Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3ETTI6)

• DOT Name: Kinesin heavy chain isoform 5A (KIF5A)
• Synonyms: Kinesin heavy chain neuron-specific 1; Neuronal kinesin heavy chain; NKHC
• Gene Name: KIF5A
• Related Disease:
  Amyotrophic lateral sclerosis, susceptibility to, 25
  Inherited neurodegenerative disorder
  Myoclonus, intractable, neonatal
  Hereditary spastic paraplegia 10
  Autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation
• UniProt ID: KIF5A_HUMAN
• PDB ID: 4UXT; 4UXY; 4UY0
• Pfam ID: PF00225
• Sequence:
  MAETNNECSIKVLCRFRPLNQAEILRGDKFIPIFQGDDSVVIGGKPYVFDRVFPPNTTQE
  QVYHACAMQIVKDVLAGYNGTIFAYGQTSSGKTHTMEGKLHDPQLMGIIPRIARDIFNHI
  YSMDENLEFHIKVSYFEIYLDKIRDLLDVTKTNLSVHEDKNRVPFVKGCTERFVSSPEEI
  LDVIDEGKSNRHVAVTNMNEHSSRSHSIFLINIKQENMETEQKLSGKLYLVDLAGSEKVS
  KTGAEGAVLDEAKNINKSLSALGNVISALAEGTKSYVPYRDSKMTRILQDSLGGNCRTTM
  FICCSPSSYNDAETKSTLMFGQRAKTIKNTASVNLELTAEQWKKKYEKEKEKTKAQKETI
  AKLEAELSRWRNGENVPETERLAGEEAALGAELCEETPVNDNSSIVVRIAPEERQKYEEE
  IRRLYKQLDDKDDEINQQSQLIEKLKQQMLDQEELLVSTRGDNEKVQRELSHLQSENDAA
  KDEVKEVLQALEELAVNYDQKSQEVEEKSQQNQLLVDELSQKVATMLSLESELQRLQEVS
  GHQRKRIAEVLNGLMKDLSEFSVIVGNGEIKLPVEISGAIEEEFTVARLYISKIKSEVKS
  VVKRCRQLENLQVECHRKMEVTGRELSSCQLLISQHEAKIRSLTEYMQSVELKKRHLEES
  YDSLSDELAKLQAQETVHEVALKDKEPDTQDADEVKKALELQMESHREAHHRQLARLRDE
  INEKQKTIDELKDLNQKLQLELEKLQADYEKLKSEEHEKSTKLQELTFLYERHEQSKQDL
  KGLEETVARELQTLHNLRKLFVQDVTTRVKKSAEMEPEDSGGIHSQKQKISFLENNLEQL
  TKVHKQLVRDNADLRCELPKLEKRLRATAERVKALEGALKEAKEGAMKDKRRYQQEVDRI
  KEAVRYKSSGKRGHSAQIAKPVRPGHYPASSPTNPYGTRSPECISYTNSLFQNYQNLYLQ
  ATPSSTSDMYFANSCTSSGATSSGGPLASYQKANMDNGNATDINDNRSDLPCGYEAEDQA
  KLFPLHQETAAS
• Function: Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL). Can induce formation of neurite-like membrane protrusions in non-neuronal cells in a ZFYVE27-dependent manner. The ZFYVE27-KIF5A complex contributes to the vesicular transport of VAPA, VAPB, SURF4, RAB11A, RAB11B and RTN3 proteins in neurons. Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation.
• Tissue Specificity: Distributed throughout the CNS but is highly enriched in subsets of neurons.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Dopaminergic sy.pse (hsa04728)
  Motor proteins (hsa04814)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Salmonella infection (hsa05132)
  Non-small cell lung cancer (hsa05223)
• Reactome Pathway:
  Insulin processing (R-HSA-264876)
  RHO GTPases activate KTN1 (R-HSA-5625970)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  Kinesins (R-HSA-983189)
  MHC class II antigen presentation (R-HSA-2132295)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis, susceptibility to, 25	DIS1NFXS	Definitive	Autosomal dominant	[1]
Inherited neurodegenerative disorder	DISPN7D2	Definitive	Autosomal dominant	[1]
Myoclonus, intractable, neonatal	DISG08IV	Definitive	Autosomal dominant	[2]
Hereditary spastic paraplegia 10	DISYFO3L	Strong	Autosomal dominant	[3]
Autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation	DIS60YTM	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Docetaxel	DMDI269	Approved	Kinesin heavy chain isoform 5A (KIF5A) decreases the response to substance of Docetaxel.	[11]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	Kinesin heavy chain isoform 5A (KIF5A) increases the hydrolysis of Adenosine triphosphate.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kinesin heavy chain isoform 5A (KIF5A).	[5]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Kinesin heavy chain isoform 5A (KIF5A).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Kinesin heavy chain isoform 5A (KIF5A).	[7]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Kinesin heavy chain isoform 5A (KIF5A).	[10]

2 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 increases the methylation of Kinesin heavy chain isoform 5A (KIF5A).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Kinesin heavy chain isoform 5A (KIF5A).	[9]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction. Ann Neurol. 2016 Oct;80(4):633-7. doi: 10.1002/ana.24744. Epub 2016 Aug 24.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2. Clin Genet. 2012 Aug;82(2):157-64. doi: 10.1111/j.1399-0004.2011.01717.x. Epub 2011 Jun 21.
• [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] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [10] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [11] Specific kinesin expression profiles associated with taxane resistance in basal-like breast cancer. Breast Cancer Res Treat. 2012 Feb;131(3):849-58. doi: 10.1007/s10549-011-1500-8. Epub 2011 Apr 9.
• [12] Kinesin-dependent motility generation as target mechanism of cadmium intoxication. Toxicol Lett. 2014 Jan 30;224(3):356-61. doi: 10.1016/j.toxlet.2013.11.004. Epub 2013 Nov 12.