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Short answer: a methyltransferase is an enzyme that transfers a methyl group from a donor molecule to a target. DNA methyltransferases (DNMTs) use S-adenosylmethionine (SAM) as the donor and add the methyl group to the fifth carbon of cytosine in CpG sites. Methionine synthase is a different enzyme, which acts on homocysteine.
What is a methyltransferase?
A methyltransferase catalyses the transfer of a methyl group (CH3) from a methyl donor to a substrate. The substrate can be DNA, RNA, a protein or a small molecule, which is why the bare word is ambiguous: “methyltransferase” names a reaction type, not a single enzyme. In this guide the term means a DNA methyltransferase, and the rest of this page uses that meaning unless it says otherwise.
In the DNMT reaction, the methyl donor is S-adenosylmethionine (SAM), which is converted to S-adenosylhomocysteine (SAH) as the methyl group moves onto the DNA (Wong et al., 2019).
What is DNA methylation and what is its function?
DNA methylation is the addition of a methyl group to the fifth carbon of cytosine bases, in specific regions of CpG dinucleotides. It is one of the most extensively studied epigenetic changes and it regulates gene expression in the normal development of mammalian cells. Hypermethylation of cytosines in a gene promoter suppresses transcription of that gene (Wong et al., 2019). For the wider picture of epigenetic marks, see what epigenetics is.
The same source describes how this goes wrong: promoter hypermethylation of tumour suppressor genes silences them and is involved in driving cancer survival, growth and metastasis. That is why DNMTs are a standard subject of cancer epigenetics research.
What is the function of the methyltransferase enzyme?
For DNA methyltransferases, the function is to write methylation marks onto cytosine and, in the case of one family member, to copy them faithfully when cells divide. Structurally, every DNMT has a variable N-terminal regulatory region and a C-terminal methyltransferase domain that carries out the catalysis (Wong et al., 2019). Three enzymes do this work, and they split the job between establishing new marks and preserving existing ones.
DNMT1, DNMT3A and DNMT3B compared
| Enzyme | Role | Domains named in the source |
|---|---|---|
| DNMT1 | Maintenance: preserves DNA methylation patterns during cell division and preferentially methylates hemimethylated DNA | DMAP-interaction region, replication foci-targeting domain, CXXC zinc finger that recognises unmethylated CpG, two BAH domains |
| DNMT3A | De novo: catalyses new DNA methylation | PWWP domain (a methyl-lysine recognition motif) and ADD zinc finger domain |
| DNMT3B | De novo: catalyses new DNA methylation | PWWP domain and ADD zinc finger domain |
Every row in the table comes from Wong et al. (2019). The maintenance versus de novo split is the part most often blurred in short explainers: DNMT1 favours hemimethylated DNA, while DNMT3A and DNMT3B establish methylation anew. For a related topic, see DNA imprinting.
Is homocysteine methyltransferase the same as methionine synthase?
It is not a DNA methyltransferase. MedlinePlus Genetics describes the MTR gene as giving instructions for an enzyme called methionine synthase, which carries out a chemical reaction that converts the amino acid homocysteine to the amino acid methionine and needs methylcobalamin, a form of vitamin B12. More than 20 mutations in the MTR gene have been identified in people with homocystinuria (MedlinePlus Genetics, page last updated July 1, 2011).
MedlinePlus Genetics uses the name methionine synthase for this enzyme and describes its reaction as converting homocysteine to methionine. A name that combines “homocysteine” and “methyltransferase” therefore points to the homocysteine reaction, not to DNA.
Cross-walk: DNMT versus methionine synthase
| Question | DNA methyltransferases | Methionine synthase (MTR) |
|---|---|---|
| What does it act on? | Cytosine bases in CpG dinucleotides of DNA | The amino acid homocysteine |
| What is made? | Methylated cytosine; SAM is converted to SAH | The amino acid methionine |
| Cofactor named in the source | SAM as methyl donor | Methylcobalamin (a form of vitamin B12) |
The two are different enzymes with different substrates.
Where it matters in the lab
DNMT biology shows up in the lab mainly through inhibitor and expression studies. A 2019 review of acute myeloid leukaemia (AML), Wong et al., reports the following:
- Azacitidine and decitabine are nucleoside analogues that are relatively non-specific, have low chemical stability and must be incorporated into DNA to act as covalent inhibitors. This is why researchers have looked for non-nucleoside DNMT inhibitors with other chemical scaffolds, several of which have been tested in AML cell lines.
- In one structure-based screen, two compounds inhibited DNMT3A activity with IC50 values of 46.5 and 41 µM and were more cytotoxic to AML cell lines than to HeLa cells.
- Because DNMT1 frequently targets the promoter of the p15 gene, the authors recommend measuring increased p15 levels as a parameter of impaired DNMT1 activity in AML research.
- In clinical trials of hypomethylating agents, DNMT expression was not predictive of response in most trials, and most studies reported downregulation of DNMT expression after treatment.
When a protocol, paper or catalogue entry says only “methyltransferase”, the tables above point to three things to read from the text: the substrate (DNA cytosine or homocysteine), the donor or cofactor (SAM or methylcobalamin), and, for DNA, whether the work concerns maintenance (DNMT1) or de novo (DNMT3A, DNMT3B) methylation. Other DNA-acting enzymes in routine bench work, such as those in restriction enzyme digests, are separate topics. For the broader field, see what molecular biology is, and for reading expression differences, differential gene expression analysis.
Common misunderstandings
- “Methylation always silences a gene.” The source ties hypermethylation of cytosines in a gene promoter to suppressed transcription; it does not say methylation anywhere in a genome has that effect.
- “DNMT1 and DNMT3A do the same job.” DNMT1 maintains patterns and prefers hemimethylated DNA; DNMT3A and DNMT3B catalyse de novo methylation.
- “Methylation changes the DNA sequence.” Epigenetic modifications are inherited changes that do not change the sequence itself (Wong et al., 2019).
- “Every methyltransferase works on DNA.” Methionine synthase acts on homocysteine, not DNA.
FAQ
What is DNA methylation and what is its function?
It is the addition of a methyl group to the fifth carbon of cytosine in CpG dinucleotides. It regulates gene expression in normal mammalian development, and hypermethylation of a promoter suppresses transcription of the gene.
What is the function of the methyltransferase enzyme?
It transfers a methyl group from a donor to a substrate. For DNMTs the donor is SAM, the substrate is cytosine in DNA, and SAM becomes SAH. DNMT1 maintains existing patterns; DNMT3A and DNMT3B establish new ones.
Is homocysteine methyltransferase the same as methionine synthase?
MedlinePlus Genetics names the enzyme encoded by MTR methionine synthase and describes it as converting homocysteine to methionine using methylcobalamin. It is not a DNA methyltransferase.
Sources
- Wong KK, Lawrie CH, Green TM. Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia. Biomark Insights 2019;14:1177271919846454. https://pmc.ncbi.nlm.nih.gov/articles/PMC6509988 (checked 2026-10-29).
- MedlinePlus Genetics, MTR gene. https://medlineplus.gov/genetics/gene/mtr/ (checked 2026-10-29).
