Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ74KFI)

• DOT Name: Max-like protein X (MLX)
• Synonyms: Class D basic helix-loop-helix protein 13; bHLHd13; Max-like bHLHZip protein; Protein BigMax; Transcription factor-like protein 4
• Gene Name: MLX
• Related Disease: Non-insulin dependent diabetes
• UniProt ID: MLX_HUMAN
• Pfam ID: PF00010
• Sequence:
  MTEPGASPEDPWVKASPVGAHAGEGRAGRARARRGAGRRGASLLSPKSPTLSVPRGCRED
  SSHPACAKVEYAYSDNSLDPGLFVESTRKGSVVSRANSIGSTSASSVPNTDDEDSDYHQE
  AYKESYKDRRRRAHTQAEQKRRDAIKRGYDDLQTIVPTCQQQDFSIGSQKLSKAIVLQKT
  IDYIQFLHKEKKKQEEEVSTLRKDVTALKIMKVNYEQIVKAHQDNPHEGEDQVSDQVKFN
  VFQGIMDSLFQSFNASISVASFQELSACVFSWIEEHCKPQTLREIVIGVLHQLKNQLY
• Function: Transcription regulator. Forms a sequence-specific DNA-binding protein complex with MAD1, MAD4, MNT, WBSCR14 and MLXIP which recognizes the core sequence 5'-CACGTG-3'. The TCFL4-MAD1, TCFL4-MAD4, TCFL4-WBSCR14 complexes are transcriptional repressors. Plays a role in transcriptional activation of glycolytic target genes. Involved in glucose-responsive gene regulation.
• Tissue Specificity: Expressed in all tissues tested, including spleen, thymus, prostate, ovary, intestine, colon, peripheral blood leukocyte, heart, liver, skeletal muscle and kidney. Lower levels of expression in testis, brain, placenta and lung.
• KEGG Pathway:
  Insulin resistance (hsa04931)
  Non-alcoholic fatty liver disease (hsa04932)
• Reactome Pathway: ChREBP activates metabolic gene expression (R-HSA-163765)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Max-like protein X (MLX).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Max-like protein X (MLX).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Max-like protein X (MLX).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Max-like protein X (MLX).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Max-like protein X (MLX).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Max-like protein X (MLX).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Max-like protein X (MLX).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Max-like protein X (MLX).	[10]

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 affects the methylation of Max-like protein X (MLX).	[8]

References

• [1] Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.Nat Genet. 2018 Apr;50(4):559-571. doi: 10.1038/s41588-018-0084-1. Epub 2018 Apr 9.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [8] 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.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.