Molecule Information

General Information of the Molecule (ID: Mol04027)

• Name: Dihydrofolate reductase (DHFR) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: DHFR
• Gene ID: 1719
• Location: chr5:80626226-80654983[-]
• Sequence:
  MVGSLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFS
  IPEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSS
  VYKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKF
  EVYEKND
• 3D-structure: PDB ID: 7ESE; Classification: Oxidoreductase; Method: X-ray diffraction; Resolution: 1.85 Å
• Function: Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFR2. .
• Uniprot ID: DYR_HUMAN
• Ensembl ID: ENSG00000228716
• HGNC ID: HGNC:2861

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

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Cytarabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Acute promyelocytic leukemia [ICD-11: 2A60.2] [1]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Cytarabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: THP1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Acute promyelocytic leukemia [ICD-11: 2A60.2] [1]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: THP1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate.

References

• Ref 1: Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy. Comput Struct Biotechnol J. 2021 Jul 8;19:4059-4066.