Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6ORKTD)

• DOT Name: Phosphatidylinositol-3-phosphatase SAC1 (SACM1L)
• Synonyms: EC 3.1.3.64; Phosphatidylinositol-4-phosphate phosphatase; Suppressor of actin mutations 1-like protein
• Gene Name: SACM1L
• Related Disease:
  Brain infarction
  Carotid stenosis
  Stroke
  Acute lymphocytic leukaemia
  Adult T-cell leukemia/lymphoma
  Breast cancer
  Hyperthyroxinemia, familial dysalbuminemic
  leukaemia
  Leukemia
  Maturity-onset diabetes of the young
  Non-insulin dependent diabetes
  Parkinsonian disorder
  T-cell leukaemia
  Type-1/2 diabetes
  Von Willebrand disease 3
  Coronary heart disease
  Factor IX deficiency
  High blood pressure
  Nephropathy
  Rheumatoid arthritis
• UniProt ID: SAC1_HUMAN
• EC Number: 3.1.3.64
• Pfam ID: PF02383
• Sequence:
  MATAAYEQLKLHITPEKFYVEACDDGADDVLTIDRVSTEVTLAVKKDVPPSAVTRPIFGI
  LGTIHLVAGNYLIVITKKIKVGEFFSHVVWKATDFDVLSYKKTMLHLTDIQLQDNKTFLA
  MLNHVLNVDGFYFSTTYDLTHTLQRLSNTSPEFQEMSLLERADQRFVWNGHLLRELSAQP
  EVHRFALPVLHGFITMHSCSINGKYFDWILISRRSCFRAGVRYYVRGIDSEGHAANFVET
  EQIVHYNGSKASFVQTRGSIPVFWSQRPNLKYKPLPQISKVANHMDGFQRHFDSQVIIYG
  KQVIINLINQKGSEKPLEQTFATMVSSLGSGMMRYIAFDFHKECKNMRWDRLSILLDQVA
  EMQDELSYFLVDSAGQVVANQEGVFRSNCMDCLDRTNVIQSLLARRSLQAQLQRLGVLHV
  GQKLEEQDEFEKIYKNAWADNANACAKQYAGTGALKTDFTRTGKRTHLGLIMDGWNSMIR
  YYKNNFSDGFRQDSIDLFLGNYSVDELESHSPLSVPRDWKFLALPIIMVVAFSMCIICLL
  MAGDTWTETLAYVLFWGVASIGTFFIILYNGKDFVDAPRLVQKEKID
• Function: Phosphoinositide phosphatase which catalyzes the hydrolysis of phosphatidylinositol 4-phosphate (PtdIns(4)P). Can also catalyze the hydrolysis of phosphatidylinositol 3-phosphate (PtdIns(3)P) and has low activity towards phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2). Shows a very robust PtdIns(4)P phosphatase activity when it binds PtdIns(4)P in a 'cis' configuration in the cellular environment, with much less activity seen when it binds PtdIns(4)P in 'trans' configuration. PtdIns(4)P phosphatase activity (when it binds PtdIns(4)P in 'trans' configuration) is enhanced in the presence of PLEKHA3.
• Tissue Specificity: Detected in heart, brain, lung, liver, kidney, pancreas and testis.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
• Reactome Pathway:
  Synthesis of PIPs at the Golgi membrane (R-HSA-1660514)
  Synthesis of PIPs at the ER membrane (R-HSA-1483248)
• BioCyc Pathway: MetaCyc:HS11932-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Brain infarction	DISPPGYK	Definitive	Genetic Variation	[1]
Carotid stenosis	DISZA8D0	Definitive	Genetic Variation	[1]
Stroke	DISX6UHX	Definitive	Genetic Variation	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[2]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Hyperthyroxinemia, familial dysalbuminemic	DIS0BPAW	Strong	Genetic Variation	[5]
leukaemia	DISS7D1V	Strong	Biomarker	[2]
Leukemia	DISNAKFL	Strong	Biomarker	[2]
Maturity-onset diabetes of the young	DISG75M5	Strong	Biomarker	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[6]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[7]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[3]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[6]
Von Willebrand disease 3	DISPVXSD	Strong	Genetic Variation	[8]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[9]
Factor IX deficiency	DISHN9SC	moderate	Biomarker	[10]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[9]
Nephropathy	DISXWP4P	Disputed	Genetic Variation	[11]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[12]

1 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 Phosphatidylinositol-3-phosphatase SAC1 (SACM1L).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phosphatidylinositol-3-phosphatase SAC1 (SACM1L).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphatidylinositol-3-phosphatase SAC1 (SACM1L).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Phosphatidylinositol-3-phosphatase SAC1 (SACM1L).	[16]

References

• [1] Gene polymorphism of apolipoprotein AI, the major protein of high density lipoprotein in predicting stroke risk among white and black subjects.Stroke. 1993 Dec;24(12 Suppl):I26-30; discussion I31-2.
• [2] Persistent detection of a novel MLL-SACM1L rearrangement in the absence of leukemia.Leuk Res. 2010 Oct;34(10):1398-401. doi: 10.1016/j.leukres.2010.05.001.
• [3] DNA blotting analysis of human retroviruses in cerebrospinal fluid of spastic paraparesis patients: the viruses are identical to human T-cell leukemia virus type-1 (HTLV-1).Int J Cancer. 1988 Aug 15;42(2):221-4. doi: 10.1002/ijc.2910420213.
• [4] Regulation of CD44 expression and focal adhesion by Golgi phosphatidylinositol 4-phosphate in breast cancer.Cancer Sci. 2016 Jul;107(7):981-90. doi: 10.1111/cas.12968. Epub 2016 Jun 24.
• [5] Familial dysalbuminemic hyperthyroxinemia: a rare example of albumin polymorphism and its rapid molecular diagnosis.J Pediatr Endocrinol Metab. 2002 Jun;15(6):801-7. doi: 10.1515/jpem.2002.15.6.801.
• [6] Molecular and clinical characterization of an insertional polymorphism of the insulin-receptor gene.Diabetes. 1989 Jun;38(6):737-43. doi: 10.2337/diab.38.6.737.
• [7] Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline. Brain. 2016 Sep;139(Pt 9):2420-30. doi: 10.1093/brain/aww180. Epub 2016 Jul 19.
• [8] The inheritance of type I and type III von Willebrand's disease in Israel: linkage analysis, carrier detection and prenatal diagnosis using three intragenic restriction fragment length polymorphisms.Blood Coagul Fibrinolysis. 1992 Apr;3(2):167-77.
• [9] Genetic studies on the APOA1-C3-A5 gene cluster in Asian Indians with premature coronary artery disease.Lipids Health Dis. 2008 Sep 19;7:33. doi: 10.1186/1476-511X-7-33.
• [10] Diagnosis of hemophilia B carriers using two novel dinucleotide polymorphisms and Hha I RFLP of the factor IX gene in Japanese subjects.Thromb Haemost. 1995 Oct;74(4):1009-14.
• [11] Immunoglobulin heavy chain switch region restriction fragment length polymorphisms are associated with renal disease.Clin Exp Immunol. 1986 Nov;66(2):406-13.
• [12] DNA polymorphism of immunoglobulin kappa confers risk of rheumatoid arthritis.Arthritis Rheum. 1989 May;32(5):634-7. doi: 10.1002/anr.1780320518.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.