Crystal Structure of<i>S</i>-Adenosylhomocysteine Hydrolase from Rat Liver<sup>,</sup>

Hu, Yongbo; Komoto, Junichi; Huang, Yafei; Gomi, Tomoharu; Ogawa, Hirofumi; Takata, Yasuyuki; Fujioka, M.; Takusagawa, Fusao

doi:10.1021/bi990332k

Cited by 110 publications

(144 citation statements)

References 77 publications

Supporting

Mentioning

129

Contrasting

Order By: Relevance

“…2B). The methionine residue targeted by the dtp mutation resides in the NAD-binding domain (Hu et al, 1999;Hu et al, 2001;Tanaka et al, 2004;Turner et al, 1998), a region of the Ahcy protein that is crucial for enzyme activation (Li et al, 2007). For this reason, we predicted that Ahcy activity was reduced in dtp mutants.…”

Section: Hepatic Steatosis In Dtp Mutantsmentioning

confidence: 99%

TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase

et al. 2009

View full text Add to dashboard Cite

Hepatic steatosis and liver degeneration are prominent features of the zebrafish ducttrip (dtp) mutant phenotype. Positional cloning identified a causative mutation in the gene encoding S-adenosylhomocysteine hydrolase (Ahcy). Reduced Ahcy activity in dtp mutants led to elevated levels of S-adenosylhomocysteine (SAH) and, to a lesser degree, of its metabolic precursor Sadenosylmethionine (SAM). Elevated SAH in dtp larvae was associated with mitochondrial defects and increased expression of tnfa and pparg, an ortholog of the mammalian lipogenic gene. Antisense knockdown of tnfa rescued hepatic steatosis and liver degeneration in dtp larvae, whereas the overexpression of tnfa and the hepatic phenotype were unchanged in dtp larvae reared under germ-free conditions. These data identify an essential role for tnfa in the mutant phenotype and suggest a direct link between SAH-induced methylation defects and TNF expression in human liver disorders associated with elevated TNFα. Although heterozygous dtp larvae had no discernible phenotype, hepatic steatosis was present in heterozygous adult dtp fish and in wildtype adult fish treated with an Ahcy inhibitor. These data argue that AHCY polymorphisms and AHCY inhibitors, which have shown promise in treating autoimmunity and other disorders, may be a risk factor for steatosis, particularly in patients with diabetes, obesity and liver disorders such as hepatitis C infection. Supporting this idea, hepatic injury and steatosis have been noted in patients with recently discovered AHCY mutations.

show abstract

Section: Hepatic Steatosis In Dtp Mutantsmentioning

confidence: 99%

TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase

et al. 2009

View full text Add to dashboard Cite

show abstract

“…In addition, these two residues are also not conserved in AHCY from other species, indicating that these two residues are not critical for AHCY activity (59) and are probably not involved in the proposed lack of AHCY activity of the AHCY-like proteins. Based upon the crystal structure, (60) residues Thr-157, Thr-158, Thr-159, Asp-223, Val-224, Glu-243, Gly-300, His-301, Asn-346 and His-353 from one subunit of an AHCY multimer, and residues Lys-426 and Tyr-430 from a second subunit, were proposed to form electrostatic bounds with the cofactor NADH. (59) Using site-directed mutagenesis, Ault-Riché et al…”

Section: Regulation Of Ahcy Activitymentioning

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

“…The viability of the homozygous point mutants isolated implies that their protein products retain some SAH hydrolase activity. SAH hydrolases are well conserved proteins, and it is possible to predict the tertiary structure of SAH hydrolase 1 to a reasonable degree of confidence by comparative modeling to the known structure of its rat homolog (Hu et al, 1999) and with which it shares 63.4% identity (P. Rocha, unpublished data). Each of the substitutions resulting from the hog1 point mutations were found in a distinct region of the predicted three-dimensional structure: the G386E (hog1-2) maps to the cofactor binding domain, and both the D444N (hog1-3) and T414I (hog1-1) substitutions are located in the substrate binding domain.…”

Section: Silencing-related Mutants and Chs Silencingmentioning

confidence: 99%

The Arabidopsis HOMOLOGY-DEPENDENT GENE SILENCING1 Gene Codes for an S-Adenosyl-l-Homocysteine Hydrolase Required for DNA Methylation-Dependent Gene Silencing

et al. 2005

View full text Add to dashboard Cite

Genes introduced into higher plant genomes can become silent (gene silencing) and/or cause silencing of homologous genes at unlinked sites (homology-dependent gene silencing or HDG silencing). Mutations of the HOMOLOGY-DEPENDENT GENE SILENCING1 (HOG1) locus relieve transcriptional gene silencing and methylation-dependent HDG silencing and result in genome-wide demethylation. The hog1 mutant plants also grow slowly and have low fertility and reduced seed germination. Three independent mutants of HOG1 were each found to have point mutations at the 39 end of a gene coding for S-adenosyl-L-homocysteine (SAH) hydrolase, and hog1-1 plants show reduced SAH hydrolase activity. A transposon (hog1-4) and a T-DNA tag (hog1-5) in the HOG1 gene each behaved as zygotic embryo lethal mutants and could not be made homozygous. The results suggest that the homozygous hog1 point mutants are leaky and result in genome demethylation and poor growth and that homozygous insertion mutations result in zygotic lethality. Complementation of the hog1-1 point mutation with a T-DNA containing the gene coding for SAH hydrolase restored gene silencing, HDG silencing, DNA methylation, fast growth, and normal seed viability. The same T-DNA also complemented the zygotic embryo lethal phenotype of the hog1-4 tagged mutant. A model relating the HOG1 gene, DNA methylation, and methylation-dependent HDG silencing is presented.

show abstract

Crystal Structure ofS-Adenosylhomocysteine Hydrolase from Rat Liver^,

Cited by 110 publications

References 77 publications

TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase

TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase

The IRBIT domain adds new functions to the AHCY family

The Arabidopsis HOMOLOGY-DEPENDENT GENE SILENCING1 Gene Codes for an S-Adenosyl-l-Homocysteine Hydrolase Required for DNA Methylation-Dependent Gene Silencing

Contact Info

Product

Resources

About

Crystal Structure ofS-Adenosylhomocysteine Hydrolase from Rat Liver,

Cited by 110 publications

References 77 publications

TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase

TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase

The IRBIT domain adds new functions to the AHCY family

The Arabidopsis HOMOLOGY-DEPENDENT GENE SILENCING1 Gene Codes for an S-Adenosyl-l-Homocysteine Hydrolase Required for DNA Methylation-Dependent Gene Silencing

Contact Info

Product

Resources

About

Crystal Structure ofS-Adenosylhomocysteine Hydrolase from Rat Liver^,