Details of Drug Off-Target (DOT)

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

• DOT Name: Peptidyl-prolyl cis-trans isomerase A (PPIA)
• Synonyms: PPIase A; EC 5.2.1.8; Cyclophilin A; Cyclosporin A-binding protein; Rotamase A
• Gene Name: PPIA
• UniProt ID: PPIA_HUMAN
• PDB ID: 1AK4 ; 1AWQ ; 1AWR ; 1AWS ; 1AWT ; 1AWU ; 1AWV ; 1BCK ; 1CWA ; 1CWB ; 1CWC ; 1CWF ; 1CWH ; 1CWI ; 1CWJ ; 1CWK ; 1CWL ; 1CWM ; 1CWO ; 1FGL ; 1M63 ; 1M9C ; 1M9D ; 1M9E ; 1M9F ; 1M9X ; 1M9Y ; 1MF8 ; 1MIK ; 1NMK ; 1OCA ; 1RMH ; 1VBS ; 1VBT ; 1W8L ; 1W8M ; 1W8V ; 1YND ; 1ZKF ; 2ALF ; 2CPL ; 2CYH ; 2MS4 ; 2MZU ; 2N0T ; 2RMA ; 2RMB ; 2X25 ; 2X2A ; 2X2C ; 2X2D ; 2XGY ; 3CYH ; 3CYS ; 3K0M ; 3K0N ; 3K0O ; 3K0P ; 3K0Q ; 3K0R ; 3ODI ; 3ODL ; 3RDD ; 4CYH ; 4IPZ ; 4N1M ; 4N1N ; 4N1O ; 4N1P ; 4N1Q ; 4N1R ; 4N1S ; 4YUG ; 4YUH ; 4YUI ; 4YUJ ; 4YUK ; 4YUL ; 4YUM ; 4YUN ; 4YUO ; 4YUP ; 5CYH ; 5F66 ; 5FJB ; 5KUL ; 5KUN ; 5KUO ; 5KUQ ; 5KUR ; 5KUS ; 5KUU ; 5KUV ; 5KUW ; 5KUZ ; 5KV0 ; 5KV1 ; 5KV2 ; 5KV3 ; 5KV4 ; 5KV5 ; 5KV6 ; 5KV7 ; 5LUD ; 5NOQ ; 5NOR ; 5NOS ; 5NOT ; 5NOU ; 5NOV ; 5NOW ; 5NOX ; 5NOY ; 5NOZ ; 5T9U ; 5T9W ; 5T9Z ; 5TA2 ; 5TA4 ; 5WC7 ; 6BTA ; 6GJI ; 6GJJ ; 6GJL ; 6GJM ; 6GJN ; 6GJP ; 6GJR ; 6GJY ; 6GS6 ; 6I42 ; 6U5C ; 6U5D ; 6U5E ; 6U5G ; 6X3R ; 6X3Y ; 6X4M ; 6X4N ; 6X4O ; 6X4P ; 6X4Q ; 6Y9V ; 6Y9W ; 6Y9X ; 6Y9Y ; 6Y9Z ; 6ZDJ ; 7ABT ; 7N9X ; 7PCJ ; 7QBW ; 7TA8 ; 7UPN ; 7UXJ ; 7UXM ; 7UXN ; 8G9P ; 8G9Q
• EC Number: 5.2.1.8
• Pfam ID: PF00160
• Sequence:
  MVNPTVFFDIAVDGEPLGRVSFELFADKVPKTAENFRALSTGEKGFGYKGSCFHRIIPGF
  MCQGGDFTRHNGTGGKSIYGEKFEDENFILKHTGPGILSMANAGPNTNGSQFFICTAKTE
  WLDGKHVVFGKVKEGMNIVEAMERFGSRNGKTSKKITIADCGQLE
• Function: Catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Exerts a strong chemotactic effect on leukocytes partly through activation of one of its membrane receptors BSG/CD147, initiating a signaling cascade that culminates in MAPK/ERK activation. Activates endothelial cells (ECs) in a pro-inflammatory manner by stimulating activation of NF-kappa-B and ERK, JNK and p38 MAP-kinases and by inducing expression of adhesion molecules including SELE and VCAM1. Induces apoptosis in ECs by promoting the FOXO1-dependent expression of CCL2 and BCL2L11 which are involved in EC chemotaxis and apoptosis. In response to oxidative stress, initiates proapoptotic and antiapoptotic signaling in ECs via activation of NF-kappa-B and AKT1 and up-regulation of antiapoptotic protein BCL2. Negatively regulates MAP3K5/ASK1 kinase activity, autophosphorylation and oxidative stress-induced apoptosis mediated by MAP3K5/ASK1. Necessary for the assembly of TARDBP in heterogeneous nuclear ribonucleoprotein (hnRNP) complexes and regulates TARDBP binding to RNA UG repeats and TARDBP-dependent expression of HDAC6, ATG7 and VCP which are involved in clearance of protein aggregates. Plays an important role in platelet activation and aggregation. Regulates calcium mobilization and integrin ITGA2B:ITGB3 bidirectional signaling via increased ROS production as well as by facilitating the interaction between integrin and the cell cytoskeleton. Binds heparan sulfate glycosaminoglycans. Inhibits replication of influenza A virus (IAV). Inhibits ITCH/AIP4-mediated ubiquitination of matrix protein 1 (M1) of IAV by impairing the interaction of ITCH/AIP4 with M1, followed by the suppression of the nuclear export of M1, and finally reduction of the replication of IAV ; (Microbial infection) May act as a mediator between human SARS coronavirus nucleoprotein and BSG/CD147 in the process of invasion of host cells by the virus ; (Microbial infection) Stimulates RNA-binding ability of HCV NS5A in a peptidyl-prolyl cis-trans isomerase activity-dependent manner.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Necroptosis (hsa04217)
• Reactome Pathway:
  Uncoating of the HIV Virion (R-HSA-162585)
  Budding and maturation of HIV virion (R-HSA-162588)
  Integration of provirus (R-HSA-162592)
  Early Phase of HIV Life Cycle (R-HSA-162594)
  Minus-strand DNA synthesis (R-HSA-164516)
  Plus-strand DNA synthesis (R-HSA-164525)
  Binding and entry of HIV virion (R-HSA-173107)
  Assembly Of The HIV Virion (R-HSA-175474)
  APOBEC3G mediated resistance to HIV-1 infection (R-HSA-180689)
  Calcineurin activates NFAT (R-HSA-2025928)
  Basigin interactions (R-HSA-210991)
  Neutrophil degranulation (R-HSA-6798695)
  Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation (R-HSA-8950505)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Alprazolam	DMC7XDN	Approved	Peptidyl-prolyl cis-trans isomerase A (PPIA) increases the hydroxylation of Alprazolam.	[25]

22 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 Peptidyl-prolyl cis-trans isomerase A (PPIA).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[15]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[16]
Etretinate	DM2CZFA	Approved	Etretinate decreases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[18]
NVP-AUY922	DMTYXQF	Phase 2	NVP-AUY922 increases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[20]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[21]
MG-132	DMKA2YS	Preclinical	MG-132 decreases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[22]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[24]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Peptidyl-prolyl cis-trans isomerase A (PPIA).	[23]

References

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