Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJBDX0Y)

• DOT Name: V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2)
• Synonyms: V-ATPase 116 kDa subunit a 2; Lysosomal H(+)-transporting ATPase V0 subunit a 2; TJ6; Vacuolar proton translocating ATPase 116 kDa subunit a isoform 2
• Gene Name: ATP6V0A2
• Related Disease:
  Wrinkly skin syndrome
  Adult glioblastoma
  ALG9-congenital disorder of glycosylation
  Arterial disorder
  Arteriosclerosis
  Atherosclerosis
  Autosomal recessive cutis laxa type 2, classic type
  Autosomal recessive cutis laxa type 2A
  Bone disease
  Breast cancer
  Breast carcinoma
  Congenital disorder of glycosylation
  Crohn disease
  Cryptococcosis
  Diabetic retinopathy
  Ehlers-Danlos syndrome
  Encephalitis
  Epilepsy
  Fetal growth restriction
  Geroderma osteodysplastica
  Glioblastoma multiforme
  Male infertility
  Malignant glioma
  Pulmonary disease
  Renal tubular acidosis
  Von willebrand disease
  High blood pressure
  Pulmonary emphysema
  Alopecia
  Autosomal recessive cutis laxa type 2C
  Autosomal recessive cutis laxa type 2D
  Neoplasm
  Woodhouse-Sakati syndrome
• UniProt ID: VPP2_HUMAN
• Pfam ID: PF01496
• Sequence:
  MGSLFRSETMCLAQLFLQSGTAYECLSALGEKGLVQFRDLNQNVSSFQRKFVGEVKRCEE
  LERILVYLVQEINRADIPLPEGEASPPAPPLKQVLEMQEQLQKLEVELREVTKNKEKLRK
  NLLELIEYTHMLRVTKTFVKRNVEFEPTYEEFPSLESDSLLDYSCMQRLGAKLGFVSGLI
  NQGKVEAFEKMLWRVCKGYTIVSYAELDESLEDPETGEVIKWYVFLISFWGEQIGHKVKK
  ICDCYHCHVYPYPNTAEERREIQEGLNTRIQDLYTVLHKTEDYLRQVLCKAAESVYSRVI
  QVKKMKAIYHMLNMCSFDVTNKCLIAEVWCPEADLQDLRRALEEGSRESGATIPSFMNII
  PTKETPPTRIRTNKFTEGFQNIVDAYGVGSYREVNPALFTIITFPFLFAVMFGDFGHGFV
  MFLFALLLVLNENHPRLNQSQEIMRMFFNGRYILLLMGLFSVYTGLIYNDCFSKSVNLFG
  SGWNVSAMYSSSHPPAEHKKMVLWNDSVVRHNSILQLDPSIPGVFRGPYPLGIDPIWNLA
  TNRLTFLNSFKMKMSVILGIIHMTFGVILGIFNHLHFRKKFNIYLVSIPELLFMLCIFGY
  LIFMIFYKWLVFSAETSRVAPSILIEFINMFLFPASKTSGLYTGQEYVQRVLLVVTALSV
  PVLFLGKPLFLLWLHNGRSCFGVNRSGYTLIRKDSEEEVSLLGSQDIEEGNHQVEDGCRE
  MACEEFNFGEILMTQVIHSIEYCLGCISNTASYLRLWALSLAHAQLSDVLWAMLMRVGLR
  VDTTYGVLLLLPVIALFAVLTIFILLIMEGLSAFLHAIRLHWVEFQNKFYVGAGTKFVPF
  SFSLLSSKFNNDDSVA
• Function: Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment. Essential component of the endosomal pH-sensing machinery. May play a role in maintaining the Golgi functions, such as glycosylation maturation, by controlling the Golgi pH. In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
  Phagosome (hsa04145)
  Sy.ptic vesicle cycle (hsa04721)
  Collecting duct acid secretion (hsa04966)
  Vibrio cholerae infection (hsa05110)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Tuberculosis (hsa05152)
  Human papillomavirus infection (hsa05165)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  Insulin receptor recycling (R-HSA-77387)
  Transferrin endocytosis and recycling (R-HSA-917977)
  Ion channel transport (R-HSA-983712)
  ROS and RNS production in phagocytes (R-HSA-1222556)
• BioCyc Pathway: MetaCyc:G66-33375-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Wrinkly skin syndrome	DISFUI2E	Definitive	Autosomal recessive	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
ALG9-congenital disorder of glycosylation	DISTGKN8	Strong	CausalMutation	[3]
Arterial disorder	DISLG4XS	Strong	Altered Expression	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Autosomal recessive cutis laxa type 2, classic type	DISMZ113	Strong	Autosomal recessive	[6]
Autosomal recessive cutis laxa type 2A	DIS9CZA4	Strong	Autosomal recessive	[7]
Bone disease	DISE1F82	Strong	Genetic Variation	[8]
Breast cancer	DIS7DPX1	Strong	Biomarker	[9]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[9]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[10]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[9]
Cryptococcosis	DISDYDTK	Strong	Biomarker	[11]
Diabetic retinopathy	DISHGUJM	Strong	Genetic Variation	[12]
Ehlers-Danlos syndrome	DISSVBRR	Strong	Biomarker	[13]
Encephalitis	DISLD1RL	Strong	Genetic Variation	[11]
Epilepsy	DISBB28L	Strong	Genetic Variation	[14]
Fetal growth restriction	DIS5WEJ5	Strong	Genetic Variation	[15]
Geroderma osteodysplastica	DISFPJ78	Strong	Biomarker	[16]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Male infertility	DISY3YZZ	Strong	Altered Expression	[17]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[2]
Pulmonary disease	DIS6060I	Strong	Genetic Variation	[4]
Renal tubular acidosis	DISE1NDR	Strong	Genetic Variation	[18]
Von willebrand disease	DIS3TZCH	Strong	Biomarker	[19]
High blood pressure	DISY2OHH	moderate	Biomarker	[20]
Pulmonary emphysema	DIS5M7HZ	moderate	Biomarker	[19]
Alopecia	DIS37HU4	Limited	Genetic Variation	[21]
Autosomal recessive cutis laxa type 2C	DISWWS8T	Limited	GermlineCausalMutation	[3]
Autosomal recessive cutis laxa type 2D	DISJUYUW	Limited	GermlineCausalMutation	[3]
Neoplasm	DISZKGEW	Limited	Biomarker	[22]
Woodhouse-Sakati syndrome	DISHLVWB	Limited	Genetic Variation	[21]

16 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 V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[25]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[26]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[27]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[28]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[29]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[30]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[28]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[32]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[29]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[35]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[29]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[36]

3 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 V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[31]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[33]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of V-type proton ATPase 116 kDa subunit a 2 (ATP6V0A2).	[33]

References

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• [17] Expression of a2 vacuolar ATPase in spermatozoa is associated with semen quality and chemokine-cytokine profiles in infertile men.PLoS One. 2013 Jul 30;8(7):e70470. doi: 10.1371/journal.pone.0070470. Print 2013.
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• [33] 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.
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