Disease relevance of S-adenosylhomocysteine

• Here we report four crystal structures of TrmD from Haemophilus influenzae, as binary complexes with either AdoMet or S-adenosyl-L-homocysteine (AdoHcy), as a ternary complex with AdoHcy and phosphate, and as an apo form [1].
• We report here the crystal structures of the bacteriophage T4Dam DNA adenine methyltransferase (MTase) in a binary complex with the methyl-donor product S-adenosyl-L-homocysteine (AdoHcy) and in a ternary complex with a synthetic 12-bp DNA duplex and AdoHcy [2].
• We have tried to determine whether inactivation of AdoHcyase might also contribute to dAdo toxicity to adenosine deaminase-inhibited cells. dAdo rapidly inactivates intracellular AdoHcyase and causes the accumulation of AdoHcy in WI-L2 human B lymphoblastoid cells [3].
• Reactivation of AdoHcy hydrolase with a concomitant decrease in cellular level of AdoHcy could also be demonstrated with mouse plasmacytoma (MPC-11) cells and mouse fibroblasts (L-929) exposed to ara-A, but the reactivation process was far less pronounced than with hepatocytes [4].
• Thus, in the presence of Hcy, lower concentrations of DHCA are needed to increase the intracellular concentration of AdoHcy and the AdoHcy/AdoMet ratio to levels that suppress replication of vaccinia virus [5].

High impact information on S-adenosylhomocysteine

• The mutation (sah1-1) led the cells to accumulate AdoMet besides AdoHcy, the substrate of Sah1p [6].
• A mutant allele of Saccharomyces cerevisiae gene SAH1 encoding S-adenosyl-l-homocysteine (AdoHcy) hydrolase, was isolated as a mutation that suppressed the Ca(2+)-sensitive phenotypes of the zds1Delta strain, such as the Ca(2+)-induced, Swe1p- and Cln2p-mediated G(2) cell-cycle arrest, and polarized bud growth [6].
• Exogenous AdoMet transiently led the cells to G(1) cell-cycle delay whereas AdoHcy caused growth inhibition irrelevant to the cell cycle [6].
• T4Dam contains two domains: a seven-stranded catalytic domain that harbors the binding site for AdoHcy and a DNA binding domain consisting of a five-helix bundle and a beta-hairpin that is conserved in the family of GATC-related MTase orthologs [2].
• Here we report the structure of the SET7/9 protein in the absence and presence of its cofactor product, S-adenosyl-L-homocysteine (AdoHcy) [7].

Biological context of S-adenosylhomocysteine

• A knot within the SET domain helps form the methyltransferase active site, where AdoHcy binds and lysine methylation is likely to occur [7].
• The location of AdoHcy and a number of conserved residues, helps define the precorrin binding site [8].
• The amino acid sequence, deduced from the cDNA sequence, contained the sequence of eight peptides obtained by tryptic and cyanogen bromide fragmentation of rat liver AdoHcy hydrolase [9].
• Rat liver cDNA libraries constructed in lambda gt11 were screened for reactivity with polyclonal antibodies to native S-adenosyl-L-homocysteine (AdoHcy) hydrolase (adenosylhomocysteinase; EC 3.3.1.1) [9].
• Binding of adenosine to S-adenosyl-L-homocysteine (AdoHcy) hydrolase (EC 3.3.1.1.) and partial conversion of bound adenosine to a substance liberating adenine has been demonstrated under conditions of enzymatic synthesis and hydrolysis of ADoHcy (Ueland, P. M., and Helland, S. (1980) J. Biol. Chem. 255, 7722-7727) [10].

Anatomical context of S-adenosylhomocysteine

• However, the rate of elimination of the complex in the hepatocytes exceeded the rate of reactivation of AdoHcy hydrolase [4].
• Whereas the inactivation in cell-free systems is an irreversible process, the AdoHcy hydrolase activity in rat hepatocytes exposed to ara-A gradually recovered upon prolonged incubation of the cells in a medium devoid of ara-A [4].
• This selective suppression was also observed when enriched murine T and B cells were stimulated with mitogens, although S-adenosyl-L-homocysteine (AdoHcy), the substrate of AdoHcyase, was similarly elevated in both populations [11].
• AdoHcy hydrolase activity in spleens of DZ2002-treated mice was substantially blocked, and not surprisingly, AdoHcy levels were significantly elevated compared with controls [12].
• Progesterone production by cells from 4 CL was unaffected by the presence of SAH when treated with Medium 199 (M199) (75 +/- 32), 10 micrograms cholera toxin, which directly stimulates adenylate cyclase on the cytoplasmic side of plasma membranes (168 +/- 19), or 3 mM dibutyryl cAMP (210 +/- 40).(ABSTRACT TRUNCATED AT 250 WORDS)[13]

Associations of S-adenosylhomocysteine with other chemical compounds

• It was concluded that adenosine is sequestered in rat hepatocytes through the interaction with AdoHcy hydrolase [10].
• Adenosine and homocysteine at concentrations (1 mM each) that enhance TNF-alpha-induced cytotoxicity accumulate S-adenosyl-L-homocysteine (AdoHcy), a potent inhibitor of S-adenosyl-L-methionine-dependent methylation reactions [14].
• In these studies, Hcy was also observed to potentiate the increase in cellular levels of AdoHcy and the ratio of AdoHcy/S-adenosyl-L-methionine (AdoMet) in DHCA-treated cells [5].
• The reversible S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor methyl 4-(adenin-9-yl)-2-hydroxybutanoate (DZ2002) suppresses macrophage activation and function [12].
• Cells from 7 CL were treated with 0 and 5 ng LH, in the presence and absence of methylation inhibitor, S-adenosyl-homocysteine (SAH, 1 mM) [13].

Gene context of S-adenosylhomocysteine

• The objective of this work was to evaluate the possible in vitro interactions of S-adenosyl-l-methionine (SAM) and its metabolites S-(5'-Adenosyl)-l-homocysteine (SAH), 5'-Deoxy-5'-(methylthio)adenosine (MTA) and methionine with cytochrome P450 enzymes, in particular CYP2E1 [15].
• DNMT2 binds AdoHcy in the same conformation as confirmed m(5)C MTases and, while DNMT2 shares all sequence and structural features with m(5)C MTases, it has failed to demonstrate detectable transmethylase activity [16].
• In addition, preloading L929 cells with AdoHcy resulted in enhanced responses to TNF-alpha, suggesting that AdoHcy potentiates TNF-alpha-induced cytotoxicity [14].
• As predicted, TM0872 has a typical MT domain, and binds endogenous AdoMet, or co-crystallized AdoHcy, in a manner consistent with other known MT structures [17].
• Here, we examined whether DZ2002 alters type 1 helper T cell (Th1) and/or type 2 helper T cell (Th2) immune responses, and whether these effects are associated with both the inhibition of AdoHcy hydrolase and intracellular elevation of endogenous AdoHcy [12].

Analytical, diagnostic and therapeutic context of S-adenosylhomocysteine

• Titration calorimetry reveals a dual mode, involving a primary dominant exothermic reaction followed by a weaker endothermic one, for the recognition of AdoMet and AdoHcy by M.HhaI [18].
• S-Adenosyl-methionine (AdoMet) and AdoHcy concentrations were determined by using a modified isotope dilution-ion exchange chromatography-high pressure liquid chromatography technique sensitive to less than 10 pmol [19].
• The result of MALDI-MS assay indicated that epimedin A and ikarisoside F from the extract could bind to AdoHcy hydrolase [20].
• Compared to TSA, AdoHcy did not induce apoptosis in the SNU-16 gastric cancer cell line, and RT-PCR was performed for selective genes to confirm the microarray data [21].
• To investigate the effects of two drugs that can reportedly affect chromatin remodeling, we analyzed the gene expression profiles of TSA and AdoHcy in a gastric cancer cell line using 14 K cDNA microarray [21].

References