Immunomodulation by an Inhibitor of S-Adenosyl-L-Homocysteine Hydrolase: Inhibition of in Vitro and in Vivo Allogeneic Responses

Wolos, Jeffrey A.; Frondorf, Kathleen; Babcock, George F.; Stripp, Sally A.; Bowlin, Terry L.

doi:10.1006/cimm.1993.1165

Cited by 33 publications

(24 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(10,11) In addition to these antiviral effects, AHCY inhibitors have also been attributed antiparasitic, (12,13) anti-arthritic (14) and immunosuppressive (15) effects.…”

Section: Discussionmentioning

confidence: 99%

The IRBIT domain adds new functions to the AHCY family

2008

View full text Add to dashboard Cite

SummaryDuring the past few years, the IRBIT domain has emerged as an important add-on of S-adenosyl-L-homocystein hydrolase (AHCY), thereby creating the new family of AHCY-like proteins. In this review, we discuss the currently available data on this new family of proteins. We describe the IRBIT domain as a unique part of these proteins and give an overview of its regulation via (de)phosphorylation and proteolysis. The second part of this review is focused on the potential functions of the AHCY-like proteins. We propose that the IRBIT domain serves as an anchor for targeting AHCY-like proteins towards cytoplasmic targets. This leads to regulation of (i) The AHCY family AHCY S-adenosyl-L-homocystein (SAH) hydrolase (AHCY) is a ubiquitous, tetrameric enzyme that catalyzes the reversible hydrolysis of SAH to adenosine and L-homocysteine. SAH is formed as a by-product of S-adenosyl-L-methionine (SAM) through transmethylation reactions. The hydrolysis of SAH is required to maintain low cellular concentrations of SAH, which is a product inhibitor of S-adenosyl-L-methionine (SAM)-dependent transmethylation reactions.(1-4) Inhibition of AHCY results in the intracellular accumulation of SAH, causing a significant increase in the intracellular SAH/SAM ratio and the subsequent inhibition of SAM-dependent methylations.( 5 -8) SAM is the major methyl donor for delivery of methyl groups to DNA, RNA, proteins and cellular metabolites in eukaryotes and SAH hydrolysis is the only source of homocysteine in mammals.(9) AHCY has become an attractive target for design of broad-spectrum antiviral agents because of the inhibitory effects of elevated intracellular SAH concentrations on viral mRNA cap-methylating enzymes. (10,11) In addition to these antiviral effects, AHCY inhibitors have also been attributed antiparasitic, (12,13) anti-arthritic (14) and immunosuppressive (15) effects.The importance of AHCY for mammalian survival is suggested by the fact that a chromosomal deletion that includes the gene encoding AHCY causes embryonic lethality in mice.(16) Elevated homocysteine levels have been reported as a risk factor for dementia and Alzheimer's disease, (17) and as a possible risk marker for vascular disease. (18,19) Human AHCY deficiency, such as in hypermethionemia, results in severe biochemical abnormalities, including plasma elevations of 150-fold in SAH, 30-fold in SAM and 12-fold in methionine. (20,21) So far, three mutations in the AHCY gene have been found to reduce the activity of the AHCY enzyme, resulting in the signs and symptoms of hypermethionemia. (22,23) AHCY orthologues have been identified in many species, including bacteria, nematodes, yeast, plants, insects and vertebrates. In contrast, the AHCY-like (AHCYL) family members AHCYL1 (also termed IRBIT, the inositol 1,4, 5-trisphosphate (IP 3 ) receptor (IP 3 R) binding protein released by IP 3 ) and AHCYL2 (KIAA0828 in human) are only predicted in segmented multicellular organisms, like vertebrates (eg Takifugu rubripes (fugu fish), Danio rerio (zebrafish), Xen...

show abstract

“…(10,11) In addition to these antiviral effects, AHCY inhibitors have also been attributed antiparasitic, (12,13) anti-arthritic (14) and immunosuppressive (15) effects.…”

Section: Discussionmentioning

confidence: 99%

The IRBIT domain adds new functions to the AHCY family

2008

View full text Add to dashboard Cite

show abstract

“…Because of its important role in regulating biological methylation reactions (2), AdoHcy hydrolase has been an attractive target for the design of antiviral (3)(4)(5)(6), antiparasitic (7), and antiarthritic agents (8).…”

Section: S-adenosyl-l-homocysteine (Adohcy)mentioning

confidence: 99%

“…Isolation and Identification of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]Carboxymethylated PeptidesThe specific radiolabeled AdoHcy hydrolases obtained from the procedures described above were heated at 100°C for 3 min in the presence of 8 M urea. To the denatured protein, dithiothreitol was added to a final concentration of 1 mM and incubated at 50°C for 10 min.…”

mentioning

confidence: 99%

Chemical Modification and Site-directed Mutagenesis of Cysteine Residues in Human Placental S-Adenosylhomocysteine Hydrolase

Yuan

Ault-Riché

Borchardt

1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…AdoHcy hydrolase inhibitors demonstrate both prophylactic and therapeutic effects in several immune-mediated processes, including collagen-and peptidoglycan-induced arthritis (Wolos et al, 1993c;Saso et al, 2001), skin graft rejection (Wolos et al, 1993a), and delayed-type hypersensitivity (DTH) responses (Saso et al, 2001). In vitro, type I inhibitors, such as MDL-28,842 and 9-[(1ЈR,2ЈS,3ЈR)-2Ј,3Ј-dihydroxycyclopent-4Ј-en-1-yl]adenine (DHCaA), block T cell proliferation and IL-2 production (Wolos et al, 1993b;Saso et al, 2001).…”

mentioning

confidence: 99%

Inhibition ofS-Adenosyl-l-homocysteine Hydrolase Induces Immunosuppression

Wu¹,

Fu²,

Zhou³

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Lymphocytes depend on transmethylation reactions for efficient activation and function. These reactions are primarily catalyzed by S-adenosylmethionine-dependent methyltransferases, which convert S-adenosylmethionine to S-adenosyl-Lhomocysteine. S-adenosyl-L-homocysteine is then hydrolyzed by S-adenosyl-L-homocysteine hydrolase to prevent feedback inhibition of transmethylation reactions. By impeding S-adenosyl-L-homocysteine hydrolase, a build-up of S-adenosyl-L-homocysteine occurs, and most intracellular transmethylation reactions cease. Thus, a nontoxic inhibitor of this enzyme might be a useful immunosuppressive therapeutic agent. We identified a potent reversible type III inhibitor of S-adenosyl-L-homocysteine hydrolase, DZ2002 [methyl 4-(adenin-9-yl)-2-hydroxybutanoate], and determined its cytotoxic and immunologic effects. We demonstrated that DZ2002 blocked S-adenosyl-Lhomocysteine hydrolase more effectively than a type I inhibitor, but cytotoxicity from DZ2002 was greatly reduced. Although DZ2002 did not prevent concanavalin A-induced T cell proliferation or interleukin (IL)-2 production, it significantly reduced both a mixed lymphocyte reaction and IL-12 production from in vitro-stimulated splenocytes. In addition, levels of CD80 and CD86 on human monocytic THP-1 cells were decreased in a dose-dependent manner in the presence of 0.1 to 10 M DZ2002, and decreases were also seen in IL-12 and tumor necrosis factor-␣ production from both mouse thioglycollatestimulated peritoneal macrophages and THP-1 cells. In vivo, DZ2002 significantly suppressed a delayed-type hypersensitivity reaction as well as antibody secretion. We conclude that DZ2002's immunosuppressive effects are likely not solely attributed to T cell inhibition but also to the obstruction of macrophage activation and function through reductions in cytokine output and/or T cell costimulation. These data suggest an important dual role for the S-adenosyl-L-homocysteine hydrolase in both macrophage and T cell function.

show abstract

Immunomodulation by an Inhibitor of S-Adenosyl-L-Homocysteine Hydrolase: Inhibition of in Vitro and in Vivo Allogeneic Responses

Cited by 33 publications

References 0 publications

The IRBIT domain adds new functions to the AHCY family

The IRBIT domain adds new functions to the AHCY family

Chemical Modification and Site-directed Mutagenesis of Cysteine Residues in Human Placental S-Adenosylhomocysteine Hydrolase

Inhibition ofS-Adenosyl-l-homocysteine Hydrolase Induces Immunosuppression

Contact Info

Product

Resources

About