Details of Drug Off-Target (DOT)

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

• DOT Name: NAD(P)H-hydrate epimerase (NAXE)
• Synonyms: EC 5.1.99.6; Apolipoprotein A-I-binding protein; AI-BP; NAD(P)HX epimerase; NAXE; YjeF N-terminal domain-containing protein 1; YjeF_N1
• Gene Name: NAXE
• Related Disease:
  Advanced cancer
  Colorectal carcinoma
  Intestinal neoplasm
  Neoplasm
  Respiratory failure
  Atherosclerosis
  Leigh syndrome
  Movement disorder
  Neurodevelopmental disorder
  Psychotic disorder
• UniProt ID: NNRE_HUMAN
• EC Number: 5.1.99.6
• Pfam ID: PF03853
• Sequence:
  MSRLRALLGLGLLVAGSRVPRIKSQTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYL
  SQEEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNN
  GGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELY
  ELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLIS
  LTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ
• Function: Catalyzes the epimerization of the S- and R-forms of NAD(P)HX, a damaged form of NAD(P)H that is a result of enzymatic or heat-dependent hydration. This is a prerequisite for the S-specific NAD(P)H-hydrate dehydratase to allow the repair of both epimers of NAD(P)HX. Accelerates cholesterol efflux from endothelial cells to high-density lipoprotein (HDL) and thereby regulates angiogenesis.
• Tissue Specificity: Ubiquitously expressed, with highest levels in kidney, heart and liver. Present in cerebrospinal fluid and urine but not in serum from healthy patients. Present in serum of sepsis patients (at protein level).
• Reactome Pathway: Nicotinamide salvaging (R-HSA-197264)
• BioCyc Pathway: MetaCyc:ENSG00000163382-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Intestinal neoplasm	DISK0GUH	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Respiratory failure	DISVMYJO	Strong	Genetic Variation	[2]
Atherosclerosis	DISMN9J3	Limited	Biomarker	[3]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[4]
Movement disorder	DISOJJ2D	Limited	Genetic Variation	[2]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[2]
Psychotic disorder	DIS4UQOT	Limited	Genetic Variation	[2]

9 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 NAD(P)H-hydrate epimerase (NAXE).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NAD(P)H-hydrate epimerase (NAXE).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NAD(P)H-hydrate epimerase (NAXE).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NAD(P)H-hydrate epimerase (NAXE).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NAD(P)H-hydrate epimerase (NAXE).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of NAD(P)H-hydrate epimerase (NAXE).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of NAD(P)H-hydrate epimerase (NAXE).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of NAD(P)H-hydrate epimerase (NAXE).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NAD(P)H-hydrate epimerase (NAXE).	[13]

References

• [1] AIBP and APOA-I synergistically inhibit intestinal tumor growth and metastasis by promoting cholesterol efflux.J Transl Med. 2019 May 17;17(1):161. doi: 10.1186/s12967-019-1910-7.
• [2] Novel NAXE variants as a cause for neurometabolic disorder: implications for treatment.J Neurol. 2020 Mar;267(3):770-782. doi: 10.1007/s00415-019-09640-2. Epub 2019 Nov 20.
• [3] AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate.Science. 2019 Mar 8;363(6431):1085-1088. doi: 10.1126/science.aav1749. Epub 2019 Jan 31.
• [4] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [9] 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.
• [10] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.