Details of Drug Off-Target (DOT)

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

• DOT Name: Squalene synthase (FDFT1)
• Synonyms: SQS; SS; EC 2.5.1.21; FPP:FPP farnesyltransferase; Farnesyl-diphosphate farnesyltransferase; Farnesyl-diphosphate farnesyltransferase 1
• Gene Name: FDFT1
• Related Disease: Squalene synthase deficiency
• UniProt ID: FDFT_HUMAN
• PDB ID: 1EZF; 3ASX; 3LEE; 3Q2Z; 3Q30; 3V66; 3VJ8; 3VJ9; 3VJA; 3VJB; 3VJC; 3WC9; 3WCD; 3WCF; 3WCH; 3WCI; 3WCJ; 3WCL; 3WCM; 3WEF; 3WEG; 3WEH; 3WEI; 3WEJ; 3WEK; 3WSA; 6PYJ; 6PYV; 6PYW; 6PZ5
• EC Number: 2.5.1.21
• Pfam ID: PF00494
• Sequence:
  MEFVKCLGHPEEFYNLVRFRIGGKRKVMPKMDQDSLSSSLKTCYKYLNQTSRSFAAVIQA
  LDGEMRNAVCIFYLVLRALDTLEDDMTISVEKKVPLLHNFHSFLYQPDWRFMESKEKDRQ
  VLEDFPTISLEFRNLAEKYQTVIADICRRMGIGMAEFLDKHVTSEQEWDKYCHYVAGLVG
  IGLSRLFSASEFEDPLVGEDTERANSMGLFLQKTNIIRDYLEDQQGGREFWPQEVWSRYV
  KKLGDFAKPENIDLAVQCLNELITNALHHIPDVITYLSRLRNQSVFNFCAIPQVMAIATL
  AACYNNQQVFKGAVKIRKGQAVTLMMDATNMPAVKAIIYQYMEEIYHRIPDSDPSSSKTR
  QIISTIRTQNLPNCQLISRSHYSPIYLSFVMLLAALSWQYLTTLSQVTEDYVQTGEH
• Function: Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP) moieties to form squalene. Proceeds in two distinct steps. In the first half-reaction, two molecules of FPP react to form the stable presqualene diphosphate intermediate (PSQPP), with concomitant release of a proton and a molecule of inorganic diphosphate. In the second half-reaction, PSQPP undergoes heterolysis, isomerization, and reduction with NADPH or NADH to form squalene. It is the first committed enzyme of the sterol biosynthesis pathway.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Steroid biosynthesis (hsa00100)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  PPARA activates gene expression (R-HSA-1989781)
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Cholesterol biosynthesis (R-HSA-191273)
• BioCyc Pathway: MetaCyc:HS01329-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Squalene synthase deficiency	DIS8EKG3	Limited	Autosomal recessive	[1]

This DOT Affected the Drug Response of 6 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Squalene synthase (FDFT1) decreases the response to substance of Doxorubicin.	[39]
Etoposide	DMNH3PG	Approved	Squalene synthase (FDFT1) affects the response to substance of Etoposide.	[40]
Paclitaxel	DMLB81S	Approved	Squalene synthase (FDFT1) affects the response to substance of Paclitaxel.	[40]
Mitomycin	DMH0ZJE	Approved	Squalene synthase (FDFT1) affects the response to substance of Mitomycin.	[40]
Topotecan	DMP6G8T	Approved	Squalene synthase (FDFT1) affects the response to substance of Topotecan.	[40]
Mitoxantrone	DMM39BF	Approved	Squalene synthase (FDFT1) affects the response to substance of Mitoxantrone.	[40]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
ANW-32821	DMMJOZD	Phase 2	Squalene synthase (FDFT1) increases the chemical synthesis of ANW-32821.	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Squalene synthase (FDFT1).	[2]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Squalene synthase (FDFT1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Squalene synthase (FDFT1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Squalene synthase (FDFT1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Squalene synthase (FDFT1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Squalene synthase (FDFT1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Squalene synthase (FDFT1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Squalene synthase (FDFT1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Squalene synthase (FDFT1).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Squalene synthase (FDFT1).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Squalene synthase (FDFT1).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Squalene synthase (FDFT1).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Squalene synthase (FDFT1).	[13]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Squalene synthase (FDFT1).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Squalene synthase (FDFT1).	[15]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Squalene synthase (FDFT1).	[16]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Squalene synthase (FDFT1).	[17]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Squalene synthase (FDFT1).	[18]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Squalene synthase (FDFT1).	[19]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Squalene synthase (FDFT1).	[20]
Lovastatin	DM9OZWQ	Approved	Lovastatin increases the activity of Squalene synthase (FDFT1).	[21]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Squalene synthase (FDFT1).	[22]
Isoflavone	DM7U58J	Phase 4	Isoflavone increases the expression of Squalene synthase (FDFT1).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Squalene synthase (FDFT1).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Squalene synthase (FDFT1).	[24]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Squalene synthase (FDFT1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Squalene synthase (FDFT1).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Squalene synthase (FDFT1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Squalene synthase (FDFT1).	[27]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Squalene synthase (FDFT1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Squalene synthase (FDFT1).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Squalene synthase (FDFT1).	[31]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Squalene synthase (FDFT1).	[8]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Squalene synthase (FDFT1).	[32]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Squalene synthase (FDFT1).	[17]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Squalene synthase (FDFT1).	[33]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the expression of Squalene synthase (FDFT1).	[34]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Squalene synthase (FDFT1).	[35]
Rutin	DMEHRAJ	Investigative	Rutin increases the expression of Squalene synthase (FDFT1).	[36]
Farnesol	DMV2X1B	Investigative	Farnesol increases the expression of Squalene synthase (FDFT1).	[37]
Ganoderic acid A	DM42EVG	Investigative	Ganoderic acid A decreases the expression of Squalene synthase (FDFT1).	[38]

References

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