Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR9MLLW)

• DOT Name: Carbohydrate-responsive element-binding protein (MLXIPL)
• Synonyms: ChREBP; Class D basic helix-loop-helix protein 14; bHLHd14; MLX interactor; MLX-interacting protein-like; WS basic-helix-loop-helix leucine zipper protein; WS-bHLH; Williams-Beuren syndrome chromosomal region 14 protein
• Gene Name: MLXIPL
• Related Disease:
  Chronic renal failure
  Diabetic kidney disease
  Acute myelogenous leukaemia
  Arteriosclerosis
  Atherosclerosis
  Cardiovascular disease
  Cervical cancer
  Cervical carcinoma
  Coronary atherosclerosis
  Coronary heart disease
  Coronary ischemia
  Cytomegalovirus infection
  Fatty liver disease
  Glycogen storage disease I
  Gout
  Hereditary fructose intolerance
  Hyperglycemia
  Hyperinsulinemia
  Hyperlipidemia
  Hyperlipidemia, familial combined, LPL related
  Hypothyroidism
  Irritable bowel syndrome
  leukaemia
  Leukemia
  Malabsorption syndrome
  Metabolic disorder
  Non-insulin dependent diabetes
  Obesity
  Prostate carcinoma
  Type-1/2 diabetes
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Retinopathy
  Non-alcoholic fatty liver disease
  Breast neoplasm
  Colorectal carcinoma
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Prediabetes syndrome
• UniProt ID: MLXPL_HUMAN
• PDB ID: 6MJL; 6YGJ
• Pfam ID: PF00010
• Sequence:
  MAGALAGLAAGLQVPRVAPSPDSDSDTDSEDPSLRRSAGGLLRSQVIHSGHFMVSSPHSD
  SLPRRRDQEGSVGPSDFGPRSIDPTLTRLFECLSLAYSGKLVSPKWKNFKGLKLLCRDKI
  RLNNAIWRAWYIQYVKRRKSPVCGFVTPLQGPEADAHRKPEAVVLEGNYWKRRIEVVMRE
  YHKWRIYYKKRLRKPSREDDLLAPKQAEGRWPPPEQWCKQLFSSVVPVLLGDPEEEPGGR
  QLLDLNCFLSDISDTLFTMTQSGPSPLQLPPEDAYVGNADMIQPDLTPLQPSLDDFMDIS
  DFFTNSRLPQPPMPSNFPEPPSFSPVVDSLFSSGTLGPEVPPASSAMTHLSGHSRLQARN
  SCPGPLDSSAFLSSDFLLPEDPKPRLPPPPVPPPLLHYPPPAKVPGLEPCPPPPFPPMAP
  PTALLQEEPLFSPRFPFPTVPPAPGVSPLPAPAAFPPTPQSVPSPAPTPFPIELLPLGYS
  EPAFGPCFSMPRGKPPAPSPRGQKASPPTLAPATASPPTTAGSNNPCLTQLLTAAKPEQA
  LEPPLVSSTLLRSPGSPQETVPEFPCTFLPPTPAPTPPRPPPGPATLAPSRPLLVPKAER
  LSPPAPSGSERRLSGDLSSMPGPGTLSVRVSPPQPILSRGRPDSNKTENRRITHISAEQK
  RRFNIKLGFDTLHGLVSTLSAQPSLKVSKATTLQKTAEYILMLQQERAGLQEEAQQLRDE
  IEELNAAINLCQQQLPATGVPITHQRFDQMRDMFDDYVRTRTLHNWKFWVFSILIRPLFE
  SFNGMVSTASVHTLRQTSLAWLDQYCSLPALRPTVLNSLRQLGTSTSILTDPGRIPEQAT
  RAVTEGTLGKPL
• Function: Binds DNA as a heterodimer with MLX/TCFL4 and activates transcription. Binds to the canonical E box sequence 5'-CACGTG-3'. Plays a role in transcriptional activation of glycolytic target genes. Involved in glucose-responsive gene regulation. Regulates transcription in response to changes in cellular carbohydrate abundance such as occurs during fasting to feeding metabolic transition. Refeeding stimulates MLXIPL/ChREBP transcription factor, leading to increased BCKDK to PPM1K expression ratio, phosphorylation and activation of ACLY that ultimately results in the generation of malonyl-CoA and oxaloacetate immediate substrates of de novo lipogenesis and gluconeogenesis, respectively.
• Tissue Specificity: Expressed in liver, heart, kidney, cerebellum and intestinal tissues.
• KEGG Pathway:
  Insulin resistance (hsa04931)
  Non-alcoholic fatty liver disease (hsa04932)
• Reactome Pathway:
  AMPK inhibits chREBP transcriptional activation activity (R-HSA-163680)
  ChREBP activates metabolic gene expression (R-HSA-163765)
  PP2A-mediated dephosphorylation of key metabolic factors (R-HSA-163767)
  PKA-mediated phosphorylation of key metabolic factors (R-HSA-163358)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic renal failure	DISGG7K6	Definitive	Biomarker	[1]
Diabetic kidney disease	DISJMWEY	Definitive	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[5]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[6]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[6]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[7]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[7]
Coronary ischemia	DISDJJ5G	Strong	Genetic Variation	[7]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[8]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[9]
Glycogen storage disease I	DISY4Q9T	Strong	Biomarker	[10]
Gout	DISHC0U7	Strong	Genetic Variation	[11]
Hereditary fructose intolerance	DISWLA0D	Strong	Biomarker	[12]
Hyperglycemia	DIS0BZB5	Strong	Altered Expression	[13]
Hyperinsulinemia	DISIDWT6	Strong	Altered Expression	[14]
Hyperlipidemia	DIS61J3S	Strong	Altered Expression	[15]
Hyperlipidemia, familial combined, LPL related	DISL1CE3	Strong	Genetic Variation	[16]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[17]
Irritable bowel syndrome	DIS27206	Strong	Biomarker	[12]
leukaemia	DISS7D1V	Strong	Biomarker	[3]
Leukemia	DISNAKFL	Strong	Biomarker	[3]
Malabsorption syndrome	DISGMUVS	Strong	Biomarker	[18]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[19]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[20]
Obesity	DIS47Y1K	Strong	Genetic Variation	[21]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[22]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[23]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[24]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Biomarker	[24]
Liver cancer	DISDE4BI	moderate	Biomarker	[24]
Retinopathy	DISB4B0F	moderate	Biomarker	[25]
Non-alcoholic fatty liver disease	DISDG1NL	Disputed	Biomarker	[26]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[27]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[28]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[24]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[27]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[29]
Prediabetes syndrome	DISH2I53	Limited	Altered Expression	[13]

17 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 Carbohydrate-responsive element-binding protein (MLXIPL).	[30]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[31]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[32]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[33]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[34]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[35]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[36]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[37]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[38]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[39]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[42]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[43]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[35]
GW-3965	DMG60ET	Investigative	GW-3965 decreases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[44]
CITCO	DM0N634	Investigative	CITCO increases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[45]
paxilline	DMPF2N1	Investigative	paxilline increases the expression of Carbohydrate-responsive element-binding protein (MLXIPL).	[44]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Carbohydrate-responsive element-binding protein (MLXIPL).	[41]

References

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