GO:0016765 transferase activity, transferring alkyl or aryl (other than methyl) groups: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0016765 describes enzymes that move an alkyl or aryl group (but not a methyl group) from a donor molecule to an acceptor molecule.
• This activity is essential for epigenetic regulation, RNA modification, mitochondrial translation, and chromatin biology [2,3,6].
• Key enzyme families include DNA methyltransferases (DNMT1, DNMT3A, DNMT3B) and tRNA methyltransferases such as METTL1-WDR4 and TRMT6/TRMT61A [2,4,5].
• Dysregulation of these enzymes drives liver tumourigenesis, anaplastic thyroid cancer, metastasis, and hematological malignancies [1,3,5,7].
• CRISPR knockout, point-mutation, knock-in, and overexpression models are powerful tools to dissect the causal roles of these transferases [1,5].
• Understanding GO:0016765 provides a framework for targeting alkyl/aryl transferases in cancer and metabolic diseases [1,3,7].
Description
GO:0016765, transferase activity, transferring alkyl or aryl (other than methyl) groups, is a molecular function term in the Gene Ontology that defines a class of enzymes catalyzing the transfer of an alkyl or aryl group from a donor compound to an acceptor compound, explicitly excluding methyl groups. This activity is fundamental to many biological processes, including epigenetic regulation, RNA modification, and mitochondrial translation [2,3,6]. The enzymes annotated with this term often use cofactors such as S-adenosylmethionine (SAM) or folate derivatives to facilitate group transfer, and they play critical roles in cellular metabolism and gene expression [2,6]. Researchers study GO:0016765 because its members are frequently dysregulated in human diseases, particularly cancer. For example, DNA methyltransferases such as DNMT1, DNMT3A, and DNMT3B are central to epigenetic silencing and are implicated in hematological malignancies [2,7]. tRNA methyltransferases like METTL1-WDR4 and TRMT6/TRMT61A modify tRNA to regulate translation and metabolic plasticity, influencing tumourigenesis and metastasis [1,3,4,5]. Mitochondrial tRNA methylation by enzymes such as NSUN3 and TRMT61B is required for efficient mitochondrial translation, linking this activity to metabolic disorders. Given the broad impact of alkyl/aryl transferases on health and disease, precise functional characterization of these enzymes is essential. This article provides a comprehensive overview of GO:0016765, covering its definition, biological significance, key genes, regulatory mechanisms, disease associations, and state-of-the-art research methods including CRISPR-based models [1,2,5].
transferase activity, transferring alkyl or aryl (other than methyl) groups At A Glance
| GO ID | GO:0016765 |
|---|---|
| GO term | transferase activity, transferring alkyl or aryl (other than methyl) groups |
| Ontology | molecular_function |
| Synonym | transferase activity, transferring alkyl or aryl groups, other than methyl groups |
| Definition | Catalysis of the transfer of an alkyl or aryl (but not methyl) group from one compound (donor) to another (acceptor). |
| Major function | Enables alkyl/aryl group transfer in epigenetic regulation, RNA modification, and mitochondrial translation. |
| Cofactors | Often utilizes S-adenosylmethionine (SAM) or folate derivatives as donors. |
| Related diseases | Cancer (liver, thyroid, hematological), metabolic disorders, metastasis. |
What Is GO:0016765?
GO:0016765 is defined as the catalysis of the transfer of an alkyl or aryl group (but not a methyl group) from one compound (donor) to another (acceptor). This activity is distinct from methyltransferase activity (GO:0008168), which specifically transfers methyl groups. Enzymes with this activity often use cofactors like S-adenosylmethionine or folate to activate the donor group, and they participate in diverse pathways such as epigenetic marking, tRNA modification, and mitochondrial translation [2,6].
Why Is transferase activity, transferring alkyl or aryl (other than methyl) groups Important in Cell Biology?
GO:0016765 is critically important because enzymes with this activity regulate fundamental cellular processes such as DNA methylation, tRNA modification, and mitochondrial translation, which are frequently hijacked in human diseases including cancer and metabolic disorders [1,2,3,6]. Understanding this term helps researchers identify therapeutic targets and develop precise CRISPR models to study gene function [1,5].
• Enables epigenetic regulation through DNA methyltransferases such as DNMT1, DNMT3A, and DNMT3B.
• Drives tRNA modifications that enhance protein translation and activate stress pathways in cancer [1,5].
• Supports mitochondrial translation via folate-dependent tRNA methylation.
• Dysregulation is linked to liver tumourigenesis and cholesterol metabolism.
• Promotes metabolic plasticity and metastasis in cancer cells.
• Implicated in hematological malignancies through DNA methyltransferase mutations.
• Provides targets for CRISPR knockout and point-mutation studies [1,5].
• Essential for understanding co-transcriptional H3K36 methylation by SETD2.
• Facilitates development of small-molecule inhibitors for cancer therapy [2,7].
• Serves as a model for studying enzyme mechanism and substrate specificity.
What Happens During transferase activity, transferring alkyl or aryl (other than methyl) groups?
Substrate Recognition and Donor Activation
In simple terms: The enzyme first grabs the molecule that carries the alkyl or aryl group and gets it ready to hand it over.
Enzymes with GO:0016765 activity typically bind a donor molecule such as S-adenosylmethionine (SAM) or a folate derivative, positioning the alkyl or aryl group for transfer [2,6]. For example, DNA methyltransferases recognize specific DNA sequences and flip the target base to access the carbon atom for transfer. tRNA methyltransferases like METTL1-WDR4 form a complex that recognizes the tRNA elbow structure to ensure precise modification.
Catalytic Transfer to Acceptor
In simple terms: The enzyme then attaches the group to the target molecule, changing its chemical properties.
The activated alkyl or aryl group is transferred to a nucleophilic acceptor atom on the substrate, such as a nitrogen or carbon atom in DNA or RNA [2,4]. This reaction often involves a conserved catalytic motif and may require metal ions or specific residues for stabilization. For instance, METTL1-WDR4 catalyzes the transfer of a methyl group to the N1 position of adenine in tRNA, a modification that enhances translation [4,5].
Product Release and Enzyme Turnover
In simple terms: After the transfer, the modified product is released and the enzyme is ready to work again.
Following catalysis, the modified substrate is released, and the enzyme undergoes conformational changes to reset for another round of transfer. This step can be regulated by post-translational modifications or interactions with accessory proteins. For example, DNMT1 maintains methylation patterns during DNA replication by recognizing hemimethylated DNA and transferring methyl groups to the new strand.
Integration with Cellular Pathways
In simple terms: The modification made by the enzyme affects how cells read genes and make proteins.
The alkyl/aryl group transfer often serves as a mark that influences downstream processes such as transcription, translation, or RNA stability [1,3,5]. tRNA modifications by TRMT6/TRMT61A enhance protein translation and activate the IRE1α-XBP1s pathway in anaplastic thyroid cancer. Mitochondrial tRNA methylation is required for efficient mitochondrial translation and metabolic plasticity [3,6].
Key Genes Involved in GO:0016765 transferase activity, transferring alkyl or aryl (other than methyl) groups
The following genes encode enzymes with transferase activity transferring alkyl or aryl (other than methyl) groups, and they are frequently studied in cancer, epigenetics, and metabolism.
| Gene | Major Role | Research Relevance |
|---|---|---|
| DNMT1 | Maintains DNA methylation patterns during replication | Epigenetic regulation; hematological malignancies [2,7] |
| DNMT3A | De novo DNA methylation | Cancer, developmental disorders [2,7] |
| DNMT3B | De novo DNA methylation | Cancer, immunodeficiency [2,7] |
| METTL1 | tRNA m7G methylation | Liver cancer, translation regulation [1,4] |
| WDR4 | Partner of METTL1 for tRNA methylation | Structural insights, cancer |
| TRMT6 | tRNA m1A methylation complex | Anaplastic thyroid cancer |
| TRMT61A | tRNA m1A methylation complex | Anaplastic thyroid cancer |
| NSUN3 | Mitochondrial tRNA methylation | Mitochondrial translation, metabolism |
| TRMT61B | Mitochondrial tRNA methylation | Mitochondrial translation |
| SETD2 | H3K36 methylation | Chromatin regulation, cancer |
| TRMT112 | Partner of methyltransferases | tRNA modification |
| FTSJ1 | tRNA methylation | Intellectual disability |
| NSUN2 | RNA m5C methylation | Cancer, neurodevelopment |
| ALKBH5 | RNA demethylation | Cancer, RNA stability |
| FTO | RNA demethylation | Metabolism, cancer |
| METTL3 | m6A RNA methylation | Cancer, translation |
| WTAP | m6A complex component | RNA modification |
How Is transferase activity, transferring alkyl or aryl (other than methyl) groups Regulated?
The activity of enzymes transferring alkyl or aryl groups is regulated at multiple levels. DNA methyltransferases are controlled by transcriptional regulation, post-translational modifications, and interaction with accessory proteins such as UHRF1. tRNA methyltransferases like METTL1-WDR4 are regulated by complex assembly and substrate availability, and their expression is often elevated in cancers [1,4]. Mitochondrial tRNA methylation is dependent on folate metabolism, linking nutrient status to translation. Additionally, the IRE1α-XBP1s pathway can be activated by tRNA modifications, creating a feedback loop that promotes cancer progression.
transferase activity, transferring alkyl or aryl (other than methyl) groups and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| TRMT6/TRMT61A | Liver tumourigenesis | Knockout in liver cancer cell lines |
| METTL1/WDR4 | Anaplastic thyroid cancer | Overexpression and knockout in thyroid cancer cells |
| DNMT3A | Hematological malignancies | Point mutation knock-in in hematopoietic stem cells |
| NSUN3 | Mitochondrial translation defects | Knockout in patient-derived fibroblasts |
| SETD2 | Chromatin regulation in cancer | Knock-in of catalytic dead mutant |
Cancer
Dysregulation of alkyl/aryl transferases is a hallmark of many cancers. N1-methyladenosine methylation in tRNA by TRMT6/TRMT61A drives liver tumourigenesis by regulating cholesterol metabolism. METTL1-WDR4-mediated tRNA methylation enhances protein translation and activates the IRE1α-XBP1s pathway in anaplastic thyroid cancer. Mitochondrial RNA modifications shape metabolic plasticity in metastasis, supporting cancer cell survival. DNA methyltransferases are frequently mutated in hematological malignancies, leading to aberrant DNA methylation patterns.
Metabolic Disorders
Mitochondrial translation requires folate-dependent tRNA methylation, and defects in this process can lead to metabolic disorders. The interplay between RNA modifications and metabolism highlights the importance of alkyl/aryl transferases in cellular energy homeostasis.
Neurological and Developmental Disorders
Mutations in tRNA methyltransferases such as FTSJ1 are associated with intellectual disability, underscoring the role of these enzymes in neurodevelopment. Proper tRNA modification is essential for translation fidelity in neurons.
From transferase activity, transferring alkyl or aryl (other than methyl) groups-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of TRMT6 affect tRNA methylation and translation? | CRISPR knockout in cancer cell lines |
| Does a specific point mutation in DNMT3A alter DNA methylation? | Point mutation knock-in in cell lines |
| Can overexpression of METTL1 drive tumourigenesis? | Overexpression in thyroid cancer cells |
| What is the role of NSUN3 in mitochondrial translation? | Knockout in mitochondrial disease models |
| How does SETD2 catalytic activity affect chromatin? | Catalytic dead knock-in |
| Does TRMT61A regulate cholesterol metabolism? | Knockout in liver cancer cells |
How to Study the transferase activity, transferring alkyl or aryl (other than methyl) groups Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcript abundance and modifications | Global effects of transferase knockout |
| Ribo-seq | Translation efficiency | Impact of tRNA methylation on protein synthesis |
| Proteomics | Protein expression and modifications | Identifying downstream targets |
| Cryo-EM | 3D structure of enzyme-substrate complexes | Mechanistic studies of METTL1-WDR4 |
| CRISPR screen | Gene essentiality and fitness | Discovering transferases in cancer |
| m1A-seq | tRNA m1A modification sites | Mapping TRMT6/TRMT61A targets |
| Mitochondrial translation assay | Mitochondrial protein synthesis | Assessing NSUN3 function |
| ChIP-seq | Histone methylation and DNA methylation | Studying SETD2 and DNMTs |
RNA Sequencing and Modifications
RNA-seq and specialized techniques like m1A-seq or m7G-seq can map tRNA modifications and quantify changes upon knockout or overexpression of transferases [1,5]. These methods reveal how alkyl/aryl group transfer affects transcript stability and translation.
Proteomics and Translation Profiling
Proteomics and ribosome profiling (Ribo-seq) measure global protein synthesis and identify translation efficiency changes caused by tRNA modifications [1,5]. This is critical for understanding how GO:0016765 enzymes influence the proteome.
Structural Biology
Cryo-EM and X-ray crystallography provide atomic-level insights into how enzymes like METTL1-WDR4 recognize substrates and catalyze transfer. These studies guide the design of inhibitors.
CRISPR Screens
Genome-wide CRISPR knockout screens can identify transferases essential for cancer cell growth and survival [1,5]. Such screens link GO:0016765 genes to specific phenotypes.
How CRISPR Can Be Used to Study GO:0016765 transferase activity, transferring alkyl or aryl (other than methyl) groups
Knockout
CRISPR knockout of transferase genes such as TRMT6, TRMT61A, or METTL1 allows researchers to assess loss-of-function phenotypes, including changes in tRNA modification, translation, and tumour growth [1,5]. Knockout models are essential for validating gene essentiality in cancer.
Point Mutation
Introducing specific point mutations in catalytic residues of transferases (e.g., DNMT3A or SETD2) via CRISPR base editing or HDR can dissect enzymatic activity from scaffolding functions [7,8]. Such models reveal the precise contribution of alkyl/aryl group transfer to disease.
Knock-in
Knock-in of tagged or mutant versions of transferases (e.g., FLAG-tagged METTL1) enables affinity purification and localization studies. Knock-in of disease-associated mutations can model human disorders.
Overexpression
CRISPR activation (CRISPRa) or lentiviral overexpression of transferases like METTL1 or TRMT6 can drive tumourigenesis and reveal oncogenic mechanisms [1,5]. Overexpression models are useful for studying gain-of-function effects.
How EDITGENE Supports transferase activity, transferring alkyl or aryl (other than methyl) groups Research
Researchers studying transferase activity, transferring alkyl or aryl (other than methyl) groups-related genes often need to determine whether a candidate gene is causally involved in a specific phenotype, such as cancer cell proliferation or metabolic reprogramming. EDITGENE provides comprehensive CRISPR-based services to accelerate this discovery process.
Contact EDITGENE today to design your custom CRISPR model for transferase activity, transferring alkyl or aryl (other than methyl) groups research.
Frequently Asked Questions About transferase activity, transferring alkyl or aryl (other than methyl) groups
What is GO:0016765?
GO:0016765 is a Gene Ontology molecular function term for enzymes that transfer an alkyl or aryl group (but not a methyl group) from a donor to an acceptor molecule.
What genes are involved in transferase activity, transferring alkyl or aryl (other than methyl) groups?
Key genes include DNMT1, DNMT3A, DNMT3B, METTL1, WDR4, TRMT6, TRMT61A, NSUN3, TRMT61B, and SETD2 [2,4,5,6,8].
How does GO:0016765 relate to cancer?
Dysregulation of these transferases drives liver tumourigenesis, anaplastic thyroid cancer, metastasis, and hematological malignancies [1,3,5,7].
What diseases are associated with alkyl/aryl transferases?
Cancers such as liver and thyroid cancer, metabolic disorders, and neurological conditions like intellectual disability [1,2,5,6].
What are the research methods to study GO:0016765?
Common methods include CRISPR knockout, RNA-seq, Ribo-seq, proteomics, cryo-EM, and CRISPR screens [1,4,5].
How can CRISPR help study transferase activity?
CRISPR enables knockout, point mutation, knock-in, and overexpression models to dissect gene function and disease mechanisms [1,5,7].
What is the role of METTL1-WDR4 in tRNA methylation?
METTL1-WDR4 catalyzes m7G methylation on tRNA, enhancing translation and promoting cancer progression [4,5].
Why is mitochondrial tRNA methylation important?
It is required for efficient mitochondrial translation and metabolic plasticity, linking to metastasis [3,6].
What is the difference between GO:0016765 and methyltransferase activity?
GO:0016765 excludes methyl group transfer, while methyltransferase activity (GO:0008168) specifically transfers methyl groups.
How does EDITGENE support research on GO:0016765?
EDITGENE offers CRISPR knockout, point mutation, knock-in, overexpression, library screening, and bioinformatics services for transferase genes [1,5].
Conclusion
GO:0016765, transferase activity, transferring alkyl or aryl (other than methyl) groups, represents a vital class of enzymes that regulate epigenetics, RNA modification, and mitochondrial translation. Their dysregulation is linked to cancer, metabolic disorders, and neurological diseases, making them attractive therapeutic targets [1,2,3,6]. Advanced CRISPR models and multi-omics approaches are essential to unravel their precise mechanisms and translate findings into clinical applications [1,5,7]. EDITGENE provides end-to-end CRISPR solutions to study these transferases, empowering researchers to uncover causal roles and develop novel interventions.
References
- 1. Wang Y et al.. 2021. N(1)-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism.. Nat Commun 12(1):6314 PMID: 34728628
- 2. Lyko F. 2018. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation.. Nat Rev Genet 19(2):81-92 PMID: 29033456
- 3. Delaunay S et al.. 2022. Mitochondrial RNA modifications shape metabolic plasticity in metastasis.. Nature 607(7919):593-603 PMID: 35768510
- 4. Ruiz-Arroyo VM et al.. 2023. Structures and mechanisms of tRNA methylation by METTL1-WDR4.. Nature 613(7943):383-390 PMID: 36599982
- 5. Ding Y et al.. 2026. TRMT6/TRMT61A-mediated tRNA m(1)A modification enhances protein translation and activates the IRE1α-XBP1s pathway to promote anaplastic thyroid cancer progression.. Cell Mol Biol Lett 31(1) PMID: 41667948
- 6. Morscher RJ et al.. 2018. Mitochondrial translation requires folate-dependent tRNA methylation.. Nature 554(7690):128-132 PMID: 29364879
- 7. Hoang NM et al.. 2020. DNA methyltransferases in hematological malignancies.. J Genet Genomics 47(7):361-372 PMID: 32994141
- 8. Walshe JL et al.. 2025. Molecular mechanism of co-transcriptional H3K36 methylation by SETD2.. Nat Commun 16(1):9565 PMID: 41162378
