Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI0DU9Y)

• DOT Name: Proprotein convertase subtilisin/kexin type 9 (PCSK9)
• Synonyms: EC 3.4.21.-; Neural apoptosis-regulated convertase 1; NARC-1; Proprotein convertase 9; PC9; Subtilisin/kexin-like protease PC9
• Gene Name: PCSK9
• Related Disease:
  Hypercholesterolemia, autosomal dominant, 3
  Homozygous familial hypercholesterolemia
• UniProt ID: PCSK9_HUMAN
• PDB ID: 2P4E ; 2PMW ; 2QTW ; 2W2M ; 2W2N ; 2W2O ; 2W2P ; 2W2Q ; 2XTJ ; 3BPS ; 3GCW ; 3GCX ; 3H42 ; 3M0C ; 3P5B ; 3P5C ; 3SQO ; 4K8R ; 4NE9 ; 4NMX ; 4OV6 ; 5OCA ; 5VL7 ; 5VLA ; 5VLH ; 5VLK ; 5VLL ; 5VLP ; 6E4Y ; 6E4Z ; 6MV5 ; 6OLZ ; 6OM0 ; 6OM7 ; 6U26 ; 6U2F ; 6U2N ; 6U2P ; 6U36 ; 6U38 ; 6U3I ; 6U3X ; 7ANQ
• EC Number: 3.4.21.-
• Pfam ID: PF05922 ; PF18459 ; PF18464 ; PF18463 ; PF00082
• Sequence:
  MGTVSSRRSWWPLPLLLLLLLLLGPAGARAQEDEDGDYEELVLALRSEEDGLAEAPEHGT
  TATFHRCAKDPWRLPGTYVVVLKEETHLSQSERTARRLQAQAARRGYLTKILHVFHGLLP
  GFLVKMSGDLLELALKLPHVDYIEEDSSVFAQSIPWNLERITPPRYRADEYQPPDGGSLV
  EVYLLDTSIQSDHREIEGRVMVTDFENVPEEDGTRFHRQASKCDSHGTHLAGVVSGRDAG
  VAKGASMRSLRVLNCQGKGTVSGTLIGLEFIRKSQLVQPVGPLVVLLPLAGGYSRVLNAA
  CQRLARAGVVLVTAAGNFRDDACLYSPASAPEVITVGATNAQDQPVTLGTLGTNFGRCVD
  LFAPGEDIIGASSDCSTCFVSQSGTSQAAAHVAGIAAMMLSAEPELTLAELRQRLIHFSA
  KDVINEAWFPEDQRVLTPNLVAALPPSTHGAGWQLFCRTVWSAHSGPTRMATAVARCAPD
  EELLSCSSFSRSGKRRGERMEAQGGKLVCRAHNAFGGEGVYAIARCCLLPQANCSVHTAP
  PAEASMGTRVHCHQQGHVLTGCSSHWEVEDLGTHKPPVLRPRGQPNQCVGHREASIHASC
  CHAPGLECKVKEHGIPAPQEQVTVACEEGWTLTGCSALPGTSHVLGAYAVDNTCVVRSRD
  VSTTGSTSEGAVTAVAICCRSRHLAQASQELQ
• Function: Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.
• Tissue Specificity: Expressed in neuro-epithelioma, colon carcinoma, hepatic and pancreatic cell lines, and in Schwann cells.
• KEGG Pathway: Cholesterol metabolism (hsa04979)
• Reactome Pathway:
  VLDLR internalisation and degradation (R-HSA-8866427)
  Post-translational protein phosphorylation (R-HSA-8957275)
  LDL clearance (R-HSA-8964038)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypercholesterolemia, autosomal dominant, 3	DIS8KE3U	Definitive	Autosomal dominant	[1]
Homozygous familial hypercholesterolemia	DISRCNCF	Supportive	Autosomal recessive	[2]

27 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 Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[10]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[11]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[12]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[13]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[14]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[15]
Bezafibrate	DMZDCS0	Approved	Bezafibrate increases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[16]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[17]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[18]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[25]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[26]
U0126	DM31OGF	Investigative	U0126 increases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[14]
PD98059	DMZC90M	Investigative	PD98059 increases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[14]
15-deoxy-Delta(12, 14)-prostaglandin J(2)	DM8VUX3	Investigative	15-deoxy-Delta(12, 14)-prostaglandin J(2) increases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[14]
Ganoderic acid A	DM42EVG	Investigative	Ganoderic acid A decreases the expression of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[20]

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 decreases the methylation of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Proprotein convertase subtilisin/kexin type 9 (PCSK9).	[23]

References

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