Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT25Z6XH)

• DOT Name: Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1)
• Synonyms: P5C dehydrogenase; EC 1.2.1.88; Aldehyde dehydrogenase family 4 member A1; L-glutamate gamma-semialdehyde dehydrogenase
• Gene Name: ALDH4A1
• Related Disease:
  Hyperprolinemia type 2
  Intellectual disability
  Non-alcoholic fatty liver disease
  Non-alcoholic steatohepatitis
  Hyperprolinemia
  Precancerous condition
• UniProt ID: AL4A1_HUMAN
• PDB ID: 3V9G; 3V9H; 3V9I; 4OE5
• EC Number: 1.2.1.88
• Pfam ID: PF00171
• Sequence:
  MLLPAPALRRALLSRPWTGAGLRWKHTSSLKVANEPVLAFTQGSPERDALQKALKDLKGR
  MEAIPCVVGDEEVWTSDVQYQVSPFNHGHKVAKFCYADKSLLNKAIEAALAARKEWDLKP
  IADRAQIFLKAADMLSGPRRAEILAKTMVGQGKTVIQAEIDAAAELIDFFRFNAKYAVEL
  EGQQPISVPPSTNSTVYRGLEGFVAAISPFNFTAIGGNLAGAPALMGNVVLWKPSDTAML
  ASYAVYRILREAGLPPNIIQFVPADGPLFGDTVTSSEHLCGINFTGSVPTFKHLWKQVAQ
  NLDRFHTFPRLAGECGGKNFHFVHRSADVESVVSGTLRSAFEYGGQKCSACSRLYVPHSL
  WPQIKGRLLEEHSRIKVGDPAEDFGTFFSAVIDAKSFARIKKWLEHARSSPSLTILAGGK
  CDDSVGYFVEPCIVESKDPQEPIMKEEIFGPVLSVYVYPDDKYKETLQLVDSTTSYGLTG
  AVFSQDKDVVQEATKVLRNAAGNFYINDKSTGSIVGQQPFGGARASGTNDKPGGPHYILR
  WTSPQVIKETHKPLGDWSYAYMQ
• Function: Irreversible conversion of delta-1-pyrroline-5-carboxylate (P5C), derived either from proline or ornithine, to glutamate. This is a necessary step in the pathway interconnecting the urea and tricarboxylic acid cycles. The preferred substrate is glutamic gamma-semialdehyde, other substrates include succinic, glutaric and adipic semialdehydes.
• Tissue Specificity: Highest expression is found in liver followed by skeletal muscle, kidney, heart, brain, placenta, lung and pancreas.
• KEGG Pathway:
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Proline catabolism (R-HSA-70688)
  Glyoxylate metabolism and glycine degradation (R-HSA-389661)
• BioCyc Pathway: MetaCyc:HS14757-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperprolinemia type 2	DISSEJ2T	Definitive	Autosomal recessive	[1]
Intellectual disability	DISMBNXP	Strong	Biomarker	[2]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[3]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[3]
Hyperprolinemia	DISV2Y24	moderate	Genetic Variation	[4]
Precancerous condition	DISV06FL	Limited	Biomarker	[5]

20 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 Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[17]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[17]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[18]
Selenium	DM25CGV	Approved	Selenium increases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[19]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[20]
Beta-carotene	DM0RXBT	Approved	Beta-carotene decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[25]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[24]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hesperetin	DMKER83	Approved	Hesperetin affects the binding of Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial (ALDH4A1).	[22]

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