Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8RY7TZ)

• DOT Name: ALS2 C-terminal-like protein (ALS2CL)
• Gene Name: ALS2CL
• Related Disease:
  Schizophrenia
  Amyotrophic lateral sclerosis
  Amyotrophic lateral sclerosis type 2, juvenile
• UniProt ID: AL2CL_HUMAN
• Pfam ID: PF02493 ; PF02204
• Sequence:
  MCNPEEAALLRLEEVFSATLAHVNSLVLQPLLPAAPDPSDPWGRECLRLLQQLHKSSQQL
  WEVTEESLHSLQERLRYPDSTGLESLLLLRGADRVLQAHIEYIESYTSCMVVQAFQKAAK
  RRSEYWRGQRKALRQLLSGVSSEGSVGASLGQALHQPLAHHVQQYVLLLLSLGDTIGEHH
  PTRELVVNAVTLFGNLQSFMKQELDQAVATQALWHTLRGRLRDVLCTPAHRLLQDSQDVP
  VTVAPLRAERVLLFDDALVLLQGHNVHTFDLKLVWVDPGQDGCTFHLLTPEEEFSFCAKD
  SQGQAVWQWKVTWAVHQALHGKKDFPVLGAGLEPSQPPDCRCAEYTFQAEGRLCQATYEG
  EWCRGRPHGKGTLKWPDGRNHVGNFCQGLEHGFGIRLLPQASEDKFDCYKCHWREGSMCG
  YGICEYSTDEVYKGYFQEGLRHGFGVLESGPQAPQPFRYTGHWERGQRSGYGIEEDGDRG
  ERYIGMWQAGQRHGPGVMVTQAGVCYQGTFQADKTVGPGILLSEDDSLYEGTFTRDLTLM
  GKGKVTFPNGFTLEGSFGSGAGRGLHTQGVLDTAALPPDPSSTCKRQLGVGAFPVESRWQ
  GVYSPFRDFVCAGCPRDLQEALLGFDVQSSRELRRSQDYLSCERTHPEDSVGSMEDILEE
  LLQHREPKALQLYLRKALSNSLHPLGKLLRTLMLTFQATYAGVGANKHLQELAQEEVKQH
  AQELWAAYRGLLRVALERKGQALEEDEDTETRDLQVHGLVLPLMLPSFYSELFTLYLLLH
  EREDSFYSQGIANLSLFPDTQLLEFLDVQKHLWPLKDLTLTSNQRYSLVRDKCFLSATEC
  LQKIMTTVDPREKLEVLERTYGEIEGTVSRVLGREYKLPMDDLLPLLIYVVSRARIQHLG
  AEIHLIRDMMDPNHTGGLYDFLLTALESCYEHIQKEDMRLHRLPGHWHSRELW
• Function: Acts as a guanine nucleotide exchange factor (GEF) for Rab5 GTPase. Regulates the ALS2-mediated endosome dynamics.
• Tissue Specificity: Expressed in heart and kidney.
• Reactome Pathway: RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Strong	Biomarker	[1]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[2]
Amyotrophic lateral sclerosis type 2, juvenile	DISYFHD8	moderate	Biomarker	[2]

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 ALS2 C-terminal-like protein (ALS2CL).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of ALS2 C-terminal-like protein (ALS2CL).	[13]

15 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 ALS2 C-terminal-like protein (ALS2CL).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ALS2 C-terminal-like protein (ALS2CL).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ALS2 C-terminal-like protein (ALS2CL).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of ALS2 C-terminal-like protein (ALS2CL).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ALS2 C-terminal-like protein (ALS2CL).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of ALS2 C-terminal-like protein (ALS2CL).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of ALS2 C-terminal-like protein (ALS2CL).	[9]
Marinol	DM70IK5	Approved	Marinol decreases the expression of ALS2 C-terminal-like protein (ALS2CL).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of ALS2 C-terminal-like protein (ALS2CL).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of ALS2 C-terminal-like protein (ALS2CL).	[12]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of ALS2 C-terminal-like protein (ALS2CL).	[4]
Ifosfamide	DMCT3I8	Approved	Ifosfamide affects the expression of ALS2 C-terminal-like protein (ALS2CL).	[4]
Clodronate	DM9Y6X7	Approved	Clodronate affects the expression of ALS2 C-terminal-like protein (ALS2CL).	[4]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of ALS2 C-terminal-like protein (ALS2CL).	[4]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of ALS2 C-terminal-like protein (ALS2CL).	[14]

References

• [1] Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet. 2011 Jul 10;43(9):860-3. doi: 10.1038/ng.886.
• [2] ALS2CL, the novel protein highly homologous to the carboxy-terminal half of ALS2, binds to Rab5 and modulates endosome dynamics.FEBS Lett. 2004 Sep 24;575(1-3):64-70. doi: 10.1016/j.febslet.2004.07.092.
• [3] 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.
• [4] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.