Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIF3AJI)

• DOT Name: Spastin (SPAST)
• Synonyms: EC 5.6.1.1; Spastic paraplegia 4 protein
• Gene Name: SPAST
• Related Disease:
  Adult glioblastoma
  Charlevoix-Saguenay spastic ataxia
  Glioblastoma multiforme
  Hereditary spastic paraplegia 15
  Hereditary spastic paraplegia 4
  Infantile-onset ascending hereditary spastic paralysis
  Neurodevelopmental disorder
  Psychotic disorder
  Alzheimer disease
  Alzheimer disease 3
  Astrocytoma
  Autism spectrum disorder
  Brain disease
  Cerebellar ataxia
  Depression
  Epilepsy
  Hereditary spastic paraplegia 10
  Hereditary spastic paraplegia 31
  Hereditary spastic paraplegia 6
  Hereditary spastic paraplegia 8
  Mental disorder
  Migraine disorder
  Motor neurone disease
  Movement disorder
  Neoplasm
  Papillon-Lefevre disease
  Paraplegia
  Peripheral neuropathy
  Pervasive developmental disorder
  Pure hereditary spastic paraplegia
  Status epilepticus seizure
  Tarsal-carpal coalition syndrome
  Temporal lobe epilepsy
  Vascular purpura
  Amyotrophic lateral sclerosis
  Dementia
  Hereditary spastic paraplegia 3A
  Intellectual disability
  Hereditary spastic paraplegia 17
  Lateral sclerosis
  Multiple sclerosis
  Nervous system disease
  Silver-Russell syndrome
• UniProt ID: SPAST_HUMAN
• PDB ID: 3EAB; 3VFD; 5Z6Q; 5Z6R; 6PEK; 6PEN; 7S7J
• EC Number: 5.6.1.1
• Pfam ID: PF00004 ; PF17862 ; PF09336
• Sequence:
  MNSPGGRGKKKGSGGASNPVPPRPPPPCLAPAPPAAGPAPPPESPHKRNLYYFSYPLFVG
  FALLRLVAFHLGLLFVWLCQRFSRALMAAKRSSGAAPAPASASAPAPVPGGEAERVRVFH
  KQAFEYISIALRIDEDEKAGQKEQAVEWYKKGIEELEKGIAVIVTGQGEQCERARRLQAK
  MMTNLVMAKDRLQLLEKMQPVLPFSKSQTDVYNDSTNLACRNGHLQSESGAVPKRKDPLT
  HTSNSLPRSKTVMKTGSAGLSGHHRAPSYSGLSMVSGVKQGSGPAPTTHKGTPKTNRTNK
  PSTPTTATRKKKDLKNFRNVDSNLANLIMNEIVDNGTAVKFDDIAGQDLAKQALQEIVIL
  PSLRPELFTGLRAPARGLLLFGPPGNGKTMLAKAVAAESNATFFNISAASLTSKYVGEGE
  KLVRALFAVARELQPSIIFIDEVDSLLCERREGEHDASRRLKTEFLIEFDGVQSAGDDRV
  LVMGATNRPQELDEAVLRRFIKRVYVSLPNEETRLLLLKNLLCKQGSPLTQKELAQLARM
  TDGYSGSDLTALAKDAALGPIRELKPEQVKNMSASEMRNIRLSDFTESLKKIKRSVSPQT
  LEAYIRWNKDFGDTTV
• Function: ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated. Preferentially recognizes and acts on microtubules decorated with short polyglutamate tails: severing activity increases as the number of glutamates per tubulin rises from one to eight, but decreases beyond this glutamylation threshold. Severing activity is not dependent on tubulin acetylation or detyrosination. Microtubule severing promotes reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. It is critical for the biogenesis and maintenance of complex microtubule arrays in axons, spindles and cilia. SPAST is involved in abscission step of cytokinesis and nuclear envelope reassembly during anaphase in cooperation with the ESCRT-III complex. Recruited at the midbody, probably by IST1, and participates in membrane fission during abscission together with the ESCRT-III complex. Recruited to the nuclear membrane by IST1 and mediates microtubule severing, promoting nuclear envelope sealing and mitotic spindle disassembly during late anaphase. Required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and endosome recycling. Recruited by IST1 to endosomes and regulates early endosomal tubulation and recycling by mediating microtubule severing. Probably plays a role in axon growth and the formation of axonal branches ; [Isoform 1]: Involved in lipid metabolism by regulating the size and distribution of lipid droplets.
• Tissue Specificity: Expressed in brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle. The short isoforms may predominate in brain and spinal cord.
• Reactome Pathway: Sealing of the nuclear envelope (NE) by ESCRT-III (R-HSA-9668328)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Charlevoix-Saguenay spastic ataxia	DISE8X81	Definitive	Autosomal recessive	[2]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Hereditary spastic paraplegia 15	DIS436G5	Definitive	Biomarker	[3]
Hereditary spastic paraplegia 4	DISFUYL2	Definitive	Autosomal dominant	[4]
Infantile-onset ascending hereditary spastic paralysis	DISFBV9C	Definitive	Genetic Variation	[5]
Neurodevelopmental disorder	DIS372XH	Definitive	Biomarker	[6]
Psychotic disorder	DIS4UQOT	Definitive	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[7]
Alzheimer disease 3	DISVT69G	Strong	Genetic Variation	[7]
Astrocytoma	DISL3V18	Strong	Altered Expression	[8]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[9]
Brain disease	DIS6ZC3X	Strong	Genetic Variation	[10]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[11]
Depression	DIS3XJ69	Strong	Genetic Variation	[12]
Epilepsy	DISBB28L	Strong	Biomarker	[13]
Hereditary spastic paraplegia 10	DISYFO3L	Strong	Biomarker	[14]
Hereditary spastic paraplegia 31	DISZZWA2	Strong	Genetic Variation	[15]
Hereditary spastic paraplegia 6	DISVB8NO	Strong	Genetic Variation	[16]
Hereditary spastic paraplegia 8	DISDDP9L	Strong	Biomarker	[17]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[10]
Migraine disorder	DISFCQTG	Strong	Genetic Variation	[11]
Motor neurone disease	DISUHWUI	Strong	Genetic Variation	[18]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[19]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Papillon-Lefevre disease	DIS3R7KX	Strong	Genetic Variation	[20]
Paraplegia	DISSKWBI	Strong	Genetic Variation	[21]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[22]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[9]
Pure hereditary spastic paraplegia	DIS8X71E	Strong	Genetic Variation	[23]
Status epilepticus seizure	DISY3BIC	Strong	Altered Expression	[10]
Tarsal-carpal coalition syndrome	DISY90L2	Strong	Genetic Variation	[24]
Temporal lobe epilepsy	DISNOPXX	Strong	Altered Expression	[10]
Vascular purpura	DIS6ZZMF	Strong	Biomarker	[25]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Genetic Variation	[26]
Dementia	DISXL1WY	moderate	Genetic Variation	[27]
Hereditary spastic paraplegia 3A	DISWGEU6	moderate	Biomarker	[28]
Intellectual disability	DISMBNXP	Disputed	Biomarker	[29]
Hereditary spastic paraplegia 17	DISI7Y7F	Limited	Biomarker	[30]
Lateral sclerosis	DISH30B8	Limited	Genetic Variation	[31]
Multiple sclerosis	DISB2WZI	Limited	Genetic Variation	[32]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[33]
Silver-Russell syndrome	DISSVJ1D	Limited	Biomarker	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Spastin (SPAST).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Spastin (SPAST).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Spastin (SPAST).	[36]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Spastin (SPAST).	[37]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Spastin (SPAST).	[38]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Spastin (SPAST).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Spastin (SPAST).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Spastin (SPAST).	[42]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Spastin (SPAST).	[43]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of Spastin (SPAST).	[45]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Spastin (SPAST).	[41]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Spastin (SPAST).	[44]

References

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