Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1A5IX5)

• DOT Name: F-actin-uncapping protein LRRC16A (CARMIL1)
• Synonyms: CARMIL homolog; Capping protein regulator and myosin 1 linker protein 1; Capping protein, Arp2/3 and myosin-I linker homolog 1; Capping protein, Arp2/3 and myosin-I linker protein 1; Leucine-rich repeat-containing protein 16A
• Gene Name: CARMIL1
• Related Disease:
  Anorexia nervosa cachexia
  Obsessive compulsive disorder
  Adult respiratory distress syndrome
  Gout
  Schizophrenia
  Scleroderma
  Systemic sclerosis
  Type-1/2 diabetes
  Stroke
  Lung carcinoma
  Lung squamous cell carcinoma
  Systemic lupus erythematosus
• UniProt ID: CARL1_HUMAN
• PDB ID: 3LK2; 3LK3
• Pfam ID: PF17888 ; PF16000 ; PF13516
• Sequence:
  MTEESSDVPRELIESIKDVIGRKIKISVKKKVKLEVKGDKVENKVLVLTSCRAFLVTARI
  PTKLELTFSYLEIHGVVCSKSAQMIVETEKCSISMKMASPEDVSEVLAHIGTCLRKIFPG
  LSPVRIMKKVSMEPSERLASLQALWDSQTVAEQGPCGGFSQMYACVCDWLGFSYREEVQW
  DVDTIYLTQDTRELNLQDFSHLDHRDLIPIIAALEYNQWFTKLSSKDLKLSTDVCEQILR
  VVSRSNRLEELVLENAGLRTDFAQKLASALAHNPNSGLHTINLAGNPLEDRGVSSLSIQF
  AKLPKGLKHLNLSKTSLSPKGVNSLSQSLSANPLTASTLVHLDLSGNVLRGDDLSHMYNF
  LAQPNAIVHLDLSNTECSLDMVCGALLRGCLQYLAVLNLSRTVFSHRKGKEVPPSFKQFF
  SSSLALMHINLSGTKLSPEPLKALLLGLACNHNLKGVSLDLSNCELRSGGAQVLEGCIAE
  IHNITSLDISDNGLESDLSTLIVWLSKNRSIQHLALGKNFNNMKSKNLTPVLDNLVQMIQ
  DEESPLQSLSLADSKLKTEVTIIINALGSNTSLTKVDISGNGMGDMGAKMLAKALQINTK
  LRTVIWDKNNITAQGFQDIAVAMEKNYTLRFMPIPMYDASQALKTNPEKTEDALQKIENY
  LLRNHETRKYLQEQAYRLQQGIVTSTTQQMIDRICVKVQDHLNSLRNCGGDAIQEDLKSA
  ERLMRDAKNSKTLLPNLYHVGGASWAGASGLLSSPIQETLESMAGEVTRVVDEQLKALLE
  SMVDAAENLCPNVMKKAHIRQDLIHASTEKISIPRTFVKNVLLEQSGIDILNKISEVKLT
  VASFLSDRIVDEILDALSHCHHKLADHFSRRGKTLPQQESLEIELAEEKPVKRSIITVEE
  LTEIERLEDLDTCMMTPKSKRKSIHSRMLRPVSRAFEMEFDLDKALEEVPIHIEDPPFPS
  LRQEKRSSGFISELPSEEGKKLEHFTKLRPKRNKKQQPTQAAVCAANIVSQDGEQNGLMG
  RVDEGVDEFFTKKVTKMDSKKWSTRGSESHELNEGGDEKKKRDSRKSSGFLNLIKSRSKS
  ERPPTILMTEEPSSPKGAVRSPPVDCPRKDTKAAEHNGNSERIEEIKTPDSFEESQGEEI
  GKVERSDSKSSPQAGRRYGVQVMGSGLLAEMKAKQEKRAACAQKKLGNDAVSQDSSSPAL
  SGVERSDGGGAVPKLHPGLPENRFGLGTPEKNTKAEPKAEAGSRSRSSSSTPTSPKPLLQ
  SPKPSLAARPVIPQKPRTASRPDDIPDSPSSPKVALLPPVLKKVPSDKERDGQSSPQPSP
  RTFSQEVSRRSWGQQAQEYQEQKQRSSSKDGHQGSKSNDSGEEAEKEFIFV
• Function: Cell membrane-cytoskeleton-associated protein that plays a role in the regulation of actin polymerization at the barbed end of actin filaments. Prevents F-actin heterodimeric capping protein (CP) activity at the leading edges of migrating cells, and hence generates uncapped barbed ends and enhances actin polymerization, however, seems unable to nucleate filaments. Plays a role in lamellipodial protrusion formations and cell migration.
• Tissue Specificity: Expressed in lung, placenta, small intestine, liver, thymus, colon, skeletal muscle, heart and brain. Higher expression in kidney.
• Reactome Pathway: Factors involved in megakaryocyte development and platelet production (R-HSA-983231)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anorexia nervosa cachexia	DISFO5RQ	Definitive	Genetic Variation	[1]
Obsessive compulsive disorder	DIS1ZMM2	Definitive	Genetic Variation	[1]
Adult respiratory distress syndrome	DISIJV47	Strong	Altered Expression	[2]
Gout	DISHC0U7	Strong	Genetic Variation	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]
Scleroderma	DISVQ342	Strong	Altered Expression	[5]
Systemic sclerosis	DISF44L6	Strong	Altered Expression	[5]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[6]
Stroke	DISX6UHX	moderate	Genetic Variation	[7]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[8]
Lung squamous cell carcinoma	DISXPIBD	Limited	Genetic Variation	[8]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	F-actin-uncapping protein LRRC16A (CARMIL1) increases the Cytology abnormal ADR of Estradiol.	[21]

10 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 F-actin-uncapping protein LRRC16A (CARMIL1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of F-actin-uncapping protein LRRC16A (CARMIL1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of F-actin-uncapping protein LRRC16A (CARMIL1).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of F-actin-uncapping protein LRRC16A (CARMIL1).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of F-actin-uncapping protein LRRC16A (CARMIL1).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of F-actin-uncapping protein LRRC16A (CARMIL1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of F-actin-uncapping protein LRRC16A (CARMIL1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of F-actin-uncapping protein LRRC16A (CARMIL1).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of F-actin-uncapping protein LRRC16A (CARMIL1).	[19]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of F-actin-uncapping protein LRRC16A (CARMIL1).	[20]

3 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 F-actin-uncapping protein LRRC16A (CARMIL1).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of F-actin-uncapping protein LRRC16A (CARMIL1).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of F-actin-uncapping protein LRRC16A (CARMIL1).	[17]

References

• [1] Examination of the shared genetic basis of anorexia nervosa and obsessive-compulsive disorder.Mol Psychiatry. 2020 Sep;25(9):2036-2046. doi: 10.1038/s41380-018-0115-4. Epub 2018 Aug 7.
• [2] A Missense Genetic Variant in LRRC16A/CARMIL1 Improves Acute Respiratory Distress Syndrome Survival by Attenuating Platelet Count Decline.Am J Respir Crit Care Med. 2017 May 15;195(10):1353-1361. doi: 10.1164/rccm.201605-0946OC.
• [3] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [4] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [5] Inhibition of EZH2 prevents fibrosis and restores normal angiogenesis in scleroderma.Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3695-3702. doi: 10.1073/pnas.1813006116. Epub 2019 Feb 12.
• [6] Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.Nat Commun. 2019 Aug 26;10(1):3842. doi: 10.1038/s41467-019-11704-w.
• [7] Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke.Nat Genet. 2012 Feb 5;44(3):328-33. doi: 10.1038/ng.1081.
• [8] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [9] Transancestral mapping and genetic load in systemic lupus erythematosus.Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [16] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [21] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.