Methionine synthase reductase, also known as MSR, is an enzyme that in humans is encoded by the MTRR gene. [5] [6]
Methionine synthase reductase, also known as MSR, is an enzyme that in humans is encoded by the MTRR gene. [5] [6]
Methionine is an essential amino acid required for protein synthesis and one-carbon metabolism. Its synthesis is catalyzed by the enzyme methionine synthase. Methionine synthase eventually becomes inactive due to the oxidation of its cobalamin cofactor. Methionine synthase reductase regenerates a functional methionine synthase via reductive methylation. It is a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. [6]
Methionine synthase reductase (MTRR) is primarily involved in the reductive methylation of homocysteine to methionine, utilizing methylcob(I)alamin as an intermediate methyl carrier. [7] Methionine is an essential amino acid in mammals, necessary for protein synthesis and one carbon metabolism. In its activated form, S-adenosylmethionine acts as a methyl donor in biological transmethylation reactions and as a propylamine donor in polyamine synthesis. [7] A major product of methionine demethylation is homocysteine. Remethylation of homocysteine occurs via a cobalamin dependent enzyme, methionine synthase (MTR). [7] The folate cycle is linked to homocysteine metabolism via MTR. [8] Circulating blood folate (5-methyl tetrahydrofolate, 5-MTHF) donates methyl groups to MTR to be utilized in cellular methylation. A methyl cobalt bond of the intermediary methyl carrier, methlycob(III)alamin is cleaved heterolytically producing cobalamin in its highly reactive oxidation state as cob(I)alamin. The enzyme bound cob(I)alamin cofactor of the MTR enzyme functions as a methyl carrier between 5-MTHF and homocysteine. [7] Cob(I)alamin is oxidised to cob(II)alamin about once every 100 methyl transfer cycles, rendering the cob(I)alamin-MTR-enzyme complex inactive. [9] Reactivation of this enzyme complex occurs through reductive remethylation by MTRR, utilizing S-adenosylmethionine as a methyl donor. MTR reactivation can also be NADPH dependent involving two redox proteins, soluble cytochrome b5 and reductase 1. However, this pathway is responsible for a minor role in reactivation, whilst MTRR remains a major contributor in this reductive reactivation.
Biological processes influenced by MTRR include: sulfur amino acid metabolic process, DNA methylation, methionine metabolic process, methionine biosynthetic process, methylation, S-adenosylmethionine cycle, homocysteine catabolic process, folic acid metabolic process, oxidation-reduction process and negative regulation of cystathionine beta-synthase activity. [7] [8]
The Methionine Synthase Reductase (MTRR) gene primarily acts in the reductive regeneration of cob(I)alamin (vitamin B12). [10] Cob(I)alamin is a cofactor that maintains activation of the methionine synthase enzyme (MTR) Methionine synthase, linking folate and methionine metabolism. Donation of methyl groups from folate are utilized for cellular and DNA methylation, influencing epigenetic inheritance. [10] [7] [11]
The gene was mapped to human chromosome 5. Gene specific primer pairs resulted in PCR amplification of a product matched by size to a hybrid-mapping panel containing only chromosome 5 as its human genetic material. [5] The product DNA sequence matched pre-established gene markers specific to this chromosome. Exact gene cytogenic position was determined by mapping to an artificial chromosomal construct containing the gene via fluorescence in situ hybridization. [5] The exact MTRR gene location was mapped to 5p15.3-p15.2. [5]
The MTRR gene is associated with a family of electron transferases known as the Ferredoxin-NADP(+) reductase (FNR) family. Found in 15 primates and over 16 tissues in humans, MTRR is 34 kb long. [12] The gene comprises 15 exons and includes numerous cytolosic mitochondrial mRNA isoforms. Multiple cofactor binding sites assist in the maintenance of MTR activity via reductive remethylation. All binding domains involve selective and non-covalent interactions except the flavodoxin_1 domain. [12]
Flavoproteins are ubiquitous biocatalysts binding specific redox active prosthetic groups. The domain is associated with electron transfer proteins and used in electron transport systems. [12] The cofactor flavin-mononucleotide (FMN) is bound non-covalently to the domain, which is functionally interchangeable with iron-sulfur constituted proteins regulating electron transfer or ferredoxins. [12]
Flavin adenine dinucleotide in its oxidized form, FAD is a cofactor of flavoprotein oxidoreductase enzymes. Flavoprotein pyridine nucleotide cytochrome reductases, including FAD catalyse the interchange of reducing equivalents (H+ or electrons). Initial electron donors and final electron acceptors comprise single electron carriers and two electron carrying nicotinamide dinucleotides respectively. [12]
Evolutionary conserved protein domain corresponding to oxidoreductase activity. NAD binding catalyzes redox reactions to alter the oxidation state of metal ions, using NADP+ as an electron acceptor. [12]
Involved in the reductive remethylation of cob(II)alamin using S-adenosylhomocysteine as a methyl donor. Catalyses the reaction:
[methionine synthase]- cob(II)alamin + NADPH + H+ + S-adenosylmethionine → [methionine synthase]-methylcob(I)alamin + S-adenosylhomocysteine + NADP+. [12]
Belongs to the oxidoreductase family, oxidizing metal ions with NADP+ acting as an electron acceptor. Uses FAD as a cofactor when catalyzing the following reaction:
2cob(II)alamin + NADP+ 2aquacob(III)alamin + NADPH + H+. [12]
Interacts with the cofactor or prosthetic group, FAD of flavoproteins and contains a flavin moiety in the form of FAD or FMN (flavin mononucleotide). The domain non-covalently binds oxidized FAD or its reduced form, hydroquinone (FADH2). [12]
Flavin mononucleotide binding domain interacts with a coenzyme of flavoprotein oxidoreductase enzymes, FMN. [12]
Nicotinamide adenine dinucleotide phosphate is a coenzyme present in redox and biosynthetic reactions. The domain binds NADP in its oxidised or reduced forms as NADP+ or NADPH respectively. [12]
Involves a non-covalent and selective interaction with the reduced form of NADP, NADPH. [12]
The domain is associated with the oxidoreductase family and acts on NADH or NADPH, using a heme protein as an electron acceptor. Requires FAD and FMN as cofactors to catalyse the reaction:
NADPH + H+ + n oxidised hemoprotein = NADP+ + n reduced hemoprotein. [12]
Binding domain involved in the interaction with proteins or protein complexes. [12]
Mutations involved in the formation of premature termination codons result in truncated mutated proteins if translated. [21] Mutants exhibit an absence of FAD/NADPH binding domains and unstable mRNA due to nonsense mediated decay (NMD). NMD is not present in (MTRR):c.1573C>T or (MTRR):c.1622_1623dupTA polymorphisms. [21] The (MTRR):c.903+469T>C variant is also associated with the formation of premature termination codons. [21]
 | This section needs more reliable medical references for verification or relies too heavily on primary sources .(October 2017) |  |
Single nucleotide polymorphisms (SNPs) in the MTRR gene impair MTR activity, resulting in elevated homocysteine levels due to compromised methylation to methionine. Elevated homocysteine levels are associated with birth defects in addition to pregnancy complications, cardiovascular disease, cancer, [23] megaloblastic anemia, Alzheimer’s diseases and cognitive dysfunction in the elderly. [24] Presence of the mutant variant (66A>G) is associated with significantly lower, up to 4 fold, plasma cobalamin and folate levels in cardiac transplant patients. [23] A consequent decrease in S-adenosylmethionine availability results in DNA hypomethylation. Low folate limits one carbon metabolism and homocysteine metabolism as vitamin B12 interacts with folate in this pathway. [24] Additionally, this mutation is associated with an increased risk in type 2 diabetes. [25]
Specific SNPs are associated with an elevated risk of lung cancer and interact with folate dietary intake in this etiology. The (MTRR):c.66A>G mutation relates to a significant increase in the risk of lung cancer. When co-expressed with the polymorphism (MTR): 2756A>G, lung cancer risk is further increased in a dose dependent manner. [24] Correlation between this polymorphism and increased risk of lung cancer is present with low folate intake and high vitamin B12, suggesting a B12 independent mechanism of action. [24] This mutation is also associated with an increased risk in colorectal cancer, [26] [27] [28] [29] acute lymphoblastic leukemia, [30] bladder cancer, [31] cervical intraepithelial neoplasia, non-Hodgkin lymphoma [32] and oesophageal squamous cell carcinoma. [33]
Remethylation of homocysteine to methionine by MTR requires the derivative of cobalamin, methylcobalamin. Cobalamin metabolism is initiated by the endocytosis of cobalamin bound to the plasma protein transcobalamin (II). Cleavage of this complex produces free cobalamin, translocating from lysosome to cytoplasm. Conversion can occur to 5’-deoxyadenosylcobalamin (AdoCbl) activating the mitochondrial enzyme methylmalonly coenzyme A mutase or to methylcobalamin (MeCbl). [34] An error in cobalamin metabolism resulting in decreased MeCbl and unaffected AdoCbl is characteristic of the CblE type of homocystinuria. [34] This complementation is rare with autosomal recessive inheritance. The inherited methionine synthase functional deficiency corresponds to a defect in the reducing system required to activate the MTR enzyme. Symptoms of this condition comprise developmental retardation, megaloblastic anemia, homocystinuria, hypomethioninemia, cerebral atrophy and hyperhomocysteinemia. [34] However, hypomethioninemia remains an inconsistent symptom. Decreased MeCbl alongside normal cobalamin uptake is suggestive of decreased intracellular methionine biosynthesis. Occurring mainly in childhood, 15 pathogenic mutations can be associated with CblE type homocystinuria. [35] Additionally, vascular abnormalities are associated with this defect. [36] Impaired reduction of an oxidised cobalt atom in the active site of MTR is associated with this condition, where enzyme activity can be corrected with reducing agents. [35] Rare polymorphisms related to this disease include (MTRR):c.1459G>A, (MTRR):c.1623-1624insTA and (MTRR):c.903+469T>C. [35] These mutations, excluding (MTRR):c.1459G>A result in a frame shift, producing premature termination codons. [35] As consequent products are distant from normal, mutant mRNA arises and nonsense mediated decay (FMN) is initiated. [35] The large insertion of 903_904ins140 corresponding to 903+469T>C is most prevalent in CblE pathology. The activation of an enhanced splicer within intron 6 is incomplete, producing small quantities of normal spliced MTRR mRNA. [35] Prenatal diagnosis of this condition is possible using [14C] methyltetrahydrofolate. [35] Mutation analysis in native chorionic villi and [14C] formate in amino acids within these villi or cultured amniocytes is indicative of the CblE defect. [35] Additionally, macrocytic anemia is a typical feature of the CblE defect and can be corrected though OH-Cobalamin administration or folate supplementation. [35]
Homocysteine, a sulfur based amino acid is the main product of methionine demethylation. Elevated homocysteine is an independent risk factor for cardiovascular disease and inversely correlated to consumed vitamin B12/B6 and folate levels. [37] Homocysteine methylation to methionine is catalyzed by MTR, resulting in appropriate intracellular levels of methionine and tetrahydrofolate, alongside non-toxic homocysteine levels. The GG phenotype promotes the development of premature coronary artery disease (CAD) independent of hyperhomocysteinemia. [37] Hyperhomocysteinemia is associated with cerebral, coronary and peripheral atherosclerotic pathology as it promotes endothelial cell dysfunction, platelet adhesion and vascular smooth muscle cell proliferation. [36] DNA damage and homocysteine levels are proportional to CAD severity. Micronucleus frequency in human lymphocytes, dependent on homocysteine levels increases reactive oxygen species and uracil incorporation in DNA methylation, promoting genetic alterations and point mutations. [36] The (MTRR):c.66A>G, polymorphism containing chromosome is prone to fragmentation. This chromosomal loss or global DNA hypomethylation results in under condensation of pericentromeric heterochromatin, micronucleus formation and elevated risks of aneuploidy. [36] Co-expression of this mutation and the 677T polymorphism in methionine tetrahydrofolate reductase (MTHFR) Methylenetetrahydrofolate reductase act to further the extent of DNA damage. [36]
Hypomethylation due to impaired methylation up regulates atherosclerotic susceptible genes whilst down regulating atherosclerosis protective genes. [36] This abnormality is present during the atherosclerotic pathology, increasing transcriptional activity of platelet derived growth factor (PDGF) and promoting smooth muscle cell proliferation. [36]
MTRR requires vitamin B12 for maintenance of the methyl synthase reaction whilst folate is needed for normal synthesis of nucleotide precursors. These ensure normal DNA synthesis and cellular methylation reactions. [7] Chronic folate or methyl deficiencies are thereby linked to abnormal DNA methylation. The 66A>G polymorphism is up-regulated in neural tube defects and increases the risk of spina bifida by two-fold. [38] Homozygosis for this mutation is an established maternal risk factor for spina bifida especially with low intracellular vitamin B12 [39] in the circulation or amniotic fluid. [13] Vitamin B12 is reflected by plasma methylmalonic acid (MMA), an elevation in which indicates impaired B12 uptake or metabolism. [7] A raised MMA combined with the MTRR mutation corresponds to a 5-fold increase in spina bifida. [7] The mechanism of action of this polymorphism is through the mother, hence there is no preferential transmission of this mutation from parent to child. Abnormal MTRR binding to the MTR-cob(I)alamin-enzyme complex down regulates the rate of homocysteine methylation. Consequent decreases in methionine and S-adenosylmethionine negatively affect DNA, gene and protein methylation, all of which are involved in neural tube closure. [7] Increased proliferation during neurulation decreases the availability of DNA nucleotides. As these are unable to be replaced due to impaired DNA methylation and nucleotide formation, consequent disturbed neurulation results in the formation of neural tube defects. [11] Co-expression of this mutation with the 677C>T MTHFR polymorphism furthers the risk of spina bifida compared to an independent acting 66A>G mutation. [7]
Trisomy 21 or Down syndrome is the most common human chromosomal anomaly arising from abnormal chromosomal segregation in meiosis. [10] [11] [40] The condition can occur during anaphase in meiosis(I) marking oocyte maturation before ovulation and/or during anaphase in meiosis (II) signifying fertilization. [11] Metabolic impact during these stages is furthered by low vitamin B12. [41] Methylation of homocysteine to methionine is affected, primarily by the (MTRR):c.66A>G polymorphism. Chronic homocysteine elevation increases s-adenosyl-L-homocysteine levels, consequently inhibiting methyltransferase activity and promoting DNA hypomethylation. [10] [42] Mothers homozygous for this mutation (GG phenotype) are at a greater risk of having a child with down syndrome compared to heterozygotes (GA phenotype). [41] Geographically, Irish populations are more likely to be homogenous whilst north American populations are commonly heterogeneous, resulting in a greater incidence of the polymorphism in the former group. [11] [41] The homozygous mutant allele promotes DNA hypomethylation and meiotic non-disjunction, increasing the risk of down syndrome. [43] This polymorphism correlates to a 2.5 fold risk increase independently and a 4 fold increase in risk when co-expressed with the 677C>T MTHFR mutation. [11] Combination with the MTR2756A>G genetic polymorphism further elevates down syndrome risk. [11] [42] [44]
Methionine is an essential amino acid in humans.
Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These terms are commonly used in chemistry, biochemistry, soil science, and biology.
Homocysteine or Hcy: is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In the body, homocysteine can be recycled into methionine or converted into cysteine with the aid of vitamin B6, B9, and B12.
S-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throughout the body, most SAM is produced and consumed in the liver. More than 40 methyl transfers from SAM are known, to various substrates such as nucleic acids, proteins, lipids and secondary metabolites. It is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase. SAM was first discovered by Giulio Cantoni in 1952.
Homocystinuria or HCU is an inherited disorder of the metabolism of the amino acid methionine due to a deficiency of cystathionine beta synthase or methionine synthase. It is an inherited autosomal recessive trait, which means a child needs to inherit a copy of the defective gene from both parents to be affected. Symptoms of homocystinuria can also be caused by a deficiency of vitamins B6, B12, or folate.
Methylenetetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the MTHFR gene. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. Natural variation in this gene is common in otherwise healthy people. Although some variants have been reported to influence susceptibility to occlusive vascular disease, neural tube defects, Alzheimer's disease and other forms of dementia, colon cancer, and acute leukemia, findings from small early studies have not been reproduced. Some mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency. Complex I deficiency with recessive spastic paraparesis has also been linked to MTHFR variants. In addition, the aberrant promoter hypermethylation of this gene is associated with male infertility and recurrent spontaneous abortion.
Trimethylglycine is an amino acid derivative that occurs in plants. Trimethylglycine was the first betaine discovered; originally it was simply called betaine because, in the 19th century, it was discovered in sugar beets.
Methionine synthase (MS, MeSe, MTR) is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle, and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle. There are two primary forms of this enzyme, the Vitamin B12 (cobalamin)-dependent (MetH) and independent (MetE) forms, although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria. The two dominant forms of the enzymes appear to be evolutionary independent and rely on considerably different chemical mechanisms. Mammals and other higher eukaryotes express only the cobalamin-dependent form. In contrast, the distribution of the two forms in Archaeplastida (plants and algae) is more complex. Plants exclusively possess the cobalamin-independent form, while algae have either one of the two, depending on species. Many different microorganisms express both the cobalamin-dependent and cobalamin-independent forms.
Methylcobalamin (mecobalamin, MeCbl, or MeB12) is a cobalamin, a form of vitamin B12. It differs from cyanocobalamin in that the cyano group at the cobalt is replaced with a methyl group. Methylcobalamin features an octahedral cobalt(III) centre and can be obtained as bright red crystals. From the perspective of coordination chemistry, methylcobalamin is notable as a rare example of a compound that contains metal–alkyl bonds. Nickel–methyl intermediates have been proposed for the final step of methanogenesis.
Hyperhomocysteinemia is a medical condition characterized by an abnormally high level of total homocysteine in the blood, conventionally described as above 15 μmol/L.
Cystathionine-β-synthase, also known as CBS, is an enzyme (EC 4.2.1.22) that in humans is encoded by the CBS gene. It catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine:
The transsulfuration pathway is a metabolic pathway involving the interconversion of cysteine and homocysteine through the intermediate cystathionine. Two transsulfurylation pathways are known: the forward and the reverse.
Transmethylation is a biologically important organic chemical reaction in which a methyl group is transferred from one compound to another.
In enzymology, a 5-methyltetrahydropteroyltriglutamate—homocysteine S-methyltransferase is an enzyme that catalyzes the chemical reaction
[Methionine synthase] reductase, or Methionine synthase reductase, encoded by the gene MTRR, is an enzyme that is responsible for the reduction of methionine synthase inside human body. This enzyme is crucial for maintaining the one carbon metabolism, specifically the folate cycle. The enzyme employs one coenzyme, flavoprotein.
Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is a protein that in humans is encoded by the MMACHC gene.
Imerslund–Gräsbeck syndrome is a rare autosomal recessive, familial form of vitamin B12 deficiency caused by malfunction of the "Cubam" receptor located in the terminal ileum. This receptor is composed of two proteins, amnionless (AMN), and cubilin. A defect in either of these protein components can cause this syndrome. This is a rare disease, with a prevalence about 1 in 200,000, and is usually seen in patients of European ancestry.
Cobalamin biosynthesis is the process by which bacteria and archea make cobalamin, vitamin B12. Many steps are involved in converting aminolevulinic acid via uroporphyrinogen III and adenosylcobyric acid to the final forms in which it is used by enzymes in both the producing organisms and other species, including humans who acquire it through their diet.
Rowena Green Matthews, born in 1938, is the G. Robert Greenberg Distinguished University professor emeritus at the University of Michigan, Ann Arbor. Her research focuses on the role of organic cofactors as partners of enzymes catalyzing difficult biochemical reactions, especially folic acid and cobalamin. Among other honors, she was elected to the National Academy of Sciences in 2002 and the Institute of Medicine in 2004.
Methylenetetrahydrofolate reductase deficiency is the most common genetic cause of elevated serum levels of homocysteine (hyperhomocysteinemia). It is caused by genetic defects in MTHFR, which is an important enzyme in the methyl cycle.