Details of Drug Off-Target (DOT)

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

• DOT Name: Prolyl endopeptidase FAP (FAP)
• Synonyms: EC 3.4.21.26; 170 kDa melanoma membrane-bound gelatinase; Dipeptidyl peptidase FAP; EC 3.4.14.5; Fibroblast activation protein alpha; FAPalpha; Gelatine degradation protease FAP; EC 3.4.21.-; Integral membrane serine protease; Post-proline cleaving enzyme; Serine integral membrane protease; SIMP; Surface-expressed protease; Seprase
• Gene Name: FAP
• UniProt ID: SEPR_HUMAN
• PDB ID: 1Z68; 6Y0F
• EC Number: 3.4.14.5; 3.4.21.-; 3.4.21.26
• Pfam ID: PF00930 ; PF00326
• Sequence:
  MKTWVKIVFGVATSAVLALLVMCIVLRPSRVHNSEENTMRALTLKDILNGTFSYKTFFPN
  WISGQEYLHQSADNNIVLYNIETGQSYTILSNRTMKSVNASNYGLSPDRQFVYLESDYSK
  LWRYSYTATYYIYDLSNGEFVRGNELPRPIQYLCWSPVGSKLAYVYQNNIYLKQRPGDPP
  FQITFNGRENKIFNGIPDWVYEEEMLATKYALWWSPNGKFLAYAEFNDTDIPVIAYSYYG
  DEQYPRTINIPYPKAGAKNPVVRIFIIDTTYPAYVGPQEVPVPAMIASSDYYFSWLTWVT
  DERVCLQWLKRVQNVSVLSICDFREDWQTWDCPKTQEHIEESRTGWAGGFFVSTPVFSYD
  AISYYKIFSDKDGYKHIHYIKDTVENAIQITSGKWEAINIFRVTQDSLFYSSNEFEEYPG
  RRNIYRISIGSYPPSKKCVTCHLRKERCQYYTASFSDYAKYYALVCYGPGIPISTLHDGR
  TDQEIKILEENKELENALKNIQLPKEEIKKLEVDEITLWYKMILPPQFDRSKKYPLLIQV
  YGGPCSQSVRSVFAVNWISYLASKEGMVIALVDGRGTAFQGDKLLYAVYRKLGVYEVEDQ
  ITAVRKFIEMGFIDEKRIAIWGWSYGGYVSSLALASGTGLFKCGIAVAPVSSWEYYASVY
  TERFMGLPTKDDNLEHYKNSTVMARAEYFRNVDYLLIHGTADDNVHFQNSAQIAKALVNA
  QVDFQAMWYSDQNHGLSGLSTNHLYTHMTHFLKQCFSLSD
• Function: Cell surface glycoprotein serine protease that participates in extracellular matrix degradation and involved in many cellular processes including tissue remodeling, fibrosis, wound healing, inflammation and tumor growth. Both plasma membrane and soluble forms exhibit post-proline cleaving endopeptidase activity, with a marked preference for Ala/Ser-Gly-Pro-Ser/Asn/Ala consensus sequences, on substrate such as alpha-2-antiplasmin SERPINF2 and SPRY2. Degrade also gelatin, heat-denatured type I collagen, but not native collagen type I and IV, vitronectin, tenascin, laminin, fibronectin, fibrin or casein. Also has dipeptidyl peptidase activity, exhibiting the ability to hydrolyze the prolyl bond two residues from the N-terminus of synthetic dipeptide substrates provided that the penultimate residue is proline, with a preference for Ala-Pro, Ile-Pro, Gly-Pro, Arg-Pro and Pro-Pro. Natural neuropeptide hormones for dipeptidyl peptidase are the neuropeptide Y (NPY), peptide YY (PYY), substance P (TAC1) and brain natriuretic peptide 32 (NPPB). The plasma membrane form, in association with either DPP4, PLAUR or integrins, is involved in the pericellular proteolysis of the extracellular matrix (ECM), and hence promotes cell adhesion, migration and invasion through the ECM. Plays a role in tissue remodeling during development and wound healing. Participates in the cell invasiveness towards the ECM in malignant melanoma cancers. Enhances tumor growth progression by increasing angiogenesis, collagen fiber degradation and apoptosis and by reducing antitumor response of the immune system. Promotes glioma cell invasion through the brain parenchyma by degrading the proteoglycan brevican. Acts as a tumor suppressor in melanocytic cells through regulation of cell proliferation and survival in a serine protease activity-independent manner.
• Tissue Specificity: Expressed in adipose tissue. Expressed in the dermal fibroblasts in the fetal skin. Expressed in the granulation tissue of healing wounds and on reactive stromal fibroblast in epithelial cancers. Expressed in activated fibroblast-like synoviocytes from inflamed synovial tissues. Expressed in activated hepatic stellate cells (HSC) and myofibroblasts from cirrhotic liver, but not detected in normal liver. Expressed in glioma cells (at protein level). Expressed in glioblastomas and glioma cells. Isoform 1 and isoform 2 are expressed in melanoma, carcinoma and fibroblast cell lines.

Molecular Interaction Atlas (MIA) of This DOT

3 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 Prolyl endopeptidase FAP (FAP).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Prolyl endopeptidase FAP (FAP).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Prolyl endopeptidase FAP (FAP).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Prolyl endopeptidase FAP (FAP).	[2]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Prolyl endopeptidase FAP (FAP).	[3]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Prolyl endopeptidase FAP (FAP).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Prolyl endopeptidase FAP (FAP).	[6]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [3] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [4] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [5] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [6] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [7] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.