produced in Escherichia coli by recombinant DNA techniques [3].
• The production of B77 avian sarcoma virions was inhibited more than 90% in infected chicken embryo fibroblasts that were treated with 100 microM 3-deazaadenosine, an inhibitor of adenosylhomocysteine hydrolase and, for this reason, an inhibitor of methylation reactions [11].
• However, when homocysteine was infused into the ischemic kidney, AdoHcy increased five-fold above control levels, during 5min ischemia [12].
• A recombinant form of human placental S-adenosylhomocysteine (AdoHcy) hydrolase expressed in E. coli, which was inactivated by a type-I mechanism-based inhibitor, has been crystallized using the hanging-drop vapour-diffusion technique [13].
• In the present study, we examined whether there was a correlation between the inhibition of prokaryotic AdoHcy hydrolase and the reported antibacterial activity of neplanocin A, e.g. Alcaligenes faecalis (Yaginuma et al., J. Antibiotics 34: 359 approximately 366, 1981) [14].

Biological context of S-adenosylhomocysteine

• It is evident, therefore, that increased cellular levels of AdoHcy or c3AdoHcy can affect cellular physiology via perturbation of cyclic AMP metabolism as well as via inhibition of S-adenosylmethionine-dependent methylation reactions [15].
• These metabolic effects were associated with a rapid inactivation of AdoHcy hydrolase, but a fraction of the enzyme activity (about 8% in liver) was not or only slowly inactivated [16].
• Thus, the combined treatment with these two types of mechanistically different methylation inhibitors resulted in significantly enhanced interference with nucleic acid methylation and cell growth, both of which correlated directly with unprecedented increases in the AdoHcy/AdoMet ratio [17].
• Comparisons of the inhibitor complexes to the adenine-bound MTA/AdoHcy nucleosidase (Lee, J. E., Cornell, K. A., Riscoe, M. K., and Howell, P. L. (2001) Structure (Camb.) 9, 941-953) structure provide evidence for a ligand-induced conformational change in the active site and the substrate preference of the enzyme [2].
• Both hydrolysis of AdoHcy and the inhibition of the hydrolysis of AdoHcy by 3-deazaadenosine are the same in sonicates of the two macrophage cell lines [18].

Anatomical context of S-adenosylhomocysteine

• Mouse lymphocytes incubated with micromolar concentrations of adenosine or 3-deazaadenosine, in medium supplemented with L-homocysteine, rapidly accumulated supramillimolar concentrations of S-adenosylhomocysteine (AdoHcy) or S-3-deazaadenosylhomocysteine (c3AdoHcy), respectively [15].
• There was a quantitatively important export of AdoHcy from the rat hepatocytes and the cultured cells into the extracellular medium, whereas no leakage of S-adenosylmethionine was detected [19].
• A single injection of ara-A (50 mg/kg) rapidly inactivated AdoHcy hydrolase in several organs (liver, kidney, spleen, lung, heart, skeletal muscle, and brain) [16].
• In the present study, we determined whether AdoHcy altered the metabolism of phosphoinositides in human polymorphonuclear leukocytes [20].
• Under physiological conditions, the major fraction of protein-bound AdoHcy resides in the microsomal fraction, whereas most free AdoHcy was recovered in the cytosol [21].

Associations of S-adenosylhomocysteine with other chemical compounds

• Both strategies have apparent limitations arising from their direct interference with only one determinant of the intracellular AdoHcy/AdoMet ratio, a parameter proposed to be indicative of methylation inhibition [17].
• In liver cells, the accumulation of AdoHcy exceeded the inhibition of L-homocysteine egress, whereas in the fibroblasts inhibition of egress equalled the accumulation of AdoHcy [22].
• The biological consequences of maximally altering this ratio have been examined by the combined use of an inhibitor of AdoMet synthetase, L-2-amino-4-methoxy-cis-but-3-enoic acid (L-cisAMB), with inhibitors of AdoHcy hydrolase, 9-(trans-2',trans-3'-di-hydroxycyclopent- 4'-enyl)adenine (DHCA) and neplanocin A [17].
• Carbocyclic-3-deazaadenosine caused no inactivation of AdoHcyase in liver cells but caused a massive accumulation of AdoHcy, suggesting that this analogue functions as a reversible inhibitor of the enzyme [23].
• Suppression and overexpression of adenosylhomocysteine hydrolase-like protein 1 (AHCYL1) influences zebrafish embryo development: a possible role for AHCYL1 in inositol phospholipid signaling [24].

Gene context of S-adenosylhomocysteine

• Adenosylhomocysteine hydrolase-like protein 1 (AHCYL1) is a novel intracellular protein with approximately 50% protein identity to adenosylhomocysteine hydrolase (AHCY), an important enzyme for metabolizing S-adenosyl-l-homocysteine, the by-product of S-adenosyl-l-homomethionine-dependent methylation [24].
• Because changes in the AdoMet/AdoHcy ratio could potentially alter the overall excitatory state of the brain, this effect may play a role in the progressive epilepsy seen in the Pcmt1-/- mice [25].
• RESULTS: Two ternary structures of human HNMT have been determined: the Thr105 variant complexed with its substrate histamine and reaction product AdoHcy and the Ile105 variant complexed with an inhibitor (quinacrine) and AdoHcy [26].
• Here we describe the crystal structure of rat PRMT1 in complex with the reaction product AdoHcy and a 19 residue substrate peptide containing three arginines [27].
• GNMT is believed to play a role in monitoring the AdoMet/AdoHcy ratio, and hence the cellular methylation capacity, but regulation of the enzyme itself is not well understood [28].

Analytical, diagnostic and therapeutic context of S-adenosylhomocysteine

• After irradiation of the reaction mixture of [2-3H]8-N3-Ado and AdoHcy hydrolase (NAD+ form) and followed by tryptic digestion, peptides specifically photolabeled by [2-3H]3'-keto-8-N3-Ado were effectively separated from peptides nonspecifically labeled with [2-3H]8-N3-Ado using boronate affinity chromatography [29].
• Adenosylhomocysteine hydrolase. Crystallization of the purified enzyme and its properties [30].
• However, surface plasmon resonance experiments in the presence of S-adenosyl-homocysteine evince that CcrM binds as a monomer to a defined hemi-methylated DNA substrate containing the canonical methylation sequence, GANTC [31].
• Because elevated AdoHcy levels are associated with reduced mRNA methylation, we studied mRNA expression in Adox-treated cells by microarray analysis [32].
• To assess the possible functional role of GNMT phosphorylation, the effect of okadaic acid on hepatocytic AdoMet and AdoHcy levels was examined, using HPLC separation for metabolite analysis [28].

References