Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFX6527)

• DOT Name: Bisphosphoglycerate mutase (BPGM)
• Synonyms: BPGM; EC 5.4.2.4; 2,3-bisphosphoglycerate mutase, erythrocyte; 2,3-bisphosphoglycerate synthase; EC 5.4.2.11; 2,3-diphosphoglycerate mutase; DPGM; BPG-dependent PGAM
• Gene Name: BPGM
• Related Disease: Hemolytic anemia due to diphosphoglycerate mutase deficiency
• UniProt ID: PMGE_HUMAN
• PDB ID: 1T8P; 2A9J; 2F90; 2H4X; 2H4Z; 2H52; 2HHJ; 3NFY; 7N3R; 7N3S; 7THI; 8X2S
• EC Number: 5.4.2.11; 5.4.2.4
• Pfam ID: PF00300
• Sequence:
  MSKYKLIMLRHGEGAWNKENRFCSWVDQKLNSEGMEEARNCGKQLKALNFEFDLVFTSVL
  NRSIHTAWLILEELGQEWVPVESSWRLNERHYGALIGLNREQMALNHGEEQVRLWRRSYN
  VTPPPIEESHPYYQEIYNDRRYKVCDVPLDQLPRSESLKDVLERLLPYWNERIAPEVLRG
  KTILISAHGNSSRALLKHLEGISDEDIINITLPTGVPILLELDENLRAVGPHQFLGDQEA
  IQAAIKKVEDQGKVKQAKK
• Function: Plays a major role in regulating hemoglobin oxygen affinity by controlling the levels of its allosteric effector 2,3-bisphosphoglycerate (2,3-BPG). Also exhibits mutase (EC 5.4.2.11) activity.
• Tissue Specificity: Expressed in red blood cells. Expressed in non-erythroid cells of the placenta; present in the syncytiotrophoblast layer of the placental villi at the feto-maternal interface (at protein level).
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Glycine, serine and threonine metabolism (hsa00260)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Glycolysis (R-HSA-70171)
• BioCyc Pathway: MetaCyc:HS10491-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hemolytic anemia due to diphosphoglycerate mutase deficiency	DISB5VIB	Strong	Autosomal recessive	[1]

12 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 Bisphosphoglycerate mutase (BPGM).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Bisphosphoglycerate mutase (BPGM).	[3]
Marinol	DM70IK5	Approved	Marinol increases the expression of Bisphosphoglycerate mutase (BPGM).	[4]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Bisphosphoglycerate mutase (BPGM).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Bisphosphoglycerate mutase (BPGM).	[6]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Bisphosphoglycerate mutase (BPGM).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Bisphosphoglycerate mutase (BPGM).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Bisphosphoglycerate mutase (BPGM).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Bisphosphoglycerate mutase (BPGM).	[12]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of Bisphosphoglycerate mutase (BPGM).	[13]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of Bisphosphoglycerate mutase (BPGM).	[14]
Alpha-naphthoflavone	DMELOIQ	Investigative	Alpha-naphthoflavone increases the expression of Bisphosphoglycerate mutase (BPGM).	[14]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Bisphosphoglycerate mutase (BPGM).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Bisphosphoglycerate mutase (BPGM).	[11]

References

• [1] Compound heterozygosity in a complete erythrocyte bisphosphoglycerate mutase deficiency. Blood. 1992 Nov 15;80(10):2643-9.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [5] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat Res. 2005 Dec 11;591(1-2):198-211.
• [8] 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.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] 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.
• [11] 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.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol In Vitro. 2018 Feb;46:102-112.
• [14] 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation. Toxicol Sci. 2013 Mar;132(1):235-49.