Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPA2FDE)

• DOT Name: E3 ubiquitin-protein transferase MAEA (MAEA)
• Synonyms: EC 2.3.2.27; Cell proliferation-inducing gene 5 protein; Erythroblast macrophage protein; Human lung cancer oncogene 10 protein; HLC-10; Macrophage erythroblast attacher; P44EMLP
• Gene Name: MAEA
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Invasive aspergillosis
  Lupus
  Prostate cancer
  Prostate carcinoma
  Systemic lupus erythematosus
  Periodontitis
• UniProt ID: MAEA_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF10607
• Sequence:
  MAVQESAAQLSMTLKVQEYPTLKVPYETLNKRFRAAQKNIDRETSHVTMVVAELEKTLSG
  CPAVDSVVSLLDGVVEKLSVLKRKAVESIQAEDESAKLCKRRIEHLKEHSSDQPAAASVW
  KRKRMDRMMVEHLLRCGYYNTAVKLARQSGIEDLVNIEMFLTAKEVEESLERRETATCLA
  WCHDNKSRLRKMKSCLEFSLRIQEFIELIRQNKRLDAVRHARKHFSQAEGSQLDEVRQAM
  GMLAFPPDTHISPYKDLLDPARWRMLIQQFRYDNYRLHQLGNNSVFTLTLQAGLSAIKTP
  QCYKEDGSSKSPDCPVCSRSLNKLAQPLPMAHCANSRLVCKISGDVMNENNPPMMLPNGY
  VYGYNSLLSIRQDDKVVCPRTKEVFHFSQAEKVYIM
• Function: Core component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1. MAEA and RMND5A are both required for catalytic activity of the CTLH E3 ubiquitin-protein ligase complex. MAEA is required for normal cell proliferation. The CTLH E3 ubiquitin-protein ligase complex is not required for the degradation of enzymes involved in gluconeogenesis, such as FBP1. Plays a role in erythroblast enucleation during erythrocyte maturation and in the development of mature macrophages. Mediates the attachment of erythroid cell to mature macrophages; this MAEA-mediated contact inhibits erythroid cell apoptosis. Participates in erythroblastic island formation, which is the functional unit of definitive erythropoiesis. Associates with F-actin to regulate actin distribution in erythroblasts and macrophages. May contribute to nuclear architecture and cells division events (Probable).
• Tissue Specificity: Detected at macrophage membranes (at protein level). Ubiquitous.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Invasive aspergillosis	DISAI029	Strong	Biomarker	[3]
Lupus	DISOKJWA	Strong	Altered Expression	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[4]
Periodontitis	DISI9JOI	Limited	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of E3 ubiquitin-protein transferase MAEA (MAEA).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein transferase MAEA (MAEA).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein transferase MAEA (MAEA).	[13]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of E3 ubiquitin-protein transferase MAEA (MAEA).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein transferase MAEA (MAEA).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein transferase MAEA (MAEA).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 ubiquitin-protein transferase MAEA (MAEA).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin-protein transferase MAEA (MAEA).	[12]

References

• [1] Circulating small-sized endothelial microparticles as predictors of clinical outcome after chemotherapy for breast cancer: an exploratory analysis.Breast Cancer Res Treat. 2018 May;169(1):83-92. doi: 10.1007/s10549-017-4656-z. Epub 2018 Jan 16.
• [2] Chemotherapy acutely impairs neurovascular and hemodynamic responses in women with breast cancer.Am J Physiol Heart Circ Physiol. 2019 Jul 1;317(7):H1-H12. doi: 10.1152/ajpheart.00756.2018. Epub 2019 Apr 19.
• [3] Treating invasive aspergillosis in patients with hematologic malignancy: diagnostic-driven approach versus empiric therapies.BMC Infect Dis. 2018 Dec 13;18(1):656. doi: 10.1186/s12879-018-3584-9.
• [4] Differential tissue expression of erythroblast macrophage protein in a MRL/lpr mouse model of lupus.Lupus. 2019 Jun;28(7):843-853. doi: 10.1177/0961203319851572. Epub 2019 May 27.
• [5] Efficacy of a neoadjuvant gonadotropin-releasing hormone antagonist plus low-dose estramustine phosphate in high-risk prostate cancer: a single-center study.Int Urol Nephrol. 2017 May;49(5):811-816. doi: 10.1007/s11255-017-1546-6. Epub 2017 Feb 17.
• [6] MAEA rs6815464 polymorphism and periodontitis in postmenopausal Japanese females: A cross-sectional study.Arch Oral Biol. 2019 Jun;102:128-134. doi: 10.1016/j.archoralbio.2019.04.008. Epub 2019 Apr 15.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] 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.
• [11] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.