Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8HA13U)

• DOT Name: Fatty acid 2-hydroxylase (FA2H)
• Synonyms: EC 1.14.18.-; Fatty acid alpha-hydroxylase; Fatty acid hydroxylase domain-containing protein 1
• Gene Name: FA2H
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Hereditary spastic paraplegia 35
  Adenocarcinoma
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Atopic dermatitis
  Autism
  Breast cancer
  Gastric neoplasm
  Hepatocellular carcinoma
  Hereditary spastic paraplegia
  Kufor-Rakeb syndrome
  Leukodystrophy
  Lung adenocarcinoma
  Movement disorder
  Neoplasm
  Neuroendocrine cancer
  Neuroferritinopathy
  Triple negative breast cancer
  Vascular purpura
  Dystonia
  Gastric cancer
  Hereditary motor and sensory neuropathy
  Neurodegeneration with brain iron accumulation
  Neurodegeneration with brain iron accumulation 2A
  Parkinson disease
  Stomach cancer
• UniProt ID: FA2H_HUMAN
• EC Number: 1.14.18.-
• Pfam ID: PF00173 ; PF04116
• Sequence:
  MAPAPPPAASFSPSEVQRRLAAGACWVRRGARLYDLSSFVRHHPGGEQLLRARAGQDISA
  DLDGPPHRHSANARRWLEQYYVGELRGEQQGSMENEPVALEETQKTDPAMEPRFKVVDWD
  KDLVDWRKPLLWQVGHLGEKYDEWVHQPVTRPIRLFHSDLIEGLSKTVWYSVPIIWVPLV
  LYLSWSYYRTFAQGNVRLFTSFTTEYTVAVPKSMFPGLFMLGTFLWSLIEYLIHRFLFHM
  KPPSDSYYLIMLHFVMHGQHHKAPFDGSRLVFPPVPASLVIGVFYLCMQLILPEAVGGTV
  FAGGLLGYVLYDMTHYYLHFGSPHKGSYLYSLKAHHVKHHFAHQKSGFGISTKLWDYCFH
  TLTPEKPHLKTQ
• Function: Catalyzes the hydroxylation of free fatty acids at the C-2 position to produce 2-hydroxy fatty acids, which are building blocks of sphingolipids and glycosphingolipids common in neural tissue and epidermis. FA2H is stereospecific for the production of (R)-2-hydroxy fatty acids. Plays an essential role in the synthesis of galactosphingolipids of the myelin sheath. Responsible for the synthesis of sphingolipids and glycosphingolipids involved in the formation of epidermal lamellar bodies critical for skin permeability barrier. Participates in the synthesis of glycosphingolipids and a fraction of type II wax diesters in sebaceous gland, specifically regulating hair follicle homeostasis. Involved in the synthesis of sphingolipids of plasma membrane rafts, controlling lipid raft mobility and trafficking of raft-associated proteins.
• Tissue Specificity: Detected in differentiating cultured keratinocytes (at protein level). Detected in epidermis and cultured keratinocytes . Highly expressed in brain and colon. Detected at lower levels in testis, prostate, pancreas and kidney .
• Reactome Pathway: Sphingolipid de novo biosynthesis (R-HSA-1660661)
• BioCyc Pathway: MetaCyc:ENSG00000103089-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Hereditary spastic paraplegia 35	DISCCQZY	Definitive	Autosomal recessive	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[6]
Autism	DISV4V1Z	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Hereditary spastic paraplegia	DISGZQV1	Strong	Biomarker	[10]
Kufor-Rakeb syndrome	DIS09C7Z	Strong	Genetic Variation	[11]
Leukodystrophy	DISVY1TT	Strong	Biomarker	[12]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[3]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[13]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Neuroendocrine cancer	DISVGJET	Strong	Altered Expression	[3]
Neuroferritinopathy	DIS0E4F3	Strong	Genetic Variation	[14]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[4]
Vascular purpura	DIS6ZZMF	Strong	Biomarker	[10]
Dystonia	DISJLFGW	Limited	Genetic Variation	[12]
Gastric cancer	DISXGOUK	Limited	Biomarker	[8]
Hereditary motor and sensory neuropathy	DISR0X2K	Limited	Genetic Variation	[15]
Neurodegeneration with brain iron accumulation	DISRK4DZ	Limited	Genetic Variation	[12]
Neurodegeneration with brain iron accumulation 2A	DIS9XEBF	Limited	Genetic Variation	[16]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[15]
Stomach cancer	DISKIJSX	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Fatty acid 2-hydroxylase (FA2H).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Fatty acid 2-hydroxylase (FA2H).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Fatty acid 2-hydroxylase (FA2H).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Fatty acid 2-hydroxylase (FA2H).	[20]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Fatty acid 2-hydroxylase (FA2H).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Fatty acid 2-hydroxylase (FA2H).	[22]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Fatty acid 2-hydroxylase (FA2H).	[23]
Marinol	DM70IK5	Approved	Marinol increases the expression of Fatty acid 2-hydroxylase (FA2H).	[24]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Fatty acid 2-hydroxylase (FA2H).	[25]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Fatty acid 2-hydroxylase (FA2H).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Fatty acid 2-hydroxylase (FA2H).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Fatty acid 2-hydroxylase (FA2H).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Fatty acid 2-hydroxylase (FA2H).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Fatty acid 2-hydroxylase (FA2H).	[29]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Fatty acid 2-hydroxylase (FA2H).	[30]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Fatty acid 2-hydroxylase (FA2H).	[31]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Fatty acid 2-hydroxylase (FA2H).	[24]
nTzDpa	DMTHB2Y	Investigative	nTzDpa increases the expression of Fatty acid 2-hydroxylase (FA2H).	[24]

References

• [1] Inhibitions of anandamide transport and FAAH synthesis decrease apoptosis and oxidative stress through inhibition of TRPV1channel in an in vitro seizure model.Mol Cell Biochem. 2019 Mar;453(1-2):143-155. doi: 10.1007/s11010-018-3439-0. Epub 2018 Aug 29.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] High FA2H and UGT8 transcript levels predict hydroxylated hexosylceramide accumulation in lung adenocarcinoma.J Lipid Res. 2019 Oct;60(10):1776-1786. doi: 10.1194/jlr.M093955. Epub 2019 Aug 13.
• [4] FA2H Exhibits Tumor Suppressive Roles on Breast Cancers via Cancer Stemness Control.Front Oncol. 2019 Oct 24;9:1089. doi: 10.3389/fonc.2019.01089. eCollection 2019.
• [5] The role of the LncRNA-FA2H-2-MLKL pathway in atherosclerosis by regulation of autophagy flux and inflammation through mTOR-dependent signaling.Cell Death Differ. 2019 Sep;26(9):1670-1687. doi: 10.1038/s41418-018-0235-z. Epub 2019 Jan 25.
• [6] Early-onset pediatric atopic dermatitis is characterized by T(H)2/T(H)17/T(H)22-centered inflammation and lipid alterations.J Allergy Clin Immunol. 2018 Jun;141(6):2094-2106. doi: 10.1016/j.jaci.2018.02.040. Epub 2018 May 3.
• [7] Heterozygous FA2H mutations in autism spectrum disorders. BMC Med Genet. 2013 Dec 3;14:124. doi: 10.1186/1471-2350-14-124.
• [8] Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer.EBioMedicine. 2019 Mar;41:256-267. doi: 10.1016/j.ebiom.2019.01.066. Epub 2019 Feb 7.
• [9] Elevated Expression of A-Raf and FA2H in Hepatocellular Carcinoma is Associated with Lipid Metabolism Dysregulation and Cancer Progression.Anticancer Agents Med Chem. 2019;19(2):236-247. doi: 10.2174/1871520618666181015142810.
• [10] Autosomal recessive hereditary spastic paraplegia type SPG35 due to a novel variant in the FA2H gene in a Czech patient.J Clin Neurosci. 2019 Jan;59:337-339. doi: 10.1016/j.jocn.2018.10.094. Epub 2018 Nov 13.
• [11] PLA2G6 mutations and other rare causes of neurodegeneration with brain iron accumulation.Curr Drug Targets. 2012 Aug;13(9):1204-6. doi: 10.2174/138945012802002401.
• [12] FAHN/SPG35: a narrow phenotypic spectrum across disease classifications.Brain. 2019 Jun 1;142(6):1561-1572. doi: 10.1093/brain/awz102.
• [13] The Interaction of Genetic Mutations in PARK2 and FA2H Causes a Novel Phenotype in a Case of Childhood-Onset Movement Disorder.Front Neurol. 2019 May 29;10:555. doi: 10.3389/fneur.2019.00555. eCollection 2019.
• [14] Iron dysregulation in movement disorders.Neurobiol Dis. 2012 Apr;46(1):1-18. doi: 10.1016/j.nbd.2011.12.054. Epub 2012 Jan 12.
• [15] Genetic and phenotypic characterization of complex hereditary spastic paraplegia.Brain. 2016 Jul;139(Pt 7):1904-18. doi: 10.1093/brain/aww111. Epub 2016 May 23.
• [16] Excess iron harms the brain: the syndromes of neurodegeneration with brain iron accumulation (NBIA).J Neural Transm (Vienna). 2013 Apr;120(4):695-703. doi: 10.1007/s00702-012-0922-8. Epub 2012 Dec 2.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [19] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [22] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [23] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [24] Induction of the fatty acid 2-hydroxylase (FA2H) gene by (9)-tetrahydrocannabinol in human breast cancer cells. J Toxicol Sci. 2013;38(2):305-8. doi: 10.2131/jts.38.305.
• [25] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [26] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [27] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [28] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [30] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [31] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.