Molecule Information

General Information of the Molecule (ID: Mol03004)

• Name: Aldo-keto reductase family 1 member B (AKR1B1) ,Homo sapiens
• Synonyms: AKR1B1; ALDR1; ALR2
• Molecule Type: Protein
• Gene Name: AKR1B1
• Gene ID: 231
• Location: chr7:134,442,356-134,459,284[-]
• Sequence:
  MASRLLLNNGAKMPILGLGTWKSPPGQVTEAVKVAIDVGYRHIDCAHVYQNENEVGVAIQ
  EKLREQVVKREELFIVSKLWCTYHEKGLVKGACQKTLSDLKLDYLDLYLIHWPTGFKPGK
  EFFPLDESGNVVPSDTNILDTWAAMEELVDEGLVKAIGISNFNHLQVEMILNKPGLKYKP
  AVNQIECHPYLTQEKLIQYCQSKGIVVTAYSPLGSPDRPWAKPEDPSLLEDPRIKAIAAK
  HNKTTAQVLIRFPMQRNLVVIPKSVTPERIAENFKVFDFELSSQDMTTLLSYNRNWRVCA
  LLSCTSHKDYPFHEEF
• 3D-structure: PDB ID: 3S3G; Classification: Oxidoreductase; Method: X-ray diffraction; Resolution: 1.80 Å
• Function: Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols. Displays enzymatic activity towards endogenous metabolites such as aromatic and aliphatic aldehydes, ketones, monosacharides, bile acids and xenobiotics substrates. Key enzyme in the polyol pathway, catalyzes reduction of glucose to sorbitol during hyperglycemia. Reduces steroids and their derivatives and prostaglandins. Displays low enzymatic activity toward all-trans-retinal, 9-cis-retinal, and 13-cis-retinal. Catalyzes the reduction of diverse phospholipid aldehydes such as 1-palmitoyl-2-(5-oxovaleroyl)-sn -glycero-3-phosphoethanolamin (POVPC) and related phospholipid aldehydes that are generated from the oxydation of phosphotidylcholine and phosphatdyleethanolamides. Plays a role in detoxifying dietary and lipid-derived unsaturated carbonyls, such as crotonaldehyde, 4-hydroxynonenal, trans-2-hexenal, trans-2,4-hexadienal and their glutathione-conjugates carbonyls (GS-carbonyls).
• Uniprot ID: ALDR_HUMAN
• Ensembl ID: ENSG00000085662
• HGNC ID: HGNC:381

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Epalrestat

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Non-small cell lung cancer [ICD-11: 2C25.Y] [1]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Epalrestat
• Molecule Alteration: Function; Inhibition
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Mycobacterium tuberculosis strain; 1773
• In Vitro Model: Escherichia coli strain; 562
• In Vivo Model: Xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Coimmunoprecipitation assay; Immunofluorescence staining assay; High-content imaging analysis; Luciferase reporter assay
• Experiment for Drug Resistance: CCK-8 assay; Colony formation assay
• Mechanism Description: Up-regulation of AKR1B1 led to enhanced glutathione synthesis and resistance to EGFR inhibitors in cell lines and xenograft mouse models. In addition, the antidiabetic drug epalrestat inhibited AKR1B1 and restored sensitivity to EGFR TKIs in patient-derived xenograft tumors.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.33E-06; Fold-change: -1.87E-01; Z-score: -4.93E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.87E-03; Fold-change: -1.12E-01; Z-score: -2.68E-01

References

• Ref 1: Targeting AKR1B1 inhibits glutathione de novo synthesis to overcome acquired resistance to EGFR-targeted therapy in lung cancer .Sci Transl Med. 2021 Oct 6;13(614):eabg6428. doi: 10.1126/scitranslmed.abg6428. Epub 2021 Oct 6. 10.1126/scitranslmed.abg6428