Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAVC6QS)

• DOT Name: Cationic amino acid transporter 4 (SLC7A4)
• Synonyms: CAT-4; CAT4; Solute carrier family 7 member 4
• Gene Name: SLC7A4
• Related Disease:
  Advanced cancer
  Anterior segment dysgenesis
  DiGeorge syndrome
  Early-onset anterior polar cataract
  Follicular lymphoma
  Idiopathic thrombocytopenic purpura
  MALT lymphoma
  Mantle cell lymphoma
  Neoplasm
  Shprintzen-Goldberg syndrome
  Small lymphocytic lymphoma
  Splenic marginal zone lymphoma
  Velocardiofacial syndrome
  B-cell lymphoma
  Adult lymphoma
  Lymphoma
  Pediatric lymphoma
  Plasma cell myeloma
  Rheumatoid arthritis
  Richter syndrome
• UniProt ID: CTR4_HUMAN
• Pfam ID: PF13520 ; PF13906
• Sequence:
  MARGLPTIASLARLCQKLNRLKPLEDSTMETSLRRCLSTLDLTLLGVGGMVGSGLYVLTG
  AVAKEVAGPAVLLSFGVAAVASLLAALCYAEFGARVPRTGSAYLFTYVSMGELWAFLIGW
  NVLLEYIIGGAAVARAWSGYLDSMFSHSIRNFTETHVGSWQVPLLGHYPDFLAAGIILLA
  SAFVSCGARVSSWLNHTFSAISLLVILFIVILGFILAQPHNWSADEGGFAPFGFSGVMAG
  TASCFYAFVGFDVIAASSEEAQNPRRSVPLAIAISLAIAAGAYILVSTVLTLMVPWHSLD
  PDSALADAFYQRGYRWAGFIVAAGSICAMNTVLLSLLFSLPRIVYAMAADGLFFQVFAHV
  HPRTQVPVAGTLAFGLLTAFLALLLDLESLVQFLSLGTLLAYTFVATSIIVLRFQKSSPP
  SSPGPASPGPLTKQQSSFSDHLQLVGTVHASVPEPGELKPALRPYLGFLDGYSPGAVVTW
  ALGVMLASAITIGCVLVFGNSTLHLPHWGYILLLLLTSVMFLLSLLVLGAHQQQYREDLF
  QIPMVPLIPALSIVLNICLMLKLSYLTWVRFSIWLLMGLAVYFGYGIRHSKENQRELPGL
  NSTHYVVFPRGSLEETVQAMQPPSQAPAQDPGHME
• Function: Involved in the transport of the cationic amino acids (arginine, lysine and ornithine).

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Anterior segment dysgenesis	DIS12OKO	Strong	Biomarker	[2]
DiGeorge syndrome	DIST1RKO	Strong	Biomarker	[3]
Early-onset anterior polar cataract	DISTOPIY	Strong	Genetic Variation	[2]
Follicular lymphoma	DISVEUR6	Strong	Altered Expression	[4]
Idiopathic thrombocytopenic purpura	DISFKGJU	Strong	Biomarker	[5]
MALT lymphoma	DIS1AVVE	Strong	Genetic Variation	[6]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Shprintzen-Goldberg syndrome	DISQH6P3	Strong	Biomarker	[3]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[9]
Splenic marginal zone lymphoma	DISCGTZY	Strong	Genetic Variation	[10]
Velocardiofacial syndrome	DISOSBTY	Strong	Biomarker	[3]
B-cell lymphoma	DISIH1YQ	moderate	Altered Expression	[11]
Adult lymphoma	DISK8IZR	Limited	Biomarker	[12]
Lymphoma	DISN6V4S	Limited	Biomarker	[12]
Pediatric lymphoma	DIS51BK2	Limited	Biomarker	[12]
Plasma cell myeloma	DIS0DFZ0	Limited	Genetic Variation	[13]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[14]
Richter syndrome	DISBX2TK	Limited	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Cationic amino acid transporter 4 (SLC7A4).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cationic amino acid transporter 4 (SLC7A4).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cationic amino acid transporter 4 (SLC7A4).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cationic amino acid transporter 4 (SLC7A4).	[17]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Cationic amino acid transporter 4 (SLC7A4).	[18]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Cationic amino acid transporter 4 (SLC7A4).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cationic amino acid transporter 4 (SLC7A4).	[21]

References

• [1] Identification of malignant cells in multiple myeloma bone marrow with immunoglobulin VH gene probes by fluorescent in situ hybridization and flow cytometry.J Clin Invest. 1995 Mar;95(3):964-72. doi: 10.1172/JCI117805.
• [2] The mouse Cat4 locus maps to chromosome 8 and mutants express lens-corneal adhesion.Mamm Genome. 1997 Jun;8(6):403-6. doi: 10.1007/s003359900456.
• [3] The gene encoding a cationic amino acid transporter (SLC7A4) maps to the region deleted in the velocardiofacial syndrome.Genomics. 1998 Apr 15;49(2):230-6. doi: 10.1006/geno.1998.5252.
• [4] Preferential use of the VH4 Ig gene family by diffuse large-cell lymphoma.Blood. 1995 Oct 15;86(8):3072-82.
• [5] Genetic analysis of autoantibodies in idiopathic thrombocytopenic purpura reveals evidence of clonal expansion and somatic mutation.Blood. 2002 Aug 15;100(4):1388-98.
• [6] Immunoglobulin VH genes in thymic MALT lymphoma are biased toward a restricted repertoire and are frequently unmutated.J Pathol. 2006 Feb;208(3):415-22. doi: 10.1002/path.1889.
• [7] Immunoglobulin V(H) gene mutational analysis suggests that blastic variant of mantle cell lymphoma derives from different stages of B-cell maturation.Leuk Res. 2000 Jan;24(1):27-31. doi: 10.1016/s0145-2126(99)00156-3.
• [8] A CD10-positive subset of malignant cells is identified in multiple myeloma using PCR with patient-specific immunoglobulin gene primers.Leukemia. 1995 Nov;9(11):1948-53.
• [9] Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post-germinal center leukemogenic selection.Blood. 2008 May 15;111(10):5101-8. doi: 10.1182/blood-2007-12-130229. Epub 2008 Mar 7.
• [10] Splenic lymphoma with villous lymphocytes involves B cells with extensively mutated Ig heavy chain variable region genes.Blood. 1995 Mar 15;85(6):1603-7.
• [11] Relationship between the mutational status of VH genes and pathogenesis of diffuse large B-cell lymphoma in Richter's syndrome.Leukemia. 2004 Feb;18(2):326-30. doi: 10.1038/sj.leu.2403249.
• [12] Ig VH gene expression among human follicular lymphomas.Blood. 1991 Sep 15;78(6):1561-8.
• [13] Comparable gene structure of the immunoglobulin heavy chain variable region between multiple myeloma and normal bone marrow lymphocytes.Leukemia. 1996 Nov;10(11):1804-12.
• [14] Polymorphism of the human immunoglobulin heavy chain locus in rheumatoid arthritis.Autoimmunity. 1997;25(2):109-16. doi: 10.3109/08916939708996277.
• [15] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [16] Gene expression profiling of human peri-implantation endometria between natural and stimulated cycles. Fertil Steril. 2008 Dec;90(6):2152-64.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [19] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [20] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.