GO:0000095 S-adenosyl-L-methionine transmembrane transporter activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0000095 describes the molecular function that moves S-adenosylmethionine (SAM) across a membrane, a rate-limiting step for one-carbon and methylation metabolism.
• SAM transport is functionally linked to methylation reactions in chloroplasts, hepatocytes, and other compartments, and defects in SAM handling alter protein methylation and cellular stress responses.
• SAM can also modulate ion channels such as RyR2, showing that SAM transport and SAM availability influence electrical signaling beyond classical methylation.
• Fasting and inflammatory challenges change hepatic SAM-related metabolites, indicating that SAM transport activity is metabolically regulated in vivo.
• CRISPR knockout, point-mutation, knock-in, and overexpression models are the main tools for testing whether candidate SAM transporter genes are causally involved in disease and metabolism.
• EDITGENE provides end-to-end CRISPR cell model and library screening services to dissect GO:0000095-related genes at scale.
Description
GO:0000095, S-adenosyl-L-methionine transmembrane transporter activity, is a molecular function that enables the transfer of S-adenosylmethionine (SAM) from one side of a membrane to the other. SAM is S-(5'-adenosyl)-L-methionine, a central intermediate in one-carbon metabolism and the universal methyl donor for most cellular methylation reactions. Because SAM is synthesized in the cytosol and used in multiple compartments, its transport across membranes is a critical control point for methylation-dependent processes.
S-adenosyl-L-methionine transmembrane transporter activity At A Glance
| GO ID | GO:0000095 |
|---|---|
| GO term | S-adenosyl-L-methionine transmembrane transporter activity |
| Ontology | molecular_function |
| Synonym | SAM transmembrane transporter activity; S-adenosylmethionine permease activity; S-adenosyl methionine transporter activity |
| Major function | Transfers S-adenosylmethionine across a membrane |
| Substrate | S-adenosyl-L-methionine (SAM) |
| Biological context | One-carbon metabolism, methylation, chloroplast protein methylation, hepatic metabolism |
| Related processes | Methylation reactions, ion channel modulation, stress responses |
What Is GO:0000095?
In plain terms, this GO term describes the ability of a protein to carry SAM across a lipid bilayer. The QuickGO definition states that it enables the transfer of S-adenosylmethionine from one side of a membrane to the other, where S-adenosylmethionine is S-(5'-adenosyl)-L-methionine, an important intermediate in one-carbon metabolism. It is a molecular_function term with synonyms including SAM transmembrane transporter activity and S-adenosylmethionine permease activity.
Why Is S-adenosyl-L-methionine transmembrane transporter activity Important in Cell Biology?
SAM transport is important because it determines the local availability of the universal methyl donor for methylation of proteins, nucleic acids, and small molecules. Perturbations in SAM handling are linked to altered protein methylation in chloroplasts, hepatocyte stress and apoptosis, and metabolic shifts during fasting or inflammation. In addition, SAM can directly modulate ion channels such as RyR2, indicating that SAM transport activity can influence electrical signaling and calcium release.
• Controls compartmental SAM supply for methylation reactions.
• Links one-carbon metabolism to protein and lipid methylation.
• Modulates ion channel activity, including RyR2 gating.
• Influences hepatocyte survival and endoplasmic reticulum stress.
• Responds to fasting and inflammatory challenges in vivo.
• Relevant to chloroplast protein methylation and light-regulated processes.
• Provides a target for metabolic and epigenetic research.
• Supports CRISPR-based causal gene testing in disease models.
What Happens During S-adenosyl-L-methionine transmembrane transporter activity?
Substrate recognition and binding
In simple terms: The transporter first grabs SAM on one side of the membrane.
SAM transporters must recognize S-adenosylmethionine, the product of methionine adenosyltransferase, and bind it with sufficient specificity to avoid transporting unrelated metabolites. This step is essential because SAM is a charged, polar molecule that cannot freely diffuse across membranes.
Translocation across the membrane
In simple terms: The transporter then flips SAM through the membrane to the other side.
After binding, the transporter undergoes conformational changes that move SAM across the lipid bilayer. This translocation step is the defining catalytic event of GO:0000095 and is required for delivering SAM to compartments where methylation enzymes reside.
Release and downstream methylation
In simple terms: Once across, SAM is released to feed methylation reactions.
Released SAM serves as the methyl donor for O-carboxyl- and N-methyltransferases active on plant aquaporins and for many other methyltransferases. In chloroplasts, light-regulated methylation of chloroplast proteins depends on SAM availability, linking transport to photosynthetic physiology.
Integration with one-carbon metabolism
In simple terms: SAM transport is tied to the broader one-carbon cycle.
Because SAM is an intermediate in one-carbon metabolism, its transport is coordinated with folate and methionine cycles. Folate protects hepatocytes of hyperhomocysteinemia mice from apoptosis via CFTR-activated endoplasmic reticulum stress, a pathway that intersects with SAM-dependent methylation.
Key Genes Involved in GO:0000095 S-adenosyl-L-methionine transmembrane transporter activity
The following genes and proteins are experimentally linked to SAM transport, SAM metabolism, or SAM-dependent processes relevant to GO:0000095.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SAM transporter candidates | Move SAM across membranes | Direct GO:0000095 activity |
| MAT1A | Synthesizes SAM in liver | Hepatic SAM supply |
| MAT2A | Synthesizes SAM in most tissues | General SAM metabolism |
| MTHFR | Folate and one-carbon cycle | SAM-linked methylation |
| MTR | Methionine synthase | SAM regeneration |
| CBS | Transsulfuration | Homocysteine and SAM balance |
| CFTR | Chloride channel | ER stress and hepatocyte apoptosis |
| RYR2 | Calcium release channel | SAM modulation of gating |
| ODC1 | Polyamine synthesis | SAM-related metabolism |
| GNMT | Glycine N-methyltransferase | SAM consumption |
| PEMT | Phosphatidylethanolamine methyltransferase | SAM-dependent methylation |
| DNMT1 | DNA methylation | SAM-dependent epigenetics |
| DNMT3A | DNA methylation | SAM-dependent epigenetics |
| PRMT1 | Protein arginine methylation | SAM-dependent signaling |
| SETD7 | Histone methylation | SAM-dependent chromatin |
| COMT | Catechol methylation | SAM-dependent neurotransmitter metabolism |
| BHMT | Betaine-homocysteine methyltransferase | One-carbon cycle |
| AHCY | S-adenosylhomocysteine hydrolase | SAM cycle |
How Is S-adenosyl-L-methionine transmembrane transporter activity Regulated?
SAM transport activity is regulated by metabolic state, including fasting and inflammatory challenges that alter hepatic SAM-related metabolites. Light regulates methylation of chloroplast proteins, implying that SAM-dependent methylation and its transport are responsive to environmental cues. Acute ethanol exposure affects cultured fetal rat hepatocytes and mitochondrial function, a context in which SAM metabolism is perturbed. Hypoxia regulates ornithine decarboxylase in pulmonary artery smooth muscle cells, linking oxygen sensing to SAM-related polyamine metabolism.
S-adenosyl-L-methionine transmembrane transporter activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CFTR | Hyperhomocysteinemia and hepatocyte apoptosis | CFTR knockout hepatocytes |
| RYR2 | Cardiac arrhythmia and calcium leak | RYR2 point-mutation knock-in |
| MAT1A | Liver SAM depletion | MAT1A knockout mice |
| MTHFR | Folate and one-carbon disorders | MTHFR point-mutation cells |
| ODC1 | Hypoxia and pulmonary vascular remodeling | ODC1 knockout smooth muscle cells |
Liver disease and hyperhomocysteinemia
Folate protects hepatocytes of hyperhomocysteinemia mice from apoptosis via CFTR-activated endoplasmic reticulum stress, a pathway that depends on SAM-dependent methylation. Acute ethanol exposure impairs mitochondrial function in cultured fetal rat hepatocytes, a model relevant to alcoholic liver injury and SAM metabolism.
Cardiac arrhythmia and ion channel dysfunction
SAM modulates RyR2 gating via the ATP binding site, producing electrical polarity-dependent effects and a unique subconductance. This suggests that SAM transport and local SAM levels can influence cardiac calcium release and arrhythmia susceptibility.
Metabolic and inflammatory stress
Fasting and inflammatory challenges alter the swine hepatic metabolome, including SAM-related metabolites, indicating that SAM transport activity is part of the systemic metabolic response. Hypoxia regulates ornithine decarboxylase in pulmonary artery smooth muscle cells, connecting oxygen stress to SAM-dependent polyamine pathways.
From S-adenosyl-L-methionine transmembrane transporter activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is a candidate gene required for SAM transport? | CRISPR knockout cell line |
| Does a specific residue control substrate specificity? | Point-mutation knock-in |
| Can a tag report transporter localization? | Tagged knock-in |
| Does overexpression increase SAM-dependent methylation? | Overexpression cell model |
| Which genes buffer SAM transport loss? | CRISPR library screening |
| Does SAM transport change during fasting? | In vivo metabolic model |
How to Study the S-adenosyl-L-methionine transmembrane transporter activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Targeted metabolomics | SAM and one-carbon metabolites | Fasting and inflammation studies |
| Methylation assay | Protein/DNA methylation | Chloroplast and aquaporin methylation |
| Patch-clamp | Ion channel gating | RyR2 modulation by SAM |
| CRISPR knockout | Gene requirement | Candidate transporter validation |
| Point-mutation knock-in | Residue function | Substrate specificity mapping |
| Overexpression | Gain-of-function effects | Methylation pathway activation |
| CRISPR library screen | Genome-wide modifiers | Pathway discovery |
| RNA-seq | Transcriptional response | Stress and metabolic regulation |
Metabolomics and SAM quantification
Targeted metabolomics can quantify SAM and related one-carbon metabolites in cells and tissues, as shown in swine hepatic metabolome studies during fasting and inflammation. This approach directly measures the substrate of GO:0000095 and its downstream products.
Methylation assays
Protein and DNA methylation assays detect the functional output of SAM transport, including light-regulated chloroplast protein methylation and SAM-dependent methyltransferase activity on aquaporins. These assays link transport activity to downstream methylation events.
Electrophysiology and ion channel recording
Patch-clamp and single-channel recordings can detect SAM-dependent modulation of RyR2 gating via the ATP binding site, revealing subconductance states. This method connects SAM availability to electrical signaling.
CRISPR screening and bioinformatics
Genome-wide CRISPR screens combined with bioinformatic pathway analysis can identify genes that buffer or modify SAM transport phenotypes. This is especially useful when direct transporter activity is redundant or context-dependent.
How CRISPR Can Be Used to Study GO:0000095 S-adenosyl-L-methionine transmembrane transporter activity
Knockout
CRISPR knockout of candidate SAM transporter genes can test whether they are required for SAM-dependent methylation and one-carbon metabolism. Knockout hepatocyte models can also probe CFTR-dependent ER stress and apoptosis under hyperhomocysteinemia.
Point Mutation
Point-mutation knock-in can map residues that control SAM binding and translocation, analogous to studies of RyR2 residues that mediate SAM modulation via the ATP binding site. Such models distinguish transport defects from folding or trafficking defects.
Knock-in
Tagged knock-in of endogenous SAM transporter loci enables live-cell localization and interaction studies without overexpression artifacts. This is valuable for tracking compartment-specific SAM delivery.
Overexpression
Overexpression of SAM transporters or methyltransferases can amplify downstream methylation and reveal rate-limiting steps in one-carbon metabolism. Overexpression models are also useful for testing whether increased SAM flux alters ion channel behavior.
How EDITGENE Supports S-adenosyl-L-methionine transmembrane transporter activity Research
Researchers studying S-adenosyl-L-methionine transmembrane transporter activity-related genes often need to determine whether a candidate gene is causally involved in SAM transport, methylation, or disease. EDITGENE provides publication-ready CRISPR cell models and screening services to answer these questions with rigor.
Contact EDITGENE today to design your custom CRISPR model for S-adenosyl-L-methionine transmembrane transporter activity research.
Frequently Asked Questions About S-adenosyl-L-methionine transmembrane transporter activity
What is GO:0000095?
GO:0000095 is the molecular function that enables transfer of S-adenosylmethionine across a membrane, as defined by QuickGO.
What does S-adenosyl-L-methionine transmembrane transporter activity do?
It moves SAM from one side of a membrane to the other, supplying the methyl donor for methylation reactions.
What genes are involved in S-adenosyl-L-methionine transmembrane transporter activity?
Candidate SAM transporters plus metabolic genes such as MAT1A, MAT2A, MTHFR, MTR, CBS, and AHCY are involved in SAM supply and cycling.
Why is SAM transport important for methylation?
Because SAM is the universal methyl donor, its transport determines local methylation capacity for proteins, DNA, and small molecules.
How is SAM transport linked to liver disease?
Folate protects hyperhomocysteinemia hepatocytes via CFTR-dependent ER stress, and ethanol impairs mitochondrial function in hepatocytes, both intersecting with SAM metabolism.
Can SAM affect ion channels?
Yes, SAM modulates RyR2 gating via the ATP binding site, producing subconductance states.
Does fasting change SAM metabolism?
Fasting and inflammatory challenges alter the swine hepatic metabolome, including SAM-related metabolites.
What methods study SAM transport?
Targeted metabolomics, methylation assays, patch-clamp, CRISPR knockout, point-mutation knock-in, overexpression, and CRISPR screens are commonly used.
What CRISPR models are used for SAM transport research?
Knockout, point-mutation knock-in, tagged knock-in, and overexpression models are used to test causality and mechanism.
How does hypoxia relate to SAM metabolism?
Hypoxia regulates ornithine decarboxylase in pulmonary artery smooth muscle cells, linking oxygen sensing to SAM-related polyamine metabolism.
Conclusion
GO:0000095, S-adenosyl-L-methionine transmembrane transporter activity, is a central molecular function that controls the compartmental supply of the universal methyl donor SAM. Its activity intersects with one-carbon metabolism, protein and DNA methylation, ion channel modulation, and stress responses in liver, heart, and other tissues. CRISPR-based knockout, point-mutation, knock-in, overexpression, and library screening models provide the most direct way to test causal roles of SAM transport genes in health and disease.
References
- 1. Chi H et al.. 2025. SAM-AMP lyases in type III CRISPR defence.. Nucleic Acids Res 53(13) PMID: 40650973
- 2. Black MT et al.. 1987. Light-regulated methylation of chloroplast proteins.. J Biol Chem 262(20):9803-7 PMID: 3597439
- 3. Kampfer AJ et al.. 2022. Electrical polarity-dependent gating and a unique subconductance of RyR2 induced by S-adenosyl methionine via the ATP binding site.. J Biochem 170(6):739-752 PMID: 34523682
- 4. Gomez AN et al.. 2025. Effects of fasting and inflammatory challenges on the swine hepatic metabolome.. Comp Biochem Physiol Part D Genomics Proteomics 54:101429 PMID: 39889585
- 5. Devi BG et al.. 1994. Effect of acute ethanol exposure on cultured fetal rat hepatocytes: relation to mitochondrial function.. Alcohol Clin Exp Res 18(6):1436-42 PMID: 7695041
- 6. Sahr T et al.. 2010. O-carboxyl- and N-methyltransferases active on plant aquaporins.. Plant Cell Physiol 51(12):2092-104 PMID: 21062871
- 7. Harrod KS et al.. 1996. Regulation of ornithine decarboxylase by hypoxia in pulmonary artery smooth muscle cells.. Am J Physiol 271(1 Pt 1):L31-7 PMID: 8760129
- 8. Yang A et al.. 2017. Folate Protects Hepatocytes of Hyperhomocysteinemia Mice From Apoptosis via Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Activated Endoplasmic Reticulum Stress.. J Cell Biochem 118(9):2921-2932 PMID: 28230279
