SHMT2

Summary

SHMT2 (serine hydroxymethyltransferase 2, HGNC:10852) is a protein-coding gene on chromosome 12q13.3, encoding Serine hydroxymethyltransferase, mitochondrial (P34897). Catalyzes the cleavage of serine to glycine accompanied with the production of 5,10-methylenetetrahydrofolate, an essential intermediate for purine biosynthesis.

This gene encodes the mitochondrial form of a pyridoxal phosphate-dependent enzyme that catalyzes the reversible reaction of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. The encoded product is primarily responsible for glycine synthesis. The activity of the encoded protein has been suggested to be the primary source of intracellular glycine. The gene which encodes the cytosolic form of this enzyme is located on chromosome 17. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 6472 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 111 total — 3 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005412

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10852
Approved symbol	SHMT2
Name	serine hydroxymethyltransferase 2
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Aliases	mSHMT
Ensembl gene	ENSG00000182199
Ensembl biotype	protein_coding
OMIM	138450
Entrez	6472

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 24 protein_coding, 9 nonsense_mediated_decay, 7 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000328923, ENST00000414700, ENST00000449049, ENST00000553324, ENST00000553474, ENST00000553529, ENST00000553837, ENST00000553868, ENST00000553949, ENST00000553950, ENST00000554310, ENST00000554467, ENST00000554600, ENST00000554604, ENST00000554656, ENST00000554975, ENST00000555116, ENST00000555213, ENST00000555563, ENST00000555634, ENST00000555773, ENST00000555774, ENST00000556689, ENST00000556737, ENST00000556798, ENST00000556825, ENST00000557269, ENST00000557302, ENST00000557348, ENST00000557427, ENST00000557433, ENST00000557487, ENST00000557529, ENST00000557703, ENST00000557740, ENST00000894751, ENST00000894752, ENST00000894753, ENST00000894754, ENST00000925589, ENST00000925590, ENST00000925591, ENST00000925592, ENST00000925593

RefSeq mRNA: 5 — MANE Select: NM_005412 NM_001166356, NM_001166357, NM_001166358, NM_001166359, NM_005412

CCDS: CCDS53805, CCDS55837, CCDS8934

Canonical transcript exons

ENST00000328923 — 12 exons

Exon	Start	End
ENSE00002459821	57234234	57234935
ENSE00003478773	57231481	57231560
ENSE00003484818	57232211	57232292
ENSE00003502162	57234003	57234110
ENSE00003528890	57232704	57232843
ENSE00003590393	57233563	57233662
ENSE00003649253	57233180	57233345
ENSE00003649983	57232453	57232575
ENSE00003658431	57230803	57231000
ENSE00003670608	57233749	57233904
ENSE00003673873	57229711	57229811
ENSE00003791545	57231713	57231913

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 157.2202 / max 1086.0057, expressed in 1825 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126181	138.6912	1824
126184	7.8902	1399
126189	5.0822	797
126185	2.0027	781
126190	0.7245	347
126183	0.7241	438
126192	0.6517	358
126188	0.5852	270
126191	0.4188	231
126186	0.3538	192

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	99.18	gold quality
cartilage tissue	UBERON:0002418	98.58	gold quality
right lobe of liver	UBERON:0001114	98.48	gold quality
oocyte	CL:0000023	98.26	gold quality
liver	UBERON:0002107	97.96	gold quality
stromal cell of endometrium	CL:0002255	97.75	gold quality
secondary oocyte	CL:0000655	96.92	gold quality
embryo	UBERON:0000922	95.87	gold quality
body of pancreas	UBERON:0001150	95.78	gold quality
tongue squamous epithelium	UBERON:0006919	95.23	gold quality
tibia	UBERON:0000979	95.20	gold quality
ganglionic eminence	UBERON:0004023	95.19	gold quality
parotid gland	UBERON:0001831	95.06	gold quality
ventricular zone	UBERON:0003053	95.00	gold quality
lymph node	UBERON:0000029	94.81	gold quality
cervix squamous epithelium	UBERON:0006922	94.80	gold quality
pancreas	UBERON:0001264	94.76	gold quality
oviduct epithelium	UBERON:0004804	94.75	gold quality
vermiform appendix	UBERON:0001154	94.51	gold quality
esophagus mucosa	UBERON:0002469	94.50	gold quality
caecum	UBERON:0001153	93.93	gold quality
medial globus pallidus	UBERON:0002477	93.82	gold quality
lower esophagus mucosa	UBERON:0035834	93.78	gold quality
nephron tubule	UBERON:0001231	93.63	gold quality
hair follicle	UBERON:0002073	93.58	gold quality
islet of Langerhans	UBERON:0000006	93.53	gold quality
squamous epithelium	UBERON:0006914	93.45	gold quality
superior surface of tongue	UBERON:0007371	93.44	gold quality
tonsil	UBERON:0002372	93.39	gold quality
gingival epithelium	UBERON:0001949	93.32	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-120	yes	43.86
E-ANND-3	yes	11.35

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

24 targeting SHMT2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-935	98.82	69.36	1072
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-193A-3P	98.59	66.36	769
HSA-MIR-193B-3P	98.59	66.62	748
HSA-MIR-18B-3P	98.05	65.55	595
HSA-MIR-4314	97.50	67.30	1369
HSA-MIR-5192	96.89	63.35	879
HSA-MIR-301A-5P	96.88	68.07	931
HSA-MIR-301B-5P	96.88	67.75	946
HSA-MIR-3157-3P	95.86	67.08	454
HSA-MIR-11401	90.58	63.72	128

Literature-anchored findings (GeneRIF, showing 40)

• SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis (PMID:19513116)
• The present study not only describes individual genetic variation that directly affects SHMT1 and SHMT2 activity, but provided insight into the overall regulation of the Folate and Methionine Cycles. (PMID:22220685)
• SHMT1 exists in solution as a tetramer, both in the absence and presence of PLP, while SHMT2 undergoes a dimer-to-tetramer transition. (PMID:25619277)
• SHMT2 is required for glioblastoma multiforme cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition (PMID:25855294)
• The SHMT-2 is the direct targets of miR-370 and miR-373, respectively, in human articular chondrocytes. (PMID:26103880)
• our results for the first time showed that miR-615-5p prevents proliferation and migration through negatively regulating SHMT2 in HCC. (PMID:26662310)
• High SHMT2 expression increases glycine-dependent nucleotide synthesis leading to bladder cancer growth. (PMID:26975021)
• Data suggest that serine hydroxymethyltransferase 2 (SHMT2) may be a potential target in the treatment of hepatocellular carcinoma (HCC). (PMID:27391339)
• Site-directed mutagenesis experiments on SHMT1 demonstrate that selective enzyme inhibition relies on the presence of a cysteine residue at the active site of SHMT1 (Cys204) that is absent in SHMT2. (PMID:27530298)
• These results indicate that SHMT2 may be a valuable prognostic biomarker in ER-negative breast cancer cases (PMID:27666119)
• High SHMT2 expression is associated with idiopathic pulmonary fibrosis. (PMID:27836973)
• Our data confirm the heterogeneity of breast tumors at a functional proteomic level and dissects the relationship between metabolism-related proteins, pathological features and patient survival. These observations highlight the importance of SHMT2 and ASCT2 as valuable individual prognostic markers and potential targets for personalized breast cancer therapy (PMID:29020998)
• The one-carbon donor formate generally rescues cells from SHMT inhibition, but paradoxically increases the inhibitor’s cytotoxicity in diffuse large B-cell lymphoma (DLBCL); this effect is rooted in defective glycine uptake in DLBCL cell lines, rendering them uniquely dependent upon SHMT enzymatic activity to meet glycine demand. (PMID:29073064)
• SHMT2 Desuccinylation is associated with Cancer Cell Proliferation. (PMID:29180469)
• Findings support the hypothesis that age-associated respiration defects in fibroblasts of elderly humans are caused not by mtDNA mutations but by epigenetic regulation of nuclear genes including SHMT2. (PMID:29323231)
• serine hydroxymethyltransferase 2 (SHMT2) is acetylated at K95 in colorectal cancer (CRC) cells. SHMT2-K95-Ac disrupts its functional tetramer structure and inhibits its enzymatic activity. SHMT2-K95-Ac promotes its degradation via the K63-ubiquitin-lysosome pathway in a glucose-dependent manner. SHMT2-K95-Ac is decreased in human CRC samples which is correlated with poorer postoperative overall survival. (PMID:30367038)
• Characterized the serine hydroxymethyltransferase reaction catalyzed by SHMT1 and SHMT2, with a focus on pH dependence and substrate inhibition. SHMT2 maintains a pronounced tetrahydrofolate substrate inhibition even at the alkaline pH characteristic of the mitochondrial matrix, whereas with SHMT1 this is almost abolished. At this pH, SHMT2 also shows a catalytic efficiency that is much higher than that of SHMT1. (PMID:30500180)
• metabolic control of BRISC-SHMT2 assembly regulates immune signaling; data reveal a mechanism in which metabolites regulate deubiquitylase activity and inflammatory signalling (PMID:31142841)
• Increased expression of SHMT2 is a negative prognostic biomarker in patients with hepatocellular carcinoma (HCC). Expression of the SHMT2 gene promoted the proliferation and migration of HepG2 HCC cells (PMID:31379360)
• Chronic inflammation might thus prime the transition of PCa cells towards more advanced stages, and SHMT2 could represent a missing factor to further understand the molecular mechanisms responsible for the transition of prostate cancer towards a more aggressive phenotype. (PMID:31500219)
• High expression of SHMT2 is correlated with tumor progression and predicts poor prognosis in gastrointestinal tumors. (PMID:31773687)
• Serine-dependent redox homeostasis regulates glioblastoma cell survival. (PMID:32203214)
• Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2. (PMID:32330411)
• Cancer proteome and metabolite changes linked to SHMT2. (PMID:32903271)
• Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome. (PMID:33015733)
• Evaluating the clinical significance of SHMT2 and its co-expressed gene in human kidney cancer. (PMID:33066813)
• BRCA1-A and BRISC: Multifunctional Molecular Machines for Ubiquitin Signaling. (PMID:33142801)
• Cytoplasmic SHMT2 drives the progression and metastasis of colorectal cancer by inhibiting beta-catenin degradation. (PMID:33456583)
• The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing. (PMID:33569544)
• Interaction analysis of gene variants related to one-carbon metabolism with chronic hepatitis B infection in Chinese patients. (PMID:33894044)
• Identification of SHMT2 as a Potential Prognostic Biomarker and Correlating with Immune Infiltrates in Lung Adenocarcinoma. (PMID:33928169)
• The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy. (PMID:33990700)
• Serine hydroxymethyltransferase 2 expression promotes tumorigenesis in rhabdomyosarcoma with 12q13-q14 amplification. (PMID:34166228)
• SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma. (PMID:34624079)
• Induction of serine hydroxymethyltransferase 2 promotes tumorigenesis and metastasis in neuroblastoma. (PMID:35018218)
• SHMT2 Drives the Progression of Colorectal Cancer by Regulating UHRF1 Expression. (PMID:35211429)
• Serine hydroxymethyltransferase 2 (SHMT2) potentiates the aggressive process of oral squamous cell carcinoma by binding to interleukin enhancer-binding factor 2 (ILF2). (PMID:35333683)
• SHMT2 promotes the tumorigenesis of renal cell carcinoma by regulating the m6A modification of PPAT. (PMID:35798250)
• Exosome-mediated transfer of circ_0063526 enhances cisplatin resistance in gastric cancer cells via regulating miR-449a/SHMT2 axis. (PMID:36206102)
• Serine hydroxymethyltransferase 2 knockdown induces apoptosis in ccRCC by causing lysosomal membrane permeabilization via metabolic reprogramming. (PMID:36806313)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	shmt2	ENSDARG00000104414
mus_musculus	Shmt2	ENSMUSG00000025403
rattus_norvegicus	Shmt2	ENSRNOG00000008106

Paralogs (1): SHMT1 (ENSG00000176974)

Protein

Protein identifiers

Serine hydroxymethyltransferase, mitochondrial — P34897 (reviewed: P34897)

Alternative names: Glycine hydroxymethyltransferase, Serine methylase

All UniProt accessions (16): P34897, G3V241, G3V2D2, G3V2E4, G3V2W0, G3V2Y1, G3V2Y4, G3V3C6, G3V3Y8, G3V4T0, G3V4W5, G3V4X0, G3V540, G3V5L0, H0YIZ0, V9HW06

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the cleavage of serine to glycine accompanied with the production of 5,10-methylenetetrahydrofolate, an essential intermediate for purine biosynthesis. Serine provides the major source of folate one-carbon in cells by catalyzing the transfer of one carbon from serine to tetrahydrofolate. 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. 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. Associates with mitochondrial DNA. 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.

Subunit / interactions. Homotetramer; in the presence of bound pyridoxal 5’-phosphate. Homodimer; in the absence of bound pyridoxal 5’-phosphate. Pyridoxal 5’-phosphate binding mediates an important conformation change that is required for tetramerization. Interacts with ABRAXAS2; the interaction is direct. Identified in a complex with ABRAXAS2 and the other subunits of the BRISC complex, at least composed of the ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Identified in a complex with ABRAXAS2 and IFNAR1. Interacts with KIRREL3.

Subcellular location. Mitochondrion. Mitochondrion matrix. Mitochondrion nucleoid. Mitochondrion inner membrane. Cytoplasm. Nucleus.

Post-translational modifications. Succinylation at Lys-280 inhibits the hydroxymethyltransferase activity. Desuccinylation by SIRT5 restores the activity, leading to promote cell proliferation.

Disease relevance. Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB) [MIM:619121] An autosomal recessive neurodevelopmental disorder characterized by global developmental delay, moderate to severe intellectual disability, spastic paraparesis, ataxia, and/or peripheral neuropathy. Patients also exhibit dysmorphic features and congenital microcephaly. Most affected individuals develop progressive hypertrophic cardiomyopathy in childhood or have cardiac developmental anomalies. Brain imaging shows corpus callosum abnormalities in all patients, and perisylvian polymicrogyria-like pattern in some individuals. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Hydroxymethyltransferase is inhibited by succinylation at Lys-280.

Pathway. One-carbon metabolism; tetrahydrofolate interconversion.

Miscellaneous. In eukaryotes there are two forms of the enzymes: a cytosolic one and a mitochondrial one.

Similarity. Belongs to the SHMT family.

Isoforms (3)

UniProt ID	Names	Canonical?
P34897-1	1	yes
P34897-2	2
P34897-3	3

RefSeq proteins (5): NP_001159828, NP_001159829, NP_001159830, NP_001159831, NP_005403* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001085	Ser_HO-MeTrfase	Family
IPR015421	PyrdxlP-dep_Trfase_major	Homologous_superfamily
IPR015422	PyrdxlP-dep_Trfase_small	Homologous_superfamily
IPR015424	PyrdxlP-dep_Trfase	Homologous_superfamily
IPR019798	Ser_HO-MeTrfase_PLP_BS	Binding_site
IPR039429	SHMT-like_dom	Domain
IPR049943	Ser_HO-MeTrfase-like	Family

Pfam: PF00464

Enzyme classification (BRENDA):

• EC 2.1.2.1 — glycine hydroxymethyltransferase (BRENDA: 81 organisms, 196 substrates, 226 inhibitors, 227 Km, 174 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-SERINE	0.0044–65.3	78
TETRAHYDROFOLATE	0.003–3.4	71
L-SER	0.13–11.2	17
5,10-METHYLENETETRAHYDROFOLATE	0.18–0.98	12
GLYCINE	0.25–5.87	11
(6S)-TETRAHYDROFOLATE	0.002–0.021	4
DL-PHENYLSERINE	0.27–131.6	4
D-SERINE	0.071–55	3
DL-3-PHENYLSERINE	57.86–61.95	2
SERINE	0.43–1.6	2
TETRAHYDROMETHANOPTERIN	0.1	1

Catalyzed reactions (Rhea), 1 shown:

• (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + glycine + H2O = (6S)-5,6,7,8-tetrahydrofolate + L-serine (RHEA:15481)

UniProt features (80 total): helix 25, strand 17, modified residue 11, mutagenesis site 10, sequence variant 6, turn 4, splice variant 2, transit peptide 1, chain 1, region of interest 1, compositionally biased region 1, sequence conflict 1

Structure

Experimental structures (PDB)

27 structures.

PDB	Method	Resolution (Å)
8AQL	X-RAY DIFFRACTION	1.23
9RWD	X-RAY DIFFRACTION	1.3
6DK3	X-RAY DIFFRACTION	2.04
9BOX	X-RAY DIFFRACTION	2.1
6QVL	X-RAY DIFFRACTION	2.28
6M5O	X-RAY DIFFRACTION	2.3
6QVG	X-RAY DIFFRACTION	2.32
8GKW	X-RAY DIFFRACTION	2.38
5V7I	X-RAY DIFFRACTION	2.47
8FJT	X-RAY DIFFRACTION	2.47
8SSJ	X-RAY DIFFRACTION	2.5
8FJU	X-RAY DIFFRACTION	2.51
4PVF	X-RAY DIFFRACTION	2.6
8GKT	X-RAY DIFFRACTION	2.64
8T4O	X-RAY DIFFRACTION	2.68
8TLC	X-RAY DIFFRACTION	2.72
8GKZ	X-RAY DIFFRACTION	2.75
7BYI	X-RAY DIFFRACTION	2.76
8GKY	X-RAY DIFFRACTION	2.77
8T4P	X-RAY DIFFRACTION	2.8
5X3V	X-RAY DIFFRACTION	2.85
8QI7	ELECTRON MICROSCOPY	2.9
8GKS	X-RAY DIFFRACTION	2.99
8GKU	X-RAY DIFFRACTION	3.06
6R8F	ELECTRON MICROSCOPY	3.8
8XNA	X-RAY DIFFRACTION	3.8
6H3C	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P34897-F1	93.24	0.90

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (11): 356, 464, 469, 470, 474, 103, 181, 196, 280, 280, 297

Mutagenesis-validated functional residues (10):

Position	Phenotype
98	abolishes serine hydroxymethyltransferase activity, leading to oxidative phosphorylation deficiency; when associated wit
103	does not affect succinylation level or hydroxymethyltransferase activity.
106	abolishes serine hydroxymethyltransferase activity, leading to oxidative phosphorylation deficiency; when associated wit
280	abolishes pyridoxal phosphate-binding, leading to oxidative phosphorylation deficiency.
280	decreased succinylation level and hydroxymethyltransferase activity.
302	does not affect succinylation level or hydroxymethyltransferase activity.
356	does not affect succinylation level or hydroxymethyltransferase activity.
464	does not affect succinylation level or hydroxymethyltransferase activity.
469	does not affect succinylation level or hydroxymethyltransferase activity.
474	does not affect succinylation level or hydroxymethyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-196757	Metabolism of folate and pterines
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 453 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_RESPONSE_TO_PEPTIDE, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_SERINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_MITOCHONDRIAL_TRANSLATION, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, CAFFAREL_RESPONSE_TO_THC_UP, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, MODULE_528

GO Biological Process (20): regulation of oxidative phosphorylation (GO:0002082), dTMP biosynthetic process (GO:0006231), glycine metabolic process (GO:0006544), L-serine metabolic process (GO:0006563), L-serine biosynthetic process (GO:0006564), one-carbon metabolic process (GO:0006730), positive regulation of cell population proliferation (GO:0008284), formate biosynthetic process (GO:0015943), obsolete glycine biosynthetic process from L-serine (GO:0019264), response to type I interferon (GO:0034340), tetrahydrofolate interconversion (GO:0035999), tetrahydrofolate metabolic process (GO:0046653), protein tetramerization (GO:0051262), protein homotetramerization (GO:0051289), regulation of mitochondrial translation (GO:0070129), protein K63-linked deubiquitination (GO:0070536), regulation of aerobic respiration (GO:1903715), regulation of translation (GO:0006417), glycine biosynthetic process (GO:0006545), methylation (GO:0032259)

GO Molecular Function (10): chromatin binding (GO:0003682), glycine hydroxymethyltransferase activity (GO:0004372), L-allo-threonine aldolase activity (GO:0008732), amino acid binding (GO:0016597), pyridoxal phosphate binding (GO:0030170), identical protein binding (GO:0042802), hydroxytrimethyllysine aldolase activity (GO:0120567), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (11): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), microtubule cytoskeleton (GO:0015630), mitochondrial nucleoid (GO:0042645), extracellular exosome (GO:0070062), BRISC complex (GO:0070552), membrane (GO:0016020), intracellular organelle lumen (GO:0070013)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1
RHO GTPase cycle	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	3
proteinogenic amino acid metabolic process	2
serine family amino acid biosynthetic process	2
proteinogenic amino acid biosynthetic process	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
mitochondrion	2
oxidative phosphorylation	1
regulation of aerobic respiration	1
pyrimidine deoxyribonucleoside monophosphate biosynthetic process	1
pyrimidine deoxyribonucleotide biosynthetic process	1
dTMP metabolic process	1
L-amino acid metabolic process	1
L-serine metabolic process	1
L-amino acid biosynthetic process	1
small molecule metabolic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
formate metabolic process	1
monocarboxylic acid biosynthetic process	1
response to cytokine	1
innate immune response	1
one-carbon metabolic process	1
tetrahydrofolate metabolic process	1
folic acid-containing compound metabolic process	1
protein complex oligomerization	1
protein homooligomerization	1
protein tetramerization	1
regulation of translation	1
mitochondrial translation	1
regulation of mitochondrial gene expression	1
protein deubiquitination	1
aerobic respiration	1
regulation of cellular respiration	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
glycine metabolic process	1
metabolic process	1

Protein interactions and networks

STRING

4260 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHMT2	GAPDH	P00354	894
SHMT2	TPI1	P00938	878
SHMT2	TYMS	P04818	850
SHMT2	MTHFD2	P13995	839
SHMT2	MTHFD1	P11586	836
SHMT2	DHFR	P00374	817
SHMT2	PSPH	P78330	815
SHMT2	PSAT1	Q9Y617	815
SHMT2	MTHFD1L	Q6UB35	790
SHMT2	CD19	P15391	777
SHMT2	PHGDH	O43175	775
SHMT2	GLDC	P23378	775
SHMT2	MTHFR	P42898	774
SHMT2	GLUD2	P49448	750
SHMT2	FCGR3B	O75015	743
SHMT2	FCGR3A	P08637	743

IntAct

246 interactions, top by confidence:

A	B	Type	Score
NDUFAF5	NDUFAF8	psi-mi:“MI:0914”(association)	0.750
LYRM2	NDUFAB1	psi-mi:“MI:0914”(association)	0.730
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
ARL6IP1	SHMT2	psi-mi:“MI:0915”(physical association)	0.720
SHMT2	ARL6IP1	psi-mi:“MI:0915”(physical association)	0.720
RCC1L	NME6	psi-mi:“MI:0914”(association)	0.720
PRELID3B	TRIAP1	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CMTM5	SHMT2	psi-mi:“MI:0915”(physical association)	0.670
SHMT2	CMTM5	psi-mi:“MI:0915”(physical association)	0.670
BABAM1	TNKS	psi-mi:“MI:0914”(association)	0.640
BABAM2	SHMT2	psi-mi:“MI:0914”(association)	0.640
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
SHMT2	MAL2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (787): SHMT2 (Affinity Capture-MS), ARL6IP1 (Two-hybrid), CMTM5 (Two-hybrid), NOC2L (Affinity Capture-RNA), HES4 (Affinity Capture-RNA), MTOR (Affinity Capture-RNA), UBR4 (Affinity Capture-RNA), HP1BP3 (Affinity Capture-RNA), E2F2 (Affinity Capture-RNA), RSRP1 (Affinity Capture-RNA), ARID1A (Affinity Capture-RNA), MAP3K6 (Affinity Capture-RNA), RCC1 (Affinity Capture-RNA), ZBTB8OS (Affinity Capture-RNA), YARS (Affinity Capture-RNA)

ESM2 similar proteins: A0A0E3Z9M4, A0QC23, A0R2V7, A4QCW6, A4TA90, A4X6P4, A5CU18, A6WF55, A8M1D3, B0RDR3, B1VFM5, B2DEV9, B2DEW0, B2DEW1, B2GM31, B6VP39, B7GTL3, B8ZSH2, B8ZSN5, D4QF24, E1CG38, O32915, O62585, P07511, P14519, P34897, P59953, P66805, P66806, P9WGI6, P9WGI7, P9WGI8, P9WGI9, Q2NAR9, Q3SZ20, Q48ME3, Q4JU69, Q5YQ76, Q6A9R8, Q6ADF0

Diamond homologs: A0B8J6, A1AE82, A1WVG6, A4J9B1, A4XL61, A5CYB7, A5N7P5, A7ZPZ4, A8A359, A9KSH6, B0K631, B0K742, B1I6M4, B1IVS6, B1LNK7, B1XB26, B2TXW4, B5YFZ0, B5Z123, B6I5C4, B7LDE3, B7M8A7, B7MIN5, B7MYI0, B7N6D8, B7NRK2, B7UGZ1, B8I2N8, B9E156, B9MR57, C4ZH69, C4ZXC6, O13425, O13426, O13972, O23254, O62585, P07511, P0A825, P0A826

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MYC	“up-regulates quantity by expression”	SHMT2	“transcriptional regulation”
SHMT2	“up-regulates quantity”	glycine	“chemical modification”
SHMT2	“up-regulates quantity”	(6R)-5,10-methylenetetrahydrofolate(2-)	“chemical modification”
TRIM21	“down-regulates quantity”	SHMT2	ubiquitination
SIRT5	“down-regulates activity”	SHMT2	“post translational modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 197 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of pyruvate dehydrogenase (PDH) complex	5	27.2×	1e-04
Mitochondrial protein import	9	11.5×	2e-05
Mitochondrial protein degradation	12	10.5×	1e-06
Complex I biogenesis	8	10.1×	1e-04
Aerobic respiration and respiratory electron transport	12	8.1×	9e-06
Respiratory electron transport	10	7.3×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial respiratory chain complex I assembly	7	16.6×	2e-04
mitochondrial electron transport, NADH to ubiquinone	6	12.4×	3e-03
proton motive force-driven mitochondrial ATP synthesis	7	10.7×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

111 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	3
Uncertain significance	69
Likely benign	9
Benign	8

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
988632	NM_005412.6(SHMT2):c.1495C>G (p.Pro499Ala)	Likely pathogenic
988637	NM_005412.6(SHMT2):c.557C>G (p.Thr186Arg)	Likely pathogenic
988638	NM_005412.6(SHMT2):c.1135A>G (p.Asn379Asp)	Likely pathogenic

SpliceAI

1745 predictions. Top by Δscore:

Variant	Effect	Δscore
12:57231474:A:AG	acceptor_gain	1.0000
12:57231479:A:AG	acceptor_gain	1.0000
12:57231480:G:GG	acceptor_gain	1.0000
12:57231556:AAGAG:A	donor_loss	1.0000
12:57231558:GAG:G	donor_gain	1.0000
12:57231558:GAGG:G	donor_loss	1.0000
12:57231560:GGTG:G	donor_loss	1.0000
12:57231561:GTGA:G	donor_loss	1.0000
12:57231707:C:CA	acceptor_gain	1.0000
12:57231711:A:AG	acceptor_gain	1.0000
12:57231712:G:GG	acceptor_gain	1.0000
12:57231909:GGCCA:G	donor_gain	1.0000
12:57231910:GCCA:G	donor_gain	1.0000
12:57231910:GCCAG:G	donor_gain	1.0000
12:57231912:CA:C	donor_gain	1.0000
12:57231913:AG:A	donor_loss	1.0000
12:57231914:G:GG	donor_gain	1.0000
12:57231915:T:A	donor_loss	1.0000
12:57231918:G:GG	donor_gain	1.0000
12:57232203:C:G	acceptor_gain	1.0000
12:57232206:C:CA	acceptor_gain	1.0000
12:57232208:CAGTC:C	acceptor_loss	1.0000
12:57232209:A:AG	acceptor_gain	1.0000
12:57232209:A:C	acceptor_loss	1.0000
12:57232210:G:GA	acceptor_gain	1.0000
12:57232210:GT:G	acceptor_gain	1.0000
12:57232210:GTC:G	acceptor_gain	1.0000
12:57232210:GTCT:G	acceptor_gain	1.0000
12:57232210:GTCTC:G	acceptor_gain	1.0000
12:57232288:TCAAC:T	donor_gain	1.0000

AlphaMissense

3247 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:57231535:T:C	Y96H	0.999
12:57233855:C:A	N410K	0.999
12:57233855:C:G	N410K	0.999
12:57231483:C:A	N78K	0.998
12:57231483:C:G	N78K	0.998
12:57231758:C:G	C119W	0.998
12:57231801:T:A	W134R	0.998
12:57231801:T:C	W134R	0.998
12:57232211:T:A	H171Q	0.998
12:57232211:T:G	H171Q	0.998
12:57232222:G:A	G175D	0.998
12:57232222:G:T	G175V	0.998
12:57232534:A:C	S226R	0.998
12:57232536:C:A	S226R	0.998
12:57232536:C:G	S226R	0.998
12:57232807:T:A	V274D	0.998
12:57232826:G:C	K280N	0.998
12:57232826:G:T	K280N	0.998
12:57233280:T:C	F320L	0.998
12:57233282:C:A	F320L	0.998
12:57233282:C:G	F320L	0.998
12:57233849:C:A	N408K	0.998
12:57233849:C:G	N408K	0.998
12:57233852:G:C	K409N	0.998
12:57233852:G:T	K409N	0.998
12:57230999:A:T	E77V	0.997
12:57231812:T:A	N137K	0.997
12:57231812:T:G	N137K	0.997
12:57231842:C:A	N147K	0.997
12:57231842:C:G	N147K	0.997

dbSNP variants (sampled 300 via entrez): RS1000212688 (12:57234123 G>A), RS1000229352 (12:57232534 A>C,G), RS1000613648 (12:57235378 C>A,G,T), RS1000943446 (12:57235225 G>A), RS1001489370 (12:57229071 A>G), RS1001624759 (12:57232931 T>C), RS1001960181 (12:57234679 G>A), RS1002344510 (12:57234947 G>A), RS1003038393 (12:57232326 G>A), RS1004266869 (12:57227954 C>G,T), RS1004601910 (12:57229528 C>A,T), RS1004602364 (12:57232974 T>A), RS1005437654 (12:57228150 T>G), RS1005884697 (12:57227727 A>G,T), RS1006574917 (12:57232385 G>A)

Disease associations

OMIM: gene MIM:138450 | disease phenotypes: MIM:619121

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities	Strong	Autosomal recessive
complex neurodevelopmental disorder	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities	Limited	AR

Mondo (3): neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (MONDO:0030866), neurodevelopmental disorder (MONDO:0700092), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000193	Bifid uvula
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000486	Strabismus
HP:0000514	Slow saccadic eye movements
HP:0000718	Aggressive behavior
HP:0000733	Motor stereotypy
HP:0001181	Adducted thumb
HP:0001310	Dysmetria
HP:0001347	Hyperreflexia
HP:0001349	Facial diplegia
HP:0001510	Growth delay
HP:0001639	Hypertrophic cardiomyopathy
HP:0001684	Secundum atrial septal defect
HP:0002064	Spastic gait
HP:0002078	Truncal ataxia
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002307	Drooling
HP:0002342	Moderate intellectual disability
HP:0002474	Expressive language delay
HP:0002510	Spastic tetraplegia
HP:0002553	Highly arched eyebrow
HP:0002650	Scoliosis
HP:0002714	Downturned corners of mouth
HP:0003390	Sensory axonal neuropathy
HP:0003487	Babinski sign

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002539_15	Schizophrenia	2.000000e-12
GCST004521_233	Autism spectrum disorder or schizophrenia	4.000000e-10
GCST006803_97	Schizophrenia	3.000000e-11
GCST008595_120	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	9.000000e-11
GCST008916_2	Asthma	2.000000e-08
GCST009600_112	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	6.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295747 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 517,921 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1071	OXAPROZIN	4	51,044
CHEMBL1175	DULOXETINE	4	28,527
CHEMBL1201303	PYRVINIUM	4	1,797
CHEMBL255044	FLUPIRTINE	4	5,706
CHEMBL34259	METHOTREXATE	4	398,396
CHEMBL506	PRIMAQUINE	4	10,279
CHEMBL19224	PAPAVERINE	3	22,172

PharmGKB: 1 entry (VIP=true, CPIC=false)

Binding affinities (BindingDB)

30 measured of 33 human assays (33 total across all organisms); most potent 30 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-[3-(6-amino-5-cyano-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazol-4-yl)-5-(trifluoromethyl)phenyl]pent-4-ynoic acid	IC50	0.17 nM	US-10077273: SHMT inhibitors
5-[3-(6-amino-5-cyano-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazol-4-yl)-5-(trifluoromethyl)phenyl]pent-4-ynamide	IC50	0.4 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-(5-hydroxypent-1-ynyl)-5-(trifluoromethyl)phenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	0.65 nM	US-10077273: SHMT inhibitors
(2S)-2-[5-[3-(6-amino-5-cyano-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazol-4-yl)-5-(trifluoromethyl)phenyl]pent-4-ynoylamino]pentanedioic acid	IC50	0.8 nM	US-10077273: SHMT inhibitors
(2R)-2-[5-[3-(6-amino-5-cyano-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazol-4-yl)-5-(trifluoromethyl)phenyl]pent-4-ynoylamino]pentanedioic acid	IC50	1 nM	US-10077273: SHMT inhibitors
5-[3-(6-amino-5-cyano-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazol-4-yl)-5-cyanophenyl]pent-4-ynoic acid	IC50	1.7 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-(4-hydroxybut-1-ynyl)-5-(trifluoromethyl)phenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	2 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-cyano-5-(5-hydroxypent-1-ynyl)phenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	2.4 nM	US-10077273: SHMT inhibitors
2-[5-[3-(6-amino-5-cyano-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazol-4-yl)-5-(trifluoromethyl)phenyl]pent-4-ynoylamino]-2-methylpropanoic acid	IC50	4 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-(hydroxymethyl)-5-phenylphenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	5 nM	US-10077273: SHMT inhibitors
methyl 5-[3-(6-amino-5-cyano-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazol-4-yl)-5-(trifluoromethyl)phenyl]pent-4-ynoate	IC50	7.5 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-(5-aminopent-1-ynyl)-5-(trifluoromethyl)phenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	8 nM	US-10077273: SHMT inhibitors
6-amino-3-methyl-4-propan-2-yl-4-[3-pyrrolidin-1-yl-5-(trifluoromethyl)phenyl]-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	13 nM	US-10077273: SHMT inhibitors
2-[3-[3-(6-amino-5-cyano-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazol-4-yl)-5-(hydroxymethyl)phenyl]phenyl]acetamide	IC50	16.9 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-(hydroxymethyl)-5-(5-hydroxypent-1-ynyl)phenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	17 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-chloro-5-(trifluoromethyl)phenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	20 nM	US-10077273: SHMT inhibitors
6-amino-4-[3,5-bis(trifluoromethyl)phenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	21 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-bromo-5-(trifluoromethyl)phenyl]-3-methyl-4-propan-2-yl-2H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	42 nM	US-10077273: SHMT inhibitors
6-amino-4-(3,5-dichlorophenyl)-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	67 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-chloro-5-(trifluoromethyl)phenyl]-4-cyclobutyl-3-methyl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	100 nM	US-10077273: SHMT inhibitors
6-amino-4-[3,5-bis(trifluoromethyl)phenyl]-4-cyclobutyl-3-methyl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	206 nM	US-10077273: SHMT inhibitors
6-amino-4-(3-chlorophenyl)-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	400 nM	US-10077273: SHMT inhibitors
(4S)-6-amino-3-methyl-4-propan-2-yl-4-[3-(trifluoromethyl)phenyl]-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	400 nM	US-10077273: SHMT inhibitors
6-amino-4-(3-chloro-5-methoxyphenyl)-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	500 nM	US-10077273: SHMT inhibitors
6-amino-4-cyclobutyl-4-(3,5-dichlorophenyl)-3-methyl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	593 nM	US-10077273: SHMT inhibitors
(4R)-6-amino-3-methyl-4-propan-2-yl-4-[3-(trifluoromethyl)phenyl]-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	756 nM	US-10077273: SHMT inhibitors
6-amino-4-(3-chlorophenyl)-4-cyclobutyl-3-methyl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	1190 nM	US-10077273: SHMT inhibitors
(4S)-6-amino-4-cyclobutyl-3-methyl-4-[3-(trifluoromethyl)phenyl]-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	1770 nM	US-10077273: SHMT inhibitors
6-amino-4-(3-chloro-5-methoxyphenyl)-4-cyclobutyl-3-methyl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	3460 nM	US-10077273: SHMT inhibitors
6-amino-4-(3-methoxyphenyl)-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	4580 nM	US-10077273: SHMT inhibitors

ChEMBL bioactivities

200 potent at pChembl≥5 of 239 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.80	Ki	16	nM	CHEMBL5440815
7.22	Ki	60	nM	CHEMBL5429283
7.10	Ki	80	nM	CHEMBL5438587
6.47	Ki	340	nM	CHEMBL5431881
6.46	Kd	345.4	nM	CHEMBL5653589
6.46	ED50	345.4	nM	CHEMBL5653589
6.36	IC50	436.5	nM	PRIMAQUINE
6.35	Ki	450	nM	CHEMBL5405010
6.34	Ki	460	nM	CHEMBL5408906
6.27	IC50	540	nM	CHEMBL4530254
6.20	Ki	630	nM	CHEMBL5427804
6.19	Ki	650	nM	CHEMBL5431331
6.16	IC50	690	nM	CHEMBL582132
6.15	IC50	710	nM	CHEMBL1528232
6.07	IC50	850	nM	CHEMBL4555669
6.03	IC50	933.2	nM	FLUPIRTINE
5.99	IC50	1020	nM	CHEMBL4519144
5.93	IC50	1170	nM	CHEMBL4559774
5.93	Ki	1170	nM	CHEMBL5402700
5.87	IC50	1350	nM	CHEMBL1300552
5.87	IC50	1350	nM	CHEMBL4593782
5.85	IC50	1410	nM	CHEMBL4447053
5.82	IC50	1510	nM	CHEMBL4449009
5.81	IC50	1550	nM	CHEMBL4573270
5.81	IC50	1550	nM	CHEMBL4557965
5.80	IC50	1580	nM	CHEMBL4553385
5.79	IC50	1620	nM	CHEMBL4514553
5.79	IC50	1620	nM	CHEMBL4447612
5.78	IC50	1660	nM	CHEMBL4531045
5.76	IC50	1740	nM	CHEMBL4584803
5.76	IC50	1740	nM	CHEMBL4475301
5.76	IC50	1740	nM	CHEMBL4575980
5.75	Ki	1780	nM	CHEMBL5418034
5.74	IC50	1820	nM	CHEMBL4557996
5.73	IC50	1860	nM	CHEMBL4436987
5.73	IC50	1860	nM	CHEMBL4451110
5.72	IC50	1910	nM	CHEMBL4464727
5.71	IC50	1950	nM	OXAPROZIN
5.70	IC50	2000	nM	CHEMBL4471334
5.69	IC50	2040	nM	CHEMBL4547456
5.69	IC50	2040	nM	CHEMBL4473357
5.67	IC50	2140	nM	CHEMBL4448873
5.67	IC50	2140	nM	CHEMBL4440546
5.67	IC50	2140	nM	CHEMBL4577602
5.66	IC50	2190	nM	CHEMBL4444905
5.65	IC50	2240	nM	CHEMBL4464489
5.65	IC50	2240	nM	CHEMBL4438740
5.65	IC50	2240	nM	CHEMBL4451169
5.63	IC50	2340	nM	CHEMBL4561599
5.63	IC50	2340	nM	CHEMBL4561726

PubChem BioAssay actives

14 with measured affinity, of 23 total; 14 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[4-[5-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl]-2-fluorobenzoyl]amino]pentanedioic acid	2011536: Binding affinity to N-terminal 6His-tagged truncated SHMT2 (30 to 504 residues) (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.0160	uM
(2S)-2-[[5-[5-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl]thiophene-2-carbonyl]amino]pentanedioic acid	2011536: Binding affinity to N-terminal 6His-tagged truncated SHMT2 (30 to 504 residues) (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.0600	uM
(2S)-2-[[4-[5-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl]benzoyl]amino]pentanedioic acid	2011536: Binding affinity to N-terminal 6His-tagged truncated SHMT2 (30 to 504 residues) (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.0800	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)propyl]benzoyl]amino]pentanedioic acid	2011536: Binding affinity to N-terminal 6His-tagged truncated SHMT2 (30 to 504 residues) (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.3400	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149393: Binding affinity to human SHMT2 incubated for 45 mins by Kinobead based pull down assay	kd	0.3454	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-2-fluorobenzoyl]amino]pentanedioic acid	2011536: Binding affinity to N-terminal 6His-tagged truncated SHMT2 (30 to 504 residues) (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.4500	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)propyl]-2-fluorobenzoyl]amino]pentanedioic acid	2011536: Binding affinity to N-terminal 6His-tagged truncated SHMT2 (30 to 504 residues) (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.4600	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-3-fluorothiophene-2-carbonyl]amino]pentanedioic acid	2011536: Binding affinity to N-terminal 6His-tagged truncated SHMT2 (30 to 504 residues) (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.6300	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)propoxy]benzoyl]amino]pentanedioic acid	2011536: Binding affinity to N-terminal 6His-tagged truncated SHMT2 (30 to 504 residues) (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.6500	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	2011536: Binding affinity to N-terminal 6His-tagged truncated SHMT2 (30 to 504 residues) (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	1.1700	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	2011536: Binding affinity to N-terminal 6His-tagged truncated SHMT2 (30 to 504 residues) (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	1.7800	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]benzoyl]amino]pentanedioic acid	2011536: Binding affinity to N-terminal 6His-tagged truncated SHMT2 (30 to 504 residues) (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	2.6200	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-2,6-difluorobenzoyl]amino]pentanedioic acid	2011536: Binding affinity to N-terminal 6His-tagged truncated SHMT2 (30 to 504 residues) (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	3.2500	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)propylsulfanyl]benzoyl]amino]pentanedioic acid	2011536: Binding affinity to N-terminal 6His-tagged truncated SHMT2 (30 to 504 residues) (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	8.8800	uM

CTD chemical–gene interactions

80 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases abundance, affects expression, increases expression	5
Benzo(a)pyrene	decreases expression, increases methylation	4
Cyclosporine	increases expression	4
methylmercuric chloride	increases expression, affects cotreatment	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
Particulate Matter	increases abundance, increases expression, affects cotreatment	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Resveratrol	affects cotreatment, increases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases expression, increases oxidation	2
Estradiol	increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tunicamycin	increases expression	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
methyleugenol	decreases expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment, increases expression	1
deoxynivalenol	decreases expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
nickel chloride	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
nivalenol	decreases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment, increases expression	1
15-acetyldeoxynivalenol	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118972	Binding	Binding affinity to SHMT2 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 1 embryonic stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1AR	HeLa-SHMT2-shSHMT2	Cancer cell line	Female
CVCL_B3RP	WAe009-A-67	Embryonic stem cell	Female
CVCL_D1YY	Abcam A-549 SHMT2 KO	Cancer cell line	Male
CVCL_D2CZ	Abcam HCT 116 SHMT2 KO	Cancer cell line	Male
CVCL_D9RK	Ubigene HEK293 SHMT2 KO	Transformed cell line	Female
CVCL_E0YR	Ubigene MDA-MB-231 SHMT2 KO	Cancer cell line	Female
CVCL_TL02	HAP1 SHMT2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

204 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism