Functional analysis of human S-adenosylhomocysteine hydrolase isoforms SAHH-2 and SAHH-3

Fumić, Ksenija; Belužić, Robert; Ćuk, Mario; Pavkov, Tea; Kloor, Doris; Barić, Ivo; Mijić, Ivana

doi:10.1038/sj.ejhg.5201757

Cited by 7 publications

(3 citation statements)

References 21 publications

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“…However, variant allozymes with Trp38 and Arg123 substitutions displayed significant, but not striking decreases in levels of enzyme activity. The apparent K m value that we observed for the WT allozyme compared favorably with that reported previously (Fumic et al. 2007).…”

Section: Discussionsupporting

confidence: 90%

Human S‐adenosylhomocysteine hydrolase: common gene sequence variation and functional genomic characterization

Feng

Keshtgarpour

Pelleymounter

et al. 2009

Journal of Neurochemistry

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S‐Adenosylhomocysteine hydrolase (AHCY) is the only mammalian enzyme known to catalyze the hydrolysis of S‐adenosylhomocysteine. We have used a genotype‐to‐phenotype strategy to study this important enzyme by resequencing AHCY in 240 DNA samples from four ethnic groups. Thirty‐nine polymorphisms were identified – 28 of which were novel. Functional genomic studies for wild type AHCY and the three variant allozymes identified showed that two variant allozymes had slight, but significant decreases in enzyme activity, but with no significant differences in levels of immunoreactive protein. Luciferase reporter gene assays for common 5′‐flanking region haplotypes revealed that one haplotype with a frequency of ∼2% in Caucasian‐American subjects displayed a decreased ability to drive transcription. The variant nucleotide at 5′‐flanking region single nucleotide polymorphism (SNP) (−34) in that haplotype altered the DNA‐protein binding pattern during electrophoresis mobility shift assay. Finally, an AHCY genotype‐phenotype association study for expression in lymphoblastoid cells identified four SNPs that were associated with decreased expression. For the IVS6 (intervening sequence 6, i.e., intron 6) G56 > C SNP among those four, electrophoresis mobility shift assay showed that a C > G nucleotide change resulted in an additional shifted band. These results represent a step toward understanding the functional consequences of common genetic variation in AHCY for the regulation of neurotransmitter, drug and macromolecule methylation.

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Section: Discussionsupporting

confidence: 90%

Human S‐adenosylhomocysteine hydrolase: common gene sequence variation and functional genomic characterization

Feng

Keshtgarpour

Pelleymounter

et al. 2009

Journal of Neurochemistry

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“…Regardless of the mechanism that accounts for the observed SAM and SAH levels in dtp heterozygous and deazaA-treated adult fish, hepatic steatosis in these fish raises the question of whether human AHCY polymorphisms that have only mild effects on methionine metabolism might be a risk factor for the development of steatosis associated with obesity, alcohol consumption and other conditions, such as chronic hepatitis C infection or drug-induced steatosis. Polymorphisms in the methionine metabolism gene MTHFR and hyperhomocysteinemia have been reported to promote steatosis and fibrosis in chronic hepatitis C patients (Adinolfi et al, 2005), and human AHCY polymorphisms that alter protein thermostability have already been described (Fumic et al, 2007). Given the potentially beneficial effects of AHCY inhibitors in treating cancer and autoimmune diseases (Hermes et al, 2008;Lawson et al, 2007;Tan et al, 2007), the population of patients that may benefit from AHCY genotyping could increase significantly in the near future.…”

Section: Relationship Of the Zebrafish And Human Ahcy Deficiency Phenmentioning

confidence: 99%

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

et al. 2009

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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.

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“…However, only few associated mutations have been characterized at the molecular level. In addition to the pathological variants that strongly affect AHCY activity, non-pathologic polymorphic isoforms of AHCY found in different populations display reduced thermal stability of the protein and enzymatic activity (Fumic et al, 2007). More recently, genetic variations of AHCY have been linked to different prognosis of children with neuroblastoma (Novak et al, 2016), thus providing evidence of the potential use of AHCY variants as a molecular biomarker.…”

Section: Resultsmentioning

confidence: 99%

Functional and Pathological Roles of AHCY

Vizán

Croce

Aranda

2021

Front. Cell Dev. Biol.

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Adenosylhomocysteinase (AHCY) is a unique enzyme and one of the most conserved proteins in living organisms. AHCY catalyzes the reversible break of S-adenosylhomocysteine (SAH), the by-product and a potent inhibitor of methyltransferases activity. In mammals, AHCY is the only enzyme capable of performing this reaction. Controlled subcellular localization of AHCY is believed to facilitate local transmethylation reactions, by removing excess of SAH. Accordingly, AHCY is recruited to chromatin during replication and active transcription, correlating with increasing demands for DNA, RNA, and histone methylation. AHCY deletion is embryonic lethal in many organisms (from plants to mammals). In humans, AHCY deficiency is associated with an incurable rare recessive disorder in methionine metabolism. In this review, we focus on the AHCY protein from an evolutionary, biochemical, and functional point of view, and we discuss the most recent, relevant, and controversial contributions to the study of this enzyme.

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Functional analysis of human S-adenosylhomocysteine hydrolase isoforms SAHH-2 and SAHH-3

Cited by 7 publications

References 21 publications

Human S‐adenosylhomocysteine hydrolase: common gene sequence variation and functional genomic characterization

Human S‐adenosylhomocysteine hydrolase: common gene sequence variation and functional genomic characterization

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

Functional and Pathological Roles of AHCY

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