Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9T2TCJ)

• DOT Name: Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1)
• Synonyms: Lissencephaly-1 protein; LIS-1; PAF acetylhydrolase 45 kDa subunit; PAF-AH 45 kDa subunit; PAF-AH alpha; PAFAH alpha
• Gene Name: PAFAH1B1
• Related Disease:
  Lissencephaly due to LIS1 mutation
  Autism
  Autism spectrum disorder
  Bone osteosarcoma
  Cardiac failure
  Classic lissencephaly
  Congestive heart failure
  Crohn disease
  Dementia
  Depression
  Inflammatory bowel disease
  Intellectual disability
  Isolated congenital microcephaly
  Late-onset Parkinson disease
  leukaemia
  Leukemia
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Metastatic malignant neoplasm
  Mood disorder
  Myelodysplastic syndrome
  Myelodysplastic/myeloproliferative neoplasm
  Non-small-cell lung cancer
  Osteosarcoma
  Parkinsonian disorder
  Periventricular nodular heterotopia
  Pervasive developmental disorder
  Plasma cell myeloma
  Schizophrenia
  Subcortical band heterotopia
  West syndrome
  Acute myelogenous leukaemia
  Adult glioblastoma
  Clear cell renal carcinoma
  Glioblastoma multiforme
  Psychotic disorder
  Renal cell carcinoma
  Advanced cancer
  Anxiety
  Anxiety disorder
  Asthma
  Epilepsy
  Hepatocellular carcinoma
  Lissencephaly spectrum disorders
  Neoplasm
  Nervous system disease
• UniProt ID: LIS1_HUMAN
• PDB ID: 7MT1; 8DYU; 8DYV; 8FDT; 8FDU
• Pfam ID: PF08513 ; PF00400
• Sequence:
  MVLSQRQRDELNRAIADYLRSNGYEEAYSVFKKEAELDVNEELDKKYAGLLEKKWTSVIR
  LQKKVMELESKLNEAKEEFTSGGPLGQKRDPKEWIPRPPEKYALSGHRSPVTRVIFHPVF
  SVMVSASEDATIKVWDYETGDFERTLKGHTDSVQDISFDHSGKLLASCSADMTIKLWDFQ
  GFECIRTMHGHDHNVSSVAIMPNGDHIVSASRDKTIKMWEVQTGYCVKTFTGHREWVRMV
  RPNQDGTLIASCSNDQTVRVWVVATKECKAELREHEHVVECISWAPESSYSSISEATGSE
  TKKSGKPGPFLLSGSRDKTIKMWDVSTGMCLMTLVGHDNWVRGVLFHSGGKFILSCADDK
  TLRVWDYKNKRCMKTLNAHEHFVTSLDFHKTAPYVVTGSVDQTVKVWECR
• Function: Regulatory subunit (beta subunit) of the cytosolic type I platelet-activating factor (PAF) acetylhydrolase (PAF-AH (I)), an enzyme that catalyzes the hydrolyze of the acetyl group at the sn-2 position of PAF and its analogs and participates in PAF inactivation. Regulates the PAF-AH (I) activity in a catalytic dimer composition-dependent manner. Required for proper activation of Rho GTPases and actin polymerization at the leading edge of locomoting cerebellar neurons and postmigratory hippocampal neurons in response to calcium influx triggered via NMDA receptors. Positively regulates the activity of the minus-end directed microtubule motor protein dynein. May enhance dynein-mediated microtubule sliding by targeting dynein to the microtubule plus end. Required for several dynein- and microtubule-dependent processes such as the maintenance of Golgi integrity, the peripheral transport of microtubule fragments and the coupling of the nucleus and centrosome. Required during brain development for the proliferation of neuronal precursors and the migration of newly formed neurons from the ventricular/subventricular zone toward the cortical plate. Neuronal migration involves a process called nucleokinesis, whereby migrating cells extend an anterior process into which the nucleus subsequently translocates. During nucleokinesis dynein at the nuclear surface may translocate the nucleus towards the centrosome by exerting force on centrosomal microtubules. May also play a role in other forms of cell locomotion including the migration of fibroblasts during wound healing. Required for dynein recruitment to microtubule plus ends and BICD2-bound cargos. May modulate the Reelin pathway through interaction of the PAF-AH (I) catalytic dimer with VLDLR.
• Tissue Specificity: Fairly ubiquitous expression in both the frontal and occipital areas of the brain.
• KEGG Pathway:
  Ether lipid metabolism (hsa00565)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  RHO GTPases Activate Formins (R-HSA-5663220)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  Mitotic Prometaphase (R-HSA-68877)
  AURKA Activation by TPX2 (R-HSA-8854518)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lissencephaly due to LIS1 mutation	DISSD2MH	Definitive	Autosomal dominant	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[4]
Cardiac failure	DISDC067	Strong	Biomarker	[5]
Classic lissencephaly	DISR8S3S	Strong	Genetic Variation	[6]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[7]
Dementia	DISXL1WY	Strong	Genetic Variation	[8]
Depression	DIS3XJ69	Strong	Genetic Variation	[9]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[10]
Intellectual disability	DISMBNXP	Strong	Biomarker	[11]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[12]
Late-onset Parkinson disease	DIS9IOUI	Strong	Biomarker	[13]
leukaemia	DISS7D1V	Strong	Biomarker	[14]
Leukemia	DISNAKFL	Strong	Biomarker	[14]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[15]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[16]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[16]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[17]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[15]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[17]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[18]
Myelodysplastic/myeloproliferative neoplasm	DISDHXQ4	Strong	Genetic Variation	[19]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[15]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[4]
Parkinsonian disorder	DISHGY45	Strong	Biomarker	[20]
Periventricular nodular heterotopia	DISU3ZRI	Strong	Genetic Variation	[21]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[3]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[22]
Schizophrenia	DISSRV2N	Strong	Biomarker	[23]
Subcortical band heterotopia	DISHN7JS	Strong	Biomarker	[24]
West syndrome	DISLIAU9	Strong	Genetic Variation	[25]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[26]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[27]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[28]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[27]
Psychotic disorder	DIS4UQOT	moderate	Genetic Variation	[29]
Renal cell carcinoma	DISQZ2X8	moderate	Altered Expression	[28]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[30]
Anxiety	DISIJDBA	Limited	Biomarker	[31]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[31]
Asthma	DISW9QNS	Limited	Genetic Variation	[32]
Epilepsy	DISBB28L	Limited	Genetic Variation	[33]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[34]
Lissencephaly spectrum disorders	DISBCZL7	Limited	Biomarker	[12]
Neoplasm	DISZKGEW	Limited	Biomarker	[35]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[11]

1 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 Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[37]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[38]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[39]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[40]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[41]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[42]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[43]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[44]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[45]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[46]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[47]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[48]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[49]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[50]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[51]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B1).	[52]

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