Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIINA3J)

• DOT Name: Serine hydroxymethyltransferase, cytosolic (SHMT1)
• Synonyms: SHMT; EC 2.1.2.1; Glycine hydroxymethyltransferase; Serine methylase
• Gene Name: SHMT1
• Related Disease:
  Lymphoma, non-Hodgkin, familial
  Acute lymphocytic leukaemia
  Alopecia
  Autism
  Bladder cancer
  Childhood acute lymphoblastic leukemia
  Chronic kidney disease
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Colorectal adenoma
  Epilepsy
  Essential hypertension
  Head and neck cancer
  Head and neck carcinoma
  Head-neck squamous cell carcinoma
  High blood pressure
  Intestinal cancer
  Large cell lymphoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Lymphosarcoma
  Nervous system disease
  Ovarian neoplasm
  Parkinson disease
  Schizophrenia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Wilms tumor
  Adenocarcinoma
  Cardiovascular disease
  Esophageal squamous cell carcinoma
  Non-alcoholic steatohepatitis
  Squamous cell carcinoma
  Stroke
  Acute myelogenous leukaemia
  Neural tube defect
  Non-hodgkin lymphoma
  Prostate cancer
  Prostate carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Hepatocellular carcinoma
  Lymphoma
  Thyroid gland papillary carcinoma
• UniProt ID: GLYC_HUMAN
• PDB ID: 1BJ4; 6FL5; 6M5W; 7RJL; 7RJP; 8A11
• EC Number: 2.1.2.1
• Pfam ID: PF00464
• Sequence:
  MTMPVNGAHKDADLWSSHDKMLAQPLKDSDVEVYNIIKKESNRQRVGLELIASENFASRA
  VLEALGSCLNNKYSEGYPGQRYYGGTEFIDELETLCQKRALQAYKLDPQCWGVNVQPYSG
  SPANFAVYTALVEPHGRIMGLDLPDGGHLTHGFMTDKKKISATSIFFESMPYKVNPDTGY
  INYDQLEENARLFHPKLIIAGTSCYSRNLEYARLRKIADENGAYLMADMAHISGLVAAGV
  VPSPFEHCHVVTTTTHKTLRGCRAGMIFYRKGVKSVDPKTGKEILYNLESLINSAVFPGL
  QGGPHNHAIAGVAVALKQAMTLEFKVYQHQVVANCRALSEALTELGYKIVTGGSDNHLIL
  VDLRSKGTDGGRAEKVLEACSIACNKNTCPGDRSALRPSGLRLGTPALTSRGLLEKDFQK
  VAHFIHRGIELTLQIQSDTGVRATLKEFKERLAGDKYQAAVQALREEVESFASLFPLPGL
  PDF
• Function: Interconversion of serine and glycine.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Glyoxylate and dicarboxylate metabolism (hsa00630)
  One carbon pool by folate (hsa00670)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Biosynthesis of amino acids (hsa01230)
  Biosynthesis of cofactors (hsa01240)
  Antifolate resistance (hsa01523)
• Reactome Pathway:
  Carnitine synthesis (R-HSA-71262)
  Metabolism of folate and pterines (R-HSA-196757)
• BioCyc Pathway: MetaCyc:HS11114-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Definitive	Genetic Variation	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[2]
Alopecia	DIS37HU4	Strong	Genetic Variation	[3]
Autism	DISV4V1Z	Strong	Genetic Variation	[4]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[5]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[6]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Genetic Variation	[8]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[8]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[9]
Colorectal adenoma	DISTSVHM	Strong	Genetic Variation	[10]
Epilepsy	DISBB28L	Strong	Genetic Variation	[11]
Essential hypertension	DIS7WI98	Strong	Posttranslational Modification	[12]
Head and neck cancer	DISBPSQZ	Strong	Genetic Variation	[13]
Head and neck carcinoma	DISOU1DS	Strong	Genetic Variation	[13]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[14]
High blood pressure	DISY2OHH	Strong	Biomarker	[12]
Intestinal cancer	DISYCNF1	Strong	Biomarker	[15]
Large cell lymphoma	DISYZHCP	Strong	Biomarker	[16]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[17]
Lung cancer	DISCM4YA	Strong	Biomarker	[15]
Lung carcinoma	DISTR26C	Strong	Biomarker	[15]
Lung neoplasm	DISVARNB	Strong	Genetic Variation	[18]
Lymphosarcoma	DISGYV3F	Strong	Biomarker	[16]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[19]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[15]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[20]
Schizophrenia	DISSRV2N	Strong	Biomarker	[21]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[5]
Wilms tumor	DISB6T16	Strong	Altered Expression	[22]
Adenocarcinoma	DIS3IHTY	moderate	Genetic Variation	[23]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[24]
Esophageal squamous cell carcinoma	DIS5N2GV	moderate	Genetic Variation	[23]
Non-alcoholic steatohepatitis	DIST4788	moderate	Biomarker	[25]
Squamous cell carcinoma	DISQVIFL	moderate	Genetic Variation	[23]
Stroke	DISX6UHX	moderate	Genetic Variation	[26]
Acute myelogenous leukaemia	DISCSPTN	Disputed	Genetic Variation	[27]
Neural tube defect	DIS5J95E	Disputed	Genetic Variation	[28]
Non-hodgkin lymphoma	DISS2Y8A	Disputed	Biomarker	[29]
Prostate cancer	DISF190Y	Disputed	Genetic Variation	[30]
Prostate carcinoma	DISMJPLE	Disputed	Genetic Variation	[30]
Breast neoplasm	DISNGJLM	Limited	Genetic Variation	[31]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[24]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[15]
Lymphoma	DISN6V4S	Limited	Genetic Variation	[32]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[33]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Serine hydroxymethyltransferase, cytosolic (SHMT1) affects the response to substance of Methotrexate.	[19]

18 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[34]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[35]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[36]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[37]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[38]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[39]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[40]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[41]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[42]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[43]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[44]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[45]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[41]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[46]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[49]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[50]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[51]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[52]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[47]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Serine hydroxymethyltransferase, cytosolic (SHMT1).	[48]

References

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• [9] Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma.Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11404-11409. doi: 10.1073/pnas.1706617114. Epub 2017 Oct 9.
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• [12] Serine hydroxymethyltransferase 1 promoter hypermethylation increases the risk of essential hypertension.J Clin Lab Anal. 2019 Mar;33(3):e22712. doi: 10.1002/jcla.22712. Epub 2018 Nov 9.
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• [28] Interaction between Maternal and Paternal SHMT1 C1420T Predisposes to Neural Tube Defects in the Fetus: Evidence from Case-Control and Family-Based Triad Approaches.Birth Defects Res. 2017 Apr 14. doi: 10.1002/bdra.23623. Online ahead of print.
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• [31] Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan.Breast Cancer Res Treat. 2008 Sep;111(1):145-55. doi: 10.1007/s10549-007-9754-x. Epub 2007 Sep 22.
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• [33] Expression of serine/glycine metabolism-related proteins is different according to the thyroid cancer subtype.J Transl Med. 2016 Jun 8;14(1):168. doi: 10.1186/s12967-016-0915-8.
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• [53] Methotrexate-induced subacute neurotoxicity in a child with acute lymphoblastic leukemia carrying genetic polymorphisms related to folate homeostasis. Am J Hematol. 2011 Jan;86(1):98-101. doi: 10.1002/ajh.21897.