Details of Drug Off-Target (DOT)

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

• DOT Name: Alpha-2-macroglobulin-like protein 1 (A2ML1)
• Synonyms: C3 and PZP-like alpha-2-macroglobulin domain-containing protein 9
• Gene Name: A2ML1
• Related Disease:
  Otitis media
  Advanced cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Chromosomal disorder
  Leukemia
  Myelodysplastic syndrome
  Neoplasm
  Osteosarcoma
  Plasma cell myeloma
  Renal cell carcinoma
  Retinoblastoma
  Small-cell lung cancer
  Acute myelogenous leukaemia
  Noonan syndrome
  Acute leukaemia
  Acute lymphocytic leukaemia
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Childhood acute lymphoblastic leukemia
  Chronic myelogenous leukaemia
  Cryohydrocytosis
• UniProt ID: A2ML1_HUMAN
• PDB ID: 7Q1Y; 7Q5Z; 7Q60; 7Q61; 7Q62
• Pfam ID: PF00207 ; PF07703 ; PF07677 ; PF01835 ; PF17791 ; PF17789 ; PF07678
• Sequence:
  MWAQLLLGMLALSPAIAEELPNYLVTLPARLNFPSVQKVCLDLSPGYSDVKFTVTLETKD
  KTQKLLEYSGLKKRHLHCISFLVPPPAGGTEEVATIRVSGVGNNISFEEKKKVLIQRQGN
  GTFVQTDKPLYTPGQQVYFRIVTMDSNFVPVNDKYSMVELQDPNSNRIAQWLEVVPEQGI
  VDLSFQLAPEAMLGTYTVAVAEGKTFGTFSVEEYVLPKFKVEVVEPKELSTVQESFLVKI
  CCRYTYGKPMLGAVQVSVCQKANTYWYREVEREQLPDKCRNLSGQTDKTGCFSAPVDMAT
  FDLIGYAYSHQINIVATVVEEGTGVEANATQNIYISPQMGSMTFEDTSNFYHPNFPFSGK
  IRVRGHDDSFLKNHLVFLVIYGTNGTFNQTLVTDNNGLAPFTLETSGWNGTDVSLEGKFQ
  MEDLVYNPEQVPRYYQNAYLHLRPFYSTTRSFLGIHRLNGPLKCGQPQEVLVDYYIDPAD
  ASPDQEISFSYYLIGKGSLVMEGQKHLNSKKKGLKASFSLSLTFTSRLAPDPSLVIYAIF
  PSGGVVADKIQFSVEMCFDNQVSLGFSPSQQLPGAEVELQLQAAPGSLCALRAVDESVLL
  LRPDRELSNRSVYGMFPFWYGHYPYQVAEYDQCPVSGPWDFPQPLIDPMPQGHSSQRSII
  WRPSFSEGTDLFSFFRDVGLKILSNAKIKKPVDCSHRSPEYSTAMGAGGGHPEAFESSTP
  LHQAEDSQVRQYFPETWLWDLFPIGNSGKEAVHVTVPDAITEWKAMSFCTSQSRGFGLSP
  TVGLTAFKPFFVDLTLPYSVVRGESFRLTATIFNYLKDCIRVQTDLAKSHEYQLESWADS
  QTSSCLCADDAKTHHWNITAVKLGHINFTISTKILDSNEPCGGQKGFVPQKGRSDTLIKP
  VLVKPEGVLVEKTHSSLLCPKGKVASESVSLELPVDIVPDSTKAYVTVLGDIMGTALQNL
  DGLVQMPSGCGEQNMVLFAPIIYVLQYLEKAGLLTEEIRSRAVGFLEIGYQKELMYKHSN
  GSYSAFGERDGNGNTWLTAFVTKCFGQAQKFIFIDPKNIQDALKWMAGNQLPSGCYANVG
  NLLHTAMKGGVDDEVSLTAYVTAALLEMGKDVDDPMVSQGLRCLKNSATSTTNLYTQALL
  AYIFSLAGEMDIRNILLKQLDQQAIISGESIYWSQKPTPSSNASPWSEPAAVDVELTAYA
  LLAQLTKPSLTQKEIAKATSIVAWLAKQHNAYGGFSSTQDTVVALQALAKYATTAYMPSE
  EINLVVKSTENFQRTFNIQSVNRLVFQQDTLPNVPGMYTLEASGQGCVYVQTVLRYNILP
  PTNMKTFSLSVEIGKARCEQPTSPRSLTLTIHTSYVGSRSSSNMAIVEVKMLSGFSPMEG
  TNQLLLQQPLVKKVEFGTDTLNIYLDELIKNTQTYTFTISQSVLVTNLKPATIKVYDYYL
  PDEQATIQYSDPCE
• Function: Is able to inhibit all four classes of proteinases by a unique 'trapping' mechanism. This protein has a peptide stretch, called the 'bait region' which contains specific cleavage sites for different proteinases. When a proteinase cleaves the bait region, a conformational change is induced in the protein which traps the proteinase. The entrapped enzyme remains active against low molecular weight substrates (activity against high molecular weight substrates is greatly reduced). Following cleavage in the bait region a thioester bond is hydrolyzed and mediates the covalent binding of the protein to the proteinase. Displays inhibitory activity against chymotrypsin, papain, thermolysin, subtilisin A and, to a lesser extent, elastase but not trypsin. May play an important role during desquamation by inhibiting extracellular proteases.
• Tissue Specificity: In the epidermis, expressed predominantly in the granular layer at the apical edge of keratinocytes (at protein level). Also detected in placenta, testis and thymus but not in epithelia of kidney, lung, small intestine or colon.

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Otitis media	DISGZDUO	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Chromosomal disorder	DISM5BB5	Strong	Altered Expression	[7]
Leukemia	DISNAKFL	Strong	Genetic Variation	[8]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[10]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[3]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[11]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[12]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[13]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[14]
Acute myelogenous leukaemia	DISCSPTN	moderate	Biomarker	[15]
Noonan syndrome	DIS7Q7DN	Supportive	Autosomal dominant	[16]
Acute leukaemia	DISDQFDI	Limited	Altered Expression	[17]
Acute lymphocytic leukaemia	DISPX75S	Limited	Altered Expression	[18]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Limited	Altered Expression	[19]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Altered Expression	[18]
Chronic myelogenous leukaemia	DIS0301E	Limited	Altered Expression	[19]
Cryohydrocytosis	DISMQHL3	Limited	Genetic Variation	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Alpha-2-macroglobulin-like protein 1 (A2ML1).	[21]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Alpha-2-macroglobulin-like protein 1 (A2ML1).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Alpha-2-macroglobulin-like protein 1 (A2ML1).	[24]

1 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 Alpha-2-macroglobulin-like protein 1 (A2ML1).	[23]

References

• [1] Rare A2ML1 variants confer susceptibility to otitis media.Nat Genet. 2015 Aug;47(8):917-20. doi: 10.1038/ng.3347. Epub 2015 Jun 29.
• [2] Cancer chemotherapy does not enhance MDR-associated 170 kd glycoprotein expression in normal blood mononuclear cells.Haematologica. 1992 Nov-Dec;77(6):470-2.
• [3] Immunocytochemical observation of multidrug resistance (MDR) p170 glycoprotein expression in human osteosarcoma cells. The clinical significance of MDR protein overexpression.Anticancer Res. 1995 Nov-Dec;15(6B):2461-8.
• [4] An immunochemical analysis of mdm2 expression in human breast cancer and the identification of a growth-regulated cross-reacting species p170.J Pathol. 1998 Nov;186(3):254-61. doi: 10.1002/(SICI)1096-9896(1998110)186:3<254::AID-PATH185>3.0.CO;2-U.
• [5] Bcl-2 has differing effects on the sensitivity of breast cancer cells depending on the antineoplastic drug used.Eur J Cancer. 2002 Dec;38(18):2455-62. doi: 10.1016/s0959-8049(02)00391-x.
• [6] Mechanisms of resistance to ansamycin antibiotics in human breast cancer cell lines.Mol Pharmacol. 1994 Oct;46(4):677-84.
• [7] Analysis of treatment failure in patients with minimally differentiated acute myeloid leukemia (AML-M0).Blood. 1994 Mar 15;83(6):1619-25.
• [8] Cellular uptake and antiproliferative effects of therapeutic concentrations of idarubicin or daunorubicin and their alcohol metabolites, with or without cyclosporin A, in MDR1+ human leukemic cells.Leuk Lymphoma. 1999 May;33(5-6):485-97. doi: 10.3109/10428199909058453.
• [9] High expression of the multidrug resistance P-glycoprotein in high-risk myelodysplasia is associated with immature phenotype.Leukemia. 1993 Jul;7(7):963-9.
• [10] Paraneoplastic pemphigus: a clinical, laboratorial, and therapeutic overview.An Bras Dermatol. 2019 Oct 17;94(4):388-398. doi: 10.1590/abd1806-4841.20199165. eCollection 2019.
• [11] Expression of p170 protein in multiple myeloma: a clinical study.Hematol Oncol. 1992 May-Aug;10(3-4):213-20. doi: 10.1002/hon.2900100312.
• [12] Expression of resistance factors (P-glycoprotein, glutathione S-transferase-pi, and topoisomerase II) and their interrelationship to proto-oncogene products in renal cell carcinomas.Cancer. 1993 Jun 15;71(12):3981-7. doi: 10.1002/1097-0142(19930615)71:12<3981::aid-cncr2820711231>3.0.co;2-a.
• [13] The genetics of retinoblastoma. Relevance to the patient.Pediatr Clin North Am. 1991 Apr;38(2):299-315. doi: 10.1016/s0031-3955(16)38079-8.
• [14] Characterization of a topoisomerase II gene rearrangement in a human small-cell lung cancer cell line.J Natl Cancer Inst. 1992 Nov 18;84(22):1710-6. doi: 10.1093/jnci/84.22.1710.
• [15] Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia.J Clin Oncol. 1997 May;15(5):1796-802. doi: 10.1200/JCO.1997.15.5.1796.
• [16] Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome. Eur J Hum Genet. 2015 Mar;23(3):317-24. doi: 10.1038/ejhg.2014.115. Epub 2014 Jun 18.
• [17] P-glycoprotein (P-170) expression in acute leukemias.Hematology. 2006 Feb;11(1):35-41. doi: 10.1080/10245330400026204.
• [18] Multidrug resistance in acute leukemia: a comparison of different diagnostic methods.Leukemia. 1997 Jul;11(7):1067-72. doi: 10.1038/sj.leu.2400691.
• [19] The role of the MDR-1/P-170 mechanism in the development of multidrug resistance in chronic myeloid leukemia.Leukemia. 1990 Oct;4(10):695-9.
• [20] CD24 Ala57Val polymorphism is associated with spontaneous viral clearance in the HCV-infected Chinese population.Liver Int. 2015 Mar;35(3):786-94. doi: 10.1111/liv.12506. Epub 2014 Mar 19.
• [21] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [22] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [23] 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.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.