| 2024 |
Cryo-EM structures of human SHMT1 in free and RNA-bound states revealed that an RNA modulator (SHMT2 mRNA) competes with polyglutamylated folates and acts as an allosteric switch, selectively altering the enzyme's reactivity toward serine. The tetrameric assembly and a flap structural motif were identified as key structural elements required for RNA binding to eukaryotic SHMT1. |
Cryo-EM structure determination, in vitro enzymatic assays, RNA-binding assays, allosteric competition experiments |
Molecular cell |
High |
38996576
|
| 2009 |
SHMT1 (cytoplasmic serine hydroxymethyltransferase) and SHMT2α (a cytoplasmic/nuclear isoform encoded by Shmt2 lacking exon 1) are functionally redundant in nuclear de novo thymidylate biosynthesis during S-phase. Purified intact mouse liver nuclei convert dUMP to dTMP in the presence of NADPH and serine; SHMT inhibitor (aminomethylphosphonate) abolishes this activity. Nuclei from Shmt1−/− mice retain ~25% of thymidylate synthesis activity due to SHMT2α. |
Intact nuclei biochemical assay (dUMP→dTMP conversion), pharmacological inhibition, Shmt1 knockout mouse model, subcellular fractionation/localization |
PloS one |
High |
19513116
|
| 2009 |
SHMT1 undergoes sumoylation and nuclear import during S-phase, along with thymidylate synthase (TYMS) and dihydrofolate reductase (DHFR), forming the nuclear de novo thymidylate synthesis complex. The SHMT1 L474F polymorphism impairs SHMT1 sumoylation and nuclear translocation. |
Subcellular fractionation, nuclear import assay, genetic variant functional analysis |
PloS one |
Medium |
19513116
|
| 2011 |
SHMT1 regulates partitioning of folate-derived one-carbon units toward thymidylate biosynthesis. Shmt1 hemizygosity decreases thymidylate synthesis capacity and downregulates thymidylate synthase and cytoplasmic thymidine kinase protein levels, without significant effects on methylation capacity or purine synthesis. |
Shmt1 hemizygous mouse model (Apcmin/+ background), biochemical thymidylate synthesis assay, protein expression analysis |
Cancer research |
Medium |
21406397
|
| 2011 |
Disruption of Shmt1 in mice causes neural tube defects (exencephaly) under folate-deficient conditions. Dietary folate deficiency alone (without choline deficiency) is sufficient to induce NTDs in Shmt1−/− embryos, establishing SHMT1-dependent thymidylate biosynthesis as causally involved in neural tube closure. |
Shmt1 knockout mouse model, dietary intervention (folate-deficient vs. choline-deficient diets), embryo phenotyping |
The American journal of clinical nutrition |
High |
21346092 22134951
|
| 2014 |
SHMT1 knockdown in lung cancer cells leads to increased uracil misincorporation into DNA and p53-dependent apoptosis. The apoptotic effect is not due to serine or glycine starvation but specifically to impaired thymidylate biosynthesis causing uracil accumulation during DNA replication. |
siRNA knockdown, cell cycle analysis, uracil incorporation assay, apoptosis assay (flow cytometry), p53 pathway analysis |
Cell death & disease |
Medium |
25412303
|
| 2014 |
SHMT1 functions as a scaffold protein for a multi-enzyme complex in the de novo thymidylate biosynthesis pathway. SHMT1 knockdown via VB6-coupled siRNA delivery disintegrates this complex, causing cell cycle arrest and decreased genomic DNA content in cancer cells. SHMT1 is a vitamin B6 (PLP)-dependent enzyme, and cancer cells exploit facilitated diffusion of VB6 for continuous SHMT1 activation. |
siRNA knockdown via VB6-coupled polymer vector, cell cycle analysis, apoptosis assay, xenograft mouse model |
Biomaterials |
Medium |
25132602
|
| 2013 |
Shmt1 disruption in mice impairs hippocampal neurogenesis: Shmt1+/− mice show elevated DG proliferation but a 98% reduction in mature newborn neurons and a 45% reduction in mnemonic recall during trace fear conditioning. Dietary folate manipulation alone does not rescue these phenotypes, implicating thymidylate biosynthesis (rather than folate availability per se) in neuronal maturation. |
Shmt1 knockout/hemizygous mouse model, BrdU/NeuN neurogenesis assay, trace fear conditioning behavioral test, dietary intervention |
The Journal of nutrition |
Medium |
23700346
|
| 2019 |
SHMT1 inhibits hepatocellular carcinoma cell migration and invasion by repressing NOX1-mediated ROS production. SHMT1 knockdown enhances ROS production via upregulation of NOX1, promoting EMT and MMP2 expression; NOX1 was identified as a downstream target of SHMT1. Rescue experiments confirmed NOX1 mediates SHMT1's functional influence on HCC cells. |
Gain/loss-of-function (overexpression/siRNA knockdown), Transwell migration/invasion assay, ROS measurement, western blotting, lung metastasis mouse model, rescue experiments |
Journal of experimental & clinical cancer research : CR |
Medium |
30755243
|
| 2018 |
SHMT1 silencing in human aortic smooth muscle cells induces osteo-/chondrogenic transdifferentiation and promotes calcification. This occurs at least in part by decreasing total antioxidant capacity and upregulating NOX4 and CYBA (NADH/NADPH oxidase components), increasing oxidative stress. Antioxidant treatment (TEMPOL or TIRON) blunts osteogenic marker induction, placing SHMT1 upstream of oxidative stress in this pathway. |
siRNA knockdown in primary human aortic smooth muscle cells, alkaline phosphatase activity assay, osteogenic marker mRNA expression, antioxidant rescue experiment |
Kidney & blood pressure research |
Medium |
30071536
|
| 2021 |
SHMT1 protein binds SHMT2 mRNA, constituting a riboregulatory interaction in lung cancer cells. This SHMT1-RNA interaction shapes serine and glycine levels across cellular compartments, as modeled computationally and validated experimentally in H1299 lung adenocarcinoma cells. RNA acts as a metabolic switch for SHMT1 enzymatic activity. |
Protein-RNA interaction assay, stochastic dynamic modeling, experimental validation in H1299 cell line |
Computational and structural biotechnology journal |
Medium |
34136101
|
| 2023 |
The transcription factor HOXD8 directly binds to the SHMT1 promoter (at the −456 to −254 bp region) and promotes SHMT1 expression in renal cell carcinoma. HOXD8 knockdown decreases SHMT1 expression and accelerates RCC growth, while SHMT1 overexpression suppresses RCC proliferation and migration. |
ChIP assay (HOXD8 binding to SHMT1 promoter), knockdown/overexpression, proliferation and migration assays, in vivo mouse tumor model |
Cancer science |
Medium |
37752684
|
| 2025 |
SHMT1 physically interacts with PEMT (phosphatidylethanolamine N-methyltransferase) in astrocytes. Disruption of the SHMT1–PEMT interaction depletes SAM, causes H3K4me1 hypomethylation, reduces Slc1a2 and Glul expression, and exacerbates neuroexcitotoxicity and dopaminergic neuron loss in a Parkinson's disease mouse model. Astrocyte-specific conditional Shmt1 knockout decreases SAM levels and worsens PD motor phenotype. |
Co-immunoprecipitation/protein interaction assay, isotopic labeling (13C-serine tracing), astrocyte-specific conditional knockout, ChIP (H3K4me1), behavioral assays in PD mouse model |
Advanced science |
Medium |
41262011
|
| 2025 |
ZNF526 transcriptionally activates SHMT1 expression in triple-negative breast cancer cells. SHMT1 activation by ZNF526 enhances flux through the serine-glycine-one-carbon (SGOC) metabolic pathway, increases glutathione (GSH) production, reduces ROS levels, and strengthens antioxidant defenses to facilitate TNBC progression. |
Overexpression/knockdown functional assays, metabolic flux analysis, GSH/ROS measurement, transcriptional regulation assays |
Molecular cancer |
Low |
41267037
|
| 2024 |
Fibronectin extra domain A (FN-EDA) derived from cancer-associated fibroblasts stimulates SHMT1 upregulation in HCC cells via the TLR4/NF-κB signaling pathway, thereby countering sorafenib-induced oxidative stress and promoting sorafenib resistance. |
In vitro co-culture/treatment experiments, in vivo xenograft model with primary CAFs, pathway inhibition, RNA-seq analysis of HCC organoids |
Genes & diseases |
Medium |
39286657
|