Disease relevance of ACSM3

• To assess its role in human hypertension, a human SA cDNA was cloned from a liver library [1].
• In conclusion, the present data offers support for variation in SAH having a role in predisposition to overweight in hypertensives [2].
• Association between SAH, an acyl-CoA synthetase gene, and hypertriglyceridemia, obesity, and hypertension [3].
• There was therefore a significant difference between the groups in the SAM/SAH (methylation) ratio (HIV 2.7 [1.0] vs control 7.6 [3.4]; p less than 0.001) [4].
• Alcoholic liver disease is associated with abnormal hepatic methionine metabolism, including increased levels of homocysteine and S-adenosylhomocysteine (SAH) and reduced levels of S-adenosylmethionine (SAM) and glutathione (GSH) [5].

Psychiatry related information on ACSM3

• Our results demonstrated that chronic alcohol consumption in mice not only decreased hepatic S-adenosylmethionine levels but also increased hepatic SAH levels, which resulted in a significantly decreased S-adenosylmethionine-to-SAH ratio [6].
• Reassurance and treatment of depressive symptoms could be important to improve the long-term outcome of PM SAH patients [7].
• This study investigates the role of brain SAH in the cognitive and neurological disruption in Alzheimer's disease [8].
• The most important changes from the previously reported method are a shorter derivatization reaction time, the use of a solid-phase extraction resulting in an increase of the method's sensitivity, and the use of only one chromatographic system to separate SAM and SAH (in which the use of an ion-pairing reagent in the mobile phase is avoided) [9].

High impact information on ACSM3

• To investigate whether the disorders share a pathogenetic mechanism, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) were measured in the cerebrospinal fluid (CSF) of 20 HIV-seropositive patients and 30 HIV-negative patients who were undergoing lumbar puncture for other medical reasons [4].
• In a pig model of subacute combined degeneration and in vitamin-B12-deficient human beings, the primary cause of the low methylation ratio is impaired recycling of SAH back to SAM, a process which requires vitamin-B12-dependent methionine synthase [4].
• There were no correlations between SAM or SAH concentrations or methylation ratio and age or sex in both groups, or serum B12 and folate concentrations, CSF folate, serum or CSF methylmalonic acid, risk factors, body mass index, specific drug treatment received, or disease stage in the HIV group [4].
• In eukaryotic cells, this inhibition is relieved by hydrolysis of SAH to adenosine and homocysteine catalyzed by SAH hydrolase (SAHH) [10].
• Several methionine metabolism-related and glutathione synthetic pathway intermediates, including S-adenosylmethionine (SAMe) and SAH, were modulated in R89C versus control mice [11].

Chemical compound and disease context of ACSM3

• Two medium-chain acyl-coenzyme A synthetase genes, SAH and MACS1, are associated with plasma high-density lipoprotein cholesterol levels, but they are not associated with essential hypertension [12].
• Increased galactose content caused increased accumulation of N-(2-hydroxypropyl)methacrylamide copolymers by two human hepatoma cell lines (Hep G2 and SAH), but accumulation by rat and mouse hepatoma (HTC and NCTC) was not galactose dependent [13].
• These results suggest that chronic elevation in plasma homocysteine levels, such as those associated with nutritional deficiencies or genetic polymorphisms in the folate pathway, may have an indirect and negative effect on cellular methylation reactions through a concomitant increase in intracellular SAH levels [14].
• BACKGROUND: We have developed an assay that uses stable-isotope-dilution liquid chromatography-mass spectrometry to assess S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) in body fluids to investigate the relationship of these metabolites to hyperhomocysteinemia [15].
• The increased antiviral activity following addition of homocysteine was observed only with those viruses (i.e. vaccinia and vesicular stomatitis virus) that belong to the activity spectrum of SAH hydrolase inhibitors [Biochem Pharmacol 36: 2567-2575, 1987], and only in those cells in which the SAH hydrolase inhibitors are normally active [16].

Biological context of ACSM3

• By using a restriction fragment length polymorphism, we carried out cosegregation analyses between the genotype of the SA gene and blood pressure in three F2 cohorts and observed significant effects of the SA gene on blood pressure in all of those cohorts [17].
• Association and linkage studies in a large sample of hypertensive patients, normotensive control subjects, and multiplex sibships with these markers and other microsatellites in close proximity to SA revealed no evidence favoring involvement of the gene in the disease in humans [1].
• The deduced amino acid sequence from the isolated human SA cDNA consisted of 578 amino acid residues and had slight homology to a bacterial enzyme, acetyl-coenzyme A synthase [17].
• A microsatellite marker was developed from a yeast artificial chromosome clone containing SA and mapped by linkage to human chromosome 16p13.11-12 [1].
• 3. Polymerase chain reaction amplification of human genomic DNA revealed two introns located in the SA gene, one of which contains a frequent polymorphism due to a single nucleotide substitution (cytosine to thymidine at residue 79 of the intron) [1].

Anatomical context of ACSM3

• In this study we have located the human homologue of the SA gene to chromosome 16p13.11, by a combination of fluorescence in-situ hybridization and analysis of somatic cell hybrids carrying different segments of chromosome 16 [18].
• Transient expression of the SA protein in mammalian cells confirmed that it is expressed in mitochondria and has medium-chain fatty acid:CoA ligase activity [3].
• Plasma SAH levels were positively correlated with intracellular lymphocyte SAH levels (r = 0.81; p < 0.001) and also with lymphocyte DNA hypomethylation (r = 0.74, p < 0.001) [14].
• DESIGN: Hematologic data and concentrations of cobalamin, red blood cell folate, serum folate, tHcy, methylmalonic acid, SAM, SAH, and other metabolites were measured in 119 serum specimens from pregnant Brazilian women (gestational age: 37-42 wk) and their newborns' placental veins at the time of delivery [19].
• The authors conclude that the elevated levels of TGF-beta1 in CSF after SAH are derived initially from blood and later from endogenous sources such as the choroid plexus [20].

Associations of ACSM3 with chemical compounds

• CONCLUSIONS: SNPs in the MACS1 and SAH genes contribute to plasma levels of high-density lipoprotein cholesterol [12].
• Haplotype analysis indicated that a haplotype defined by the I/D polymorphism of SAH and the L513S polymorphism in MACS2 was highly significantly associated with the triglyceride level [21].
• The HIV-seropositive patients had significantly lower CSF concentrations of SAM (mean 77 [SD 25] vs 131 [35] nmol/l; p less than 0.001) and significantly higher concentrations of SAH (30.5 [6.8] vs 19.0 [7.1] nmol/l; p less than 0.001) than the controls [4].
• S-adenosylhomocysteine (SAH) is product of methionine in transsulfuration pathway and a potent competitive inhibitor of most methyltransferases [6].
• Mutation-associated decreases in SAH and SAMe could compromise needed cysteine availability to generate glutathione during oxidative stress [11].

Other interactions of ACSM3

• SNP in exon 8 of the A/G polymorphism of the MACS1 gene and the G/T SNP in intron 3 of the SAH gene were associated with plasma levels of plasma high-density lipoprotein cholesterol [12].
• We recently reported that genetic polymorphisms of SAH, an acyl-CoA synthetase for fatty acids, might contribute to multiple risk factors, especially hypertriglyceridemia [21].

Analytical, diagnostic and therapeutic context of ACSM3

• The SA genotype was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) with Pst I [22].
• To extend this finding we carried out a case-control study of several recently identified polymorphisms in SAH: 1) an insertion/deletion of TTTAA at nucleotide --1037 in the promoter; 2) an insertion/deletion of two Alu like sequences in intron 1; and 3) an A-G variant in intron 12 located 7 bp upstream from exon 13 [2].
• The previously observed associations between an SAH polymorphism and the waist-to-hip ratio appear to be due to linkage disequilibrium with the L513S polymorphism [21].
• We therefore propose that Siva-1 or its SAH region can be used as a potentiator of cisplatin-based chemotherapy [23].
• Using a sensitive new high pressure liquid chromatography method with coulometric electrochemical detection, plasma SAH levels in healthy young women were found to increase linearly with mild elevation in homocysteine levels (r = 0.73; p < 0.001); however, S-adenosylmethionine levels were not affected [14].

References