Details of Drug Off-Target (DOT)

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

• DOT Name: 5-aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2)
• Synonyms: ALAS-E; EC 2.3.1.37; 5-aminolevulinic acid synthase 2; Delta-ALA synthase 2; Delta-aminolevulinate synthase 2
• Gene Name: ALAS2
• Related Disease:
  X-linked erythropoietic protoporphyria
  X-linked sideroblastic anemia 1
• UniProt ID: HEM0_HUMAN
• PDB ID: 5QQQ; 5QQR; 5QQS; 5QQT; 5QQU; 5QQV; 5QQW; 5QQX; 5QQY; 5QQZ; 5QR0; 5QR1; 5QR2; 5QR3; 5QR4; 5QR5; 5QR6; 5QR7; 5QR8; 5QR9; 5QRA; 5QRB; 5QRC; 5QRD; 5QRE; 5QT3; 6HRH
• EC Number: 2.3.1.37
• Pfam ID: PF00155 ; PF09029
• Sequence:
  MVTAAMLLQCCPVLARGPTSLLGKVVKTHQFLFGIGRCPILATQGPNCSQIHLKATKAGG
  DSPSWAKGHCPFMLSELQDGKSKIVQKAAPEVQEDVKAFKTDLPSSLVSVSLRKPFSGPQ
  EQEQISGKVTHLIQNNMPGNYVFSYDQFFRDKIMEKKQDHTYRVFKTVNRWADAYPFAQH
  FSEASVASKDVSVWCSNDYLGMSRHPQVLQATQETLQRHGAGAGGTRNISGTSKFHVELE
  QELAELHQKDSALLFSSCFVANDSTLFTLAKILPGCEIYSDAGNHASMIQGIRNSGAAKF
  VFRHNDPDHLKKLLEKSNPKIPKIVAFETVHSMDGAICPLEELCDVSHQYGALTFVDEVH
  AVGLYGSRGAGIGERDGIMHKIDIISGTLGKAFGCVGGYIASTRDLVDMVRSYAAGFIFT
  TSLPPMVLSGALESVRLLKGEEGQALRRAHQRNVKHMRQLLMDRGLPVIPCPSHIIPIRV
  GNAALNSKLCDLLLSKHGIYVQAINYPTVPRGEELLRLAPSPHHSPQMMEDFVEKLLLAW
  TAVGLPLQDVSVAACNFCRRPVHFELMSEWERSYFGNMGPQYVTTYA
• Function: Catalyzes the pyridoxal 5'-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products. Contributes significantly to heme formation during erythropoiesis ; [Isoform 3]: Catalyzes the pyridoxal 5'-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products. Catalytic activity is 75-85% of isoform 1 activity ; [Isoform 4]: Catalyzes the pyridoxal 5'-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products. Catalytic activity is 65-75% of isoform 1 activity.
• Tissue Specificity: .Erythroid-specific.; [Isoform 2]: Erythroid-specific.; [Isoform 3]: Erythroid-specific.; [Isoform 4]: Erythroid-specific.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Porphyrin metabolism (hsa00860)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Heme biosynthesis (R-HSA-189451)
• BioCyc Pathway: MetaCyc:HS08311-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked erythropoietic protoporphyria	DIS9LXSQ	Definitive	X-linked	[1]
X-linked sideroblastic anemia 1	DISWBQC7	Strong	X-linked	[2]

3 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 5-aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of 5-aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 5-aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of 5-aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of 5-aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2).	[5]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of 5-aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2).	[6]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of 5-aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2).	[5]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of 5-aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2).	[9]
Protoporphyrin IX	DMWYE7A	Investigative	Protoporphyrin IX increases the expression of 5-aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2).	[10]
Catechol	DML0YEK	Investigative	Catechol increases the expression of 5-aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2).	[11]

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 Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] 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.
• [4] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [5] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [6] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [7] 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.
• [8] 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.
• [9] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [10] Changes in DNA methylation of erythroid-specific genes in K562 cells exposed to phenol and hydroquinone. Toxicology. 2013 Oct 4;312:108-14. doi: 10.1016/j.tox.2013.08.007. Epub 2013 Aug 20.
• [11] The role of DNA methylation in catechol-enhanced erythroid differentiation of K562 cells. Toxicol Appl Pharmacol. 2012 Nov 15;265(1):43-50. doi: 10.1016/j.taap.2012.09.018. Epub 2012 Sep 27.