Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7FR69A)

• DOT Name: Fructose-bisphosphate aldolase B (ALDOB)
• Synonyms: EC 4.1.2.13; Liver-type aldolase
• Gene Name: ALDOB
• Related Disease:
  Hereditary fructose intolerance
  Hyperglycemia
  Obesity
  Carbohydrate metabolism disease
  Colorectal carcinoma
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Liver and intrahepatic bile duct neoplasm
  Liver cirrhosis
  Mismatch repair cancer syndrome
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Ulcerative colitis
  Clear cell renal carcinoma
  Neoplasm
  Renal cell carcinoma
  Cataract
  Complex neurodevelopmental disorder
  Rectal carcinoma
• UniProt ID: ALDOB_HUMAN
• PDB ID: 1QO5; 1XDL; 1XDM; 8D44
• EC Number: 4.1.2.13
• Pfam ID: PF00274
• Sequence:
  MAHRFPALTQEQKKELSEIAQSIVANGKGILAADESVGTMGNRLQRIKVENTEENRRQFR
  EILFSVDSSINQSIGGVILFHETLYQKDSQGKLFRNILKEKGIVVGIKLDQGGAPLAGTN
  KETTIQGLDGLSERCAQYKKDGVDFGKWRAVLRIADQCPSSLAIQENANALARYASICQQ
  NGLVPIVEPEVIPDGDHDLEHCQYVTEKVLAAVYKALNDHHVYLEGTLLKPNMVTAGHAC
  TKKYTPEQVAMATVTALHRTVPAAVPGICFLSGGMSEEDATLNLNAINLCPLPKPWKLSF
  SYGRALQASALAAWGGKAANKEATQEAFMKRAMANCQAAKGQYVHTGSSGAASTQSLFTA
  CYTY
• Function: Catalyzes the aldol cleavage of fructose 1,6-biphosphate to form two triosephosphates dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in glycolysis as well as the reverse stereospecific aldol addition reaction in gluconeogenesis. In fructolysis, metabolizes fructose 1-phosphate derived from the phosphorylation of dietary fructose by fructokinase into dihydroxyacetone phosphate and D-glyceraldehyde. Acts as an adapter independently of its enzymatic activity, exerts a tumor suppressor role by stabilizing the ternary complex with G6PD and TP53 to inhibit G6PD activity and keep oxidative pentose phosphate metabolism in check.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Pentose phosphate pathway (hsa00030)
  Fructose and mannose metabolism (hsa00051)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Biosynthesis of amino acids (hsa01230)
  HIF-1 sig.ling pathway (hsa04066)
• Reactome Pathway:
  Glycolysis (R-HSA-70171)
  Gluconeogenesis (R-HSA-70263)
  Fructose catabolism (R-HSA-70350)
  Hereditary fructose intolerance (R-HSA-5657560)
• BioCyc Pathway: MetaCyc:HS06234-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
Hereditary fructose intolerance	DISWLA0D	Definitive	Autosomal recessive	[1]
Hyperglycemia	DIS0BZB5	Definitive	Altered Expression	[2]
Obesity	DIS47Y1K	Definitive	Biomarker	[2]
Carbohydrate metabolism disease	DISWRYYA	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[5]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[5]
Liver and intrahepatic bile duct neoplasm	DISRQ76N	Strong	Biomarker	[6]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[7]
Mismatch repair cancer syndrome	DISIXHJ2	Strong	Altered Expression	[8]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[7]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[9]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[10]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[11]
Neoplasm	DISZKGEW	moderate	Biomarker	[11]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[11]
Cataract	DISUD7SL	Limited	Genetic Variation	[12]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal recessive	[13]
Rectal carcinoma	DIS8FRR7	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[18]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[16]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[19]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[20]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[20]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[21]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[22]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[24]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Fructose-bisphosphate aldolase B (ALDOB).	[26]

References

• [1] 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.
• [2] The Expression of Aldolase B in Islets Is Negatively Associated With Insulin Secretion in Humans.J Clin Endocrinol Metab. 2018 Dec 1;103(12):4373-4383. doi: 10.1210/jc.2018-00791.
• [3] Six novel alleles identified in Italian hereditary fructose intolerance patients enlarge the mutation spectrum of the aldolase B gene.Hum Mutat. 2004 Dec;24(6):534. doi: 10.1002/humu.9290.
• [4] Dynamic bioenergetic alterations in colorectal adenomatous polyps and adenocarcinomas.EBioMedicine. 2019 Jun;44:334-345. doi: 10.1016/j.ebiom.2019.05.031. Epub 2019 May 20.
• [5] Two-dimensional differential in-gel electrophoresis for identification of gastric cancer-specific protein markers.Oncol Rep. 2009 Jun;21(6):1429-37. doi: 10.3892/or_00000371.
• [6] Effect of Plumbagin on some glucose metabolising enzymes studied in rats in experimental hepatoma.Mol Cell Biochem. 1993 Aug 11;125(1):59-63. doi: 10.1007/BF00926835.
• [7] Plasma proteome profiling discovers novel proteins associated with non-alcoholic fatty liver disease.Mol Syst Biol. 2019 Mar 1;15(3):e8793. doi: 10.15252/msb.20188793.
• [8] Aldolase B impairs DNA mismatch repair and induces apoptosis in colon adenocarcinoma.Pathol Res Pract. 2019 Nov;215(11):152597. doi: 10.1016/j.prp.2019.152597. Epub 2019 Aug 16.
• [9] The heme oxygenase system abates hyperglycemia in Zucker diabetic fatty rats by potentiating insulin-sensitizing pathways.Endocrinology. 2009 May;150(5):2098-108. doi: 10.1210/en.2008-0239. Epub 2008 Dec 23.
• [10] Five mucosal transcripts of interest in ulcerative colitis identified by quantitative real-time PCR: a prospective study.BMC Gastroenterol. 2008 Aug 12;8:34. doi: 10.1186/1471-230X-8-34.
• [11] Clinical Relevance of Gene Copy Number Variation in Metastatic Clear Cell Renal Cell Carcinoma.Clin Genitourin Cancer. 2018 Aug;16(4):e795-e805. doi: 10.1016/j.clgc.2018.02.013. Epub 2018 Feb 23.
• [12] Electronic medical records and genomics (eMERGE) network exploration in cataract: several new potential susceptibility loci.Mol Vis. 2014 Sep 19;20:1281-95. eCollection 2014.
• [13] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [14] High Expression of Aldolase B Confers a Poor Prognosis for Rectal Cancer Patients Receiving Neoadjuvant Chemoradiotherapy.J Cancer. 2017 Apr 9;8(7):1197-1204. doi: 10.7150/jca.18197. eCollection 2017.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [20] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [21] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [22] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [23] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [24] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [25] 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.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.