A Structured-based Model for the Decreased Activity of Ala222Val and Glu429Ala Methylenetetrahydrofolate Reductase (MTHFR) Mutants

Shahzad, Khuram; Hai, Abdul; Ahmed, Awais; Kizilbash, Nadeem; Alruwaili, Jamal

doi:10.6026/97320630009929

Cited by 26 publications

(27 citation statements)

References 33 publications

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“…46 The C677T SNP is located in the N-terminal catalytic domain and is responsible for the reduction of 75% of the enzyme activity in homozygous individuals as demonstrated by in vivo assays in human lymphocytes, in vitro assays using recombinant proteins and by bioinformatics predictions. [46][47][48] The A1298C SNP is situated in the C-terminal catalytic domain binding S-adenosylmethionine (SAM), the allosteric inhibitor that negatively regulates MTHFR activity in response to methionine levels, and also acts as the main methyl donor for DNA methylation. 49 This SNP was associated with a moderate reduction of MTHFR activity (by 39% in human lymphocytes), however this was not confirmed by in vitro studies, suggesting in fact that it does not directly impact the catalytic activity of the enzyme, but rather the ability of SAM to exercise its regulatory function.…”

Section: Discussionmentioning

confidence: 99%

Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues

Llanos

Marian²,

Brasky

et al. 2015

Epigenetics

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Genome-wide DNA hypomethylation is an early event in the carcinogenic process. Percent methylation of long interspersed nucleotide element-1 (LINE-1) is a biomarker of genome-wide methylation and is a potential biomarker for breast cancer. Understanding factors associated with percent LINE-1 DNA methylation in histologically normal tissues could provide insight into early stages of carcinogenesis. In a cross-sectional study of 121 healthy women with no prior history of cancer who underwent reduction mammoplasty, we examined associations between plasma and breast folate, genetic variation in one-carbon metabolism, and percent LINE-1 methylation using multivariable regression models (adjusting for race, oral contraceptive use, and alcohol use). Results are expressed as the ratio of LINE-1 methylation relative to that of the referent group, with the corresponding 95% confidence intervals (CI). We found no significant associations between plasma or breast folate and percent LINE-1 methylation. Variation in MTHFR, MTR, and MTRR were significantly associated with percent LINE-1 methylation. Variant allele carriers of MTHFR A1289C had 4% lower LINE-1 methylation (Ratio 0.96, 95% CI 0.93-0.98), while variant allele carriers of MTR A2756G (Ratio 1.03, 95% CI 1.01-1.06) and MTRR A66G (Ratio 1.03, 95% CI 1.01-1.06) had 3% higher LINE-1 methylation, compared to those carrying the more common genotypes of these SNPs. DNA methylation of LINE-1 elements in histologically normal breast tissues is influenced by polymorphisms in genes in the one-carbon metabolism pathway. Future studies are needed to investigate the sociodemographic, environmental and additional genetic determinants of DNA methylation in breast tissues and the impact on breast cancer susceptibility.

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Section: Discussionmentioning

confidence: 99%

Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues

Llanos

Marian²,

Brasky

et al. 2015

Epigenetics

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“…The MTHFR C677T mutation is located in the catalytic domain of the enzyme and causes an alanine-tovaline substitution at position 222 (27). A previous study demonstrated that this mutation results in a thermolabile enzyme; the homozygous mutation causes an approximately 70% decrease and the heterozygous mutation results in a 35% decrease in the mean MTHFR activity (28).…”

Section: Discussionmentioning

confidence: 99%

“…However, our results showed the mutation of MTHFR C677T decreased the serum AST level (Table 2). MTHFR A1298C is located in the regulatory domain named NADPH and S-adenosylmethionine (SAM) binding site (27). The A1298C mutation does not result in synthesis of a thermolabile protein (30).…”

Section: Discussionmentioning

confidence: 99%

Folate Deficiency Was Associated with Increased Alanine Aminotransferase and Glutamyl Transpeptidase Concentrations in a Chinese Hypertensive Population: A Cross-Sectional Study

Wei

Cao

et al. 2016

J Nutr Sci Vitaminol

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Summary Alanine aminotransferase (ALT), aspartate transaminase (AST), and glutamyl transpeptidase (GGT) were three key enzymes in the hepatic metabolism. This study aimed to investigate the effect of homocysteine (Hcy) metabolism gene polymorphisms and serum Hcy and folate level on the hepatic functions in a Chinese hypertensive population. A representative sample with 480 subjects aged 28-75 was enrolled in 2005.9-2005.12 from six hospitals in different Chinese regions. Serum ALT, AST and GGT were measured by using an automatic biochemistry analyzer. Serum Hcy was measured by high-performance liquid chromatography, and serum folate was measured by chemiluminescent immunoassay. Known genotypes were detected by PCR-RFLP methods. The results showed that the MTHFR C677T mutation was related a decreased serum AST level (r520.11, p50.026), whereas the MTHFR A1298C mutation elevated serum AST level (r50.11, p50.032). Furthermore, multiple regression analysis showed that folate deficiency was associated with higher serum ALT (b (SE): 0.13 (0.06), p50.031) and GGT level (b (SE): 0.18 (0.07), p50.011). However, serum Hcy level may not affect the hepatic functions. Our data suggested that hepatic functions were affected by MTHFR gene polymorphisms and serum folate level. Further studies are needed to confirm these correlations in a larger population. Key Words folate deficiency, MTHFR gene polymorphisms, alanine aminotransferase, aspartate transaminase, glutamyl transpeptidase Fatty liver disease (FLD), including primary non-alcoholic fatty liver disease (NAFLD) and the severe form, non-alcoholic steatohepatitis (NASH) is the most common form of liver disease and is increasing throughout the world (1). In Western adults, the prevalence of NAFLD assessed by ultrasound is 20-30% and the prevalence of NASH is 3-16% (2). Alanine aminotransferase (ALT), aspartate transaminase (AST) and glutamyl transpeptidase (GGT) are three key enzymes in the liver metabolism. Studies showed that high levels of ALT, AST and GGT were associated with liver disease (3). Furthermore, serum ALT and AST levels showed relevance with the histopathological changes in liver biopsies of hepatitis C patients (4). In one carbon metabolism, folate is closely related to many important biochemical processes in vivo. A mouse experiment suggested that maternal low folate and selenium diet altered liver gene expression patterns in the offspring after weaning (5). And a previous study showed that folate supplementation reduced the serum ALT level in high baseline ALT (.40 IU/L) individuals (6). In addition, a higher serum homocysteine (Hcy) level also showed strongly correlation with liver disease (7,8).Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR) are three key regulatory enzymes in the folate and Hcy metabolisms (9). MTHFR catalyses the reduction of 5,10-methylenetetrahydrofolate (5,10-MTHF) to 5-methyltetrahydrofolate (5-MTHF) and 5-MTHF is a cofactor for Hcy methylation to methionine when cata...

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“…It has been shown that Ala222Val substitution in human MTHFR affect the phosphorylation sites in the enzyme structure by affecting the FAD-binding sites. Phosphorylation may play an essential role in the function of wild-type enzyme (Shahzad et al, 2013). Karimian and Hosseinzadeh Colagar (2014) reported that Ala222Val changes physicochemical properties of MTHFR.…”

Section: Q5mentioning

confidence: 99%

MTHFR-Ala222Val and male infertility: a study in Iranian men, an updated meta-analysis and an in silico-analysis

Nikzad

Karimian

Sareban

et al. 2015

Reproductive BioMedicine Online

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Methylenetetrahydrofolate reductase (MTHFR) functions as a main regulatory enzyme in folate metabolism. The association of MTHFR gene Ala222Val polymorphism with male infertility in an Iranian population was investigated by undertaking a meta-analysis and in-silico approach. A genetic association study included 497 men; 242 had unexplained infertility and 255 were healthy controls. Polymerase chain reaction restriction fragment length polymorphism was used for genotyping MTHFR-Ala222Val. OpenMeta[Analyst] software was used to conduct the analysis; 22 studies were identified by searching PubMed and the currently reported genetic association study. A novel in-silico approach was used to analyse the effects of Ala222Val substitution on the structure of mRNA and protein. Genetic association study revealed a significant association of MTHFR-222Val/Val genotype with oligozoospermia (OR 2.32; 95% CI, 1.12 to 4.78; P = 0.0451) and azoospermia (OR 2.59; 95% CI 1.09 to 6.17; P = 0.0314). Meta-analysis for allelic, dominant and codominant models showed a significant association between Ala222Val polymorphism and the risk of male infertility (P < 0.001). In silico-analysis showed MTHFR-Ala222Val affects enzyme structure and could also change the mRNA properties (P = 0.1641; P < 0.2 is significant). The meta-analysis suggested significant association of MTHFR-Ala222Val with risk of male infertility, especially in Asian populations.

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A Structured-based Model for the Decreased Activity of Ala222Val and Glu429Ala Methylenetetrahydrofolate Reductase (MTHFR) Mutants

Cited by 26 publications

References 33 publications

Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues

Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues

Folate Deficiency Was Associated with Increased Alanine Aminotransferase and Glutamyl Transpeptidase Concentrations in a Chinese Hypertensive Population: A Cross-Sectional Study

MTHFR-Ala222Val and male infertility: a study in Iranian men, an updated meta-analysis and an in silico-analysis

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