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Last update 08 May 2025

SHMT2

Last update 08 May 2025

Basic Info

Synonyms

Glycine hydroxymethyltransferase, serine hydroxymethyltransferase 2, Serine hydroxymethyltransferase, mitochondrial

+ [3]

Introduction

Catalyzes the cleavage of serine to glycine accompanied with the production of 5,10-methylenetetrahydrofolate, an essential intermediate for purine biosynthesis (PubMed:24075985, PubMed:25619277, PubMed:29364879, PubMed:33015733). Serine provides the major source of folate one-carbon in cells by catalyzing the transfer of one carbon from serine to tetrahydrofolate (PubMed:25619277). Contributes to the de novo mitochondrial thymidylate biosynthesis pathway via its role in glycine and tetrahydrofolate metabolism: thymidylate biosynthesis is required to prevent uracil accumulation in mtDNA (PubMed:21876188). Also required for mitochondrial translation by producing 5,10-methylenetetrahydrofolate; 5,10-methylenetetrahydrofolate providing methyl donors to produce the taurinomethyluridine base at the wobble position of some mitochondrial tRNAs (PubMed:29364879, PubMed:29452640). Associates with mitochondrial DNA (PubMed:18063578). In addition to its role in mitochondria, also plays a role in the deubiquitination of target proteins as component of the BRISC complex: required for IFNAR1 deubiquitination by the BRISC complex (PubMed:24075985).

Drugs associated with SHMT2

Cancer metabolism therapeutics(Cornerstone Pharmaceuticals)

Target

SHMT1 x SHMT2

Mechanism

SHMT1 inhibitors [+1]

Active Org.

Cornerstone Pharmaceuticals, Inc.

Originator Org.

Cornerstone Pharmaceuticals, Inc.

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with SHMT2

100 Translational Medicine associated with SHMT2

0 Patents (Medical) associated with SHMT2

253

Literatures (Medical) associated with SHMT2

01 Jun 2025·Bioorganic Chemistry

Ginsenoside Rd and chrysophanol: Modulating the serine-glycine-one-carbon pathway to enhance neuroprotection in intracerebral hemorrhage

Article

Author: Guo, JianWen ; Zhou, Huifen ; Pan, Zhiyong ; Wan, HaiTong ; Zhao, Xingping ; Yang, Jiehong

BACKGROUNDIntracerebral hemorrhage (ICH) is a devastating neurological disorder characterized by oxidative stress, inflammatory cascades, and metabolic dysregulation. Ginsenoside Rd (G-Rd) and chrysophanol (Chr), two natural compounds with antioxidative and anti-inflammatory properties, have demonstrated neuroprotective potential, however, their mechanisms in ICH remain unclear.OBJECTIVEThis study aimed to investigate the protective effects of G-Rd and Chr against heme-induced injury in HT22 cells and in a rat model of ICH, with a focus on oxidative stress, inflammation, apoptosis, and metabolic regulation.METHODSIn vitro, HT22 cells were exposed with heme (10 μmol/L, 12 h) to simulate ICH injury, followed by treatment with G-Rd and Chr (80 μmol/L). Reactive oxygen species (ROS), apoptosis, mitochondrial membrane potential, and inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10) were assessed using flow cytometry, fluorescence microscopy, and ELISA. In vivo, ICH was induced in rats via collagenase injection. Neurological function, hematoma volume, histopathology, and metabolic enzymes (SOD, MDA, NAD+, Ca²⁺-ATPase) were evaluated. Western blotting was used to analyze key enzymes in the serine-glycine-one‑carbon (SGOC) pathway.RESULTSG-Rd and Chr significantly suppressed ROS production (P < 0.05), downregulated pro-inflammatory cytokines (TNF-α, IL-1β, IL-6; P < 0.01), and inhibited apoptosis (P < 0.01) in HT22 cells. Both compounds restored mitochondrial membrane potential and alleviated cellular damage. In the ICH rat model, combined treatment improved neurological scores by 45 % (P < 0.01), decreased hematoma volume by 38 % (P < 0.01), and restored metabolic homeostasis through modulation of SGOC pathway enzymes (PHGDH, PSAT1, PSPH, SHMT2; P < 0.05). Synergistic effects were observed in both hematoma resolution and neuroprotection.CONCLUSIONG-Rd and Chr confer neuroprotection in ICH through antioxidative, anti-inflammatory, anti-apoptotic, and metabolic regulatory mechanisms. Their synergistic efficacy underscores their promise as therapeutic candidates, meriting further investigation of their molecular targets and translational potential.

01 Jun 2025·Molecular Therapy Nucleic Acids

SHMT2 is essential for mammalian preimplantation embryonic development through de novo biosynthesis of nucleotide metabolites

Article

Author: Zhang, Chuanxin ; Zhao, Han ; Zhang, Yiwen ; Deng, Tiantian ; Wang, Jiawei ; Shi, Mingze ; Chen, Zi-Jiang ; Song, Jinzhu ; Huai, Yingxue ; Liu, Boyang ; Wu, Keliang

Assisted reproductive technology (ART) is used widely and efficiently to treat infertility. During the ART procedure, one of the main factors affecting the success rate is abnormal development of preimplantation embryos. The establishment and maintenance of developmental competence are precisely regulated at different levels, while minor errors at early stages may result in adverse outcomes, including developmental arrest and implantation failure. As one of the major inputs, the regulatory mechanisms of metabolites in embryonic development are less known. In this study, we investigated the functional relevance of the metabolic enzyme serine hydroxymethyltransferase 2 (SHMT2) and deoxyribonucleotide (dNTP) metabolites in mouse preimplantation embryonic development. By using a well-characterized SHMT2 inhibitor, SHMT-IN-2, we effectively inhibited the catalytic activity of the SHMT2 enzyme, which led to developmental arrest at the pronuclear stage of the embryo. A low-input liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and applied for detecting dNTP content in embryos. We found that SHMT2 inhibition led to an insufficient dTTP supply and replication stress during the first mitotic cleavage, thereby causing failure of pronuclear fusion and developmental arrest. Our findings demonstrate a specific mechanism where, apart from building blocks of DNA, the availability of dNTPs contributes to the control of mouse preimplantation embryonic development.

01 Feb 2025·eBioMedicine

SHMT2 regulates CD8+ T cell senescence via the reactive oxygen species axis in HIV-1 infected patients on antiretroviral therapy

Article

Author: Yang, Tian-Ling ; Li, Si-Yao ; Liu, Ding-Ning ; Li, Jia-Qi ; Zhang, Zi-Ning ; Shang, Hong ; Wang, Jia-Ning ; Zhang, Qi-Sheng

BACKGROUNDAlthough antiretroviral therapy (ART) effectively inhibits viral replication, it does not fully mitigate the immunosenescence instigated by HIV infection. Cellular metabolism regulates cellular differentiation, survival, and senescence. Serine hydroxymethyltransferase 2 (SHMT2) is the first key enzyme for the entry of serine into the mitochondria from the de novo synthesis pathway that orchestrates its conversion glutathione (GSH), a key molecule in neutralising ROS and ensuring the stability of the immune system. It remains incompletely understood whether SHMT2 is involved in the senescence of CD8+ T cells, crucial for immune vigilance against HIV.METHODSHIV-infected individuals receiving antiretroviral therapy were enrolled in our study. SHMT2-siRNA was electroporated into T cells to disrupt the gene expression of SHMT2, followed by the quantification of mRNA levels of crucial serine metabolism enzymes using real-time PCR. Immunophenotyping, proliferation, cellular and mitochondrial function, and senescence-associated signalling pathways were examined using flow cytometry in CD8+ T cell subsets.FINDINGSOur findings revealed that CD8+ T cells in HIV-infected subjects are inclined towards senescence, and we identified that SHMT2, a key enzyme in serine metabolism, plays a role in CD8+ T cell senescence. SHMT2 can regulate glutathione (GSH) synthesis and protect mitochondrial function, thus effectively controlling intracellular reactive oxygen species (ROS) levels. Moreover, SHMT2 significantly contributes to averting immunosenescence and sustaining CD8+ T cell competence by modulating downstream DNA damage and phosphorylation cascades in pathways intricately linked to cellular senescence. Additionally, our study identified glycine can ameliorate CD8+ T cell senescence in HIV-infected individuals.INTERPRETATIONDecreased SHMT2 levels in HIV-infected CD8+ T cells affect ROS levels by altering mitochondrial function and GSH content. Increased ROS levels activate senescence-related signalling pathways in the nucleus. However, glycine supplementation counteracts these effects and moderates senescence.FUNDINGThis study was supported by grants from the National Key R&D Program of China (2021YFC2301900-2021YFC2301901), National Natural Science Foundation of China (82372240), and Department of Science and Technology of Liaoning Province Project for the High-Quality Scientific and Technological Development of China Medical University (2022JH2/20200074).

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SHMT2

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