Molecule Information

General Information of the Molecule (ID: Mol00335)

• Name: Dihydrofolate reductase (DHFR) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: DHFR
• Gene ID: 1719
• Location: chr5:80626226-80654983[-]
• Sequence:
  MVGSLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFS
  IPEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSS
  VYKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKF
  EVYEKND
• 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

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Co-trimoxazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Pneumocystis jirovecii infection [1]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Co-trimoxazole
• Molecule Alteration: Missense mutation; p.S37T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Methotrexate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Osteosarcoma [2]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Resistant Drug: Methotrexate
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Disease Class: Colon cancer [2]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Resistant Drug: Methotrexate
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Pentamidine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Pneumocystis jirovecii infection [1]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Pentamidine
• Molecule Alteration: Missense mutation; p.D153V
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Pyrimethamine/Sulfadoxine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Pneumocystis jirovecii infection [1]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Molecule Alteration: Missense mutation; p.I158V+p.V79I
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Disease Class: Pneumocystis jirovecii infection [1]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Molecule Alteration: Missense mutation; p.Y197L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Disease Class: Pneumocystis jirovecii infection [1]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Molecule Alteration: Missense mutation; p.T14A+p.P26Q
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Disease Class: Pneumocystis jirovecii infection [1]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Molecule Alteration: Missense mutation; p.M52I+p.E63G+p.T144A+p.K171E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Disease Class: Pneumocystis jirovecii infection [1]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Molecule Alteration: Missense mutation; p.S106P+p.E127G+p.R170G
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Raltitrexed

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Osteosarcoma [2]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Resistant Drug: Raltitrexed
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Disease Class: Colon cancer [2]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Resistant Drug: Raltitrexed
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

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

Pyrimethamine/Atovaquone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Pneumocystis jirovecii infection [1]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Pyrimethamine/Atovaquone
• Molecule Alteration: Missense mutation; p.S37T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Colon cancer [ICD-11: 2B90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Colon
• The Specified Disease: Colon cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.35E-17; Fold-change: 4.30E-01; Z-score: 8.72E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.77E-24; Fold-change: 7.42E-01; Z-score: 1.32E+00

References

• Ref 1: Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis. Antimicrob Agents Chemother. 2004 Nov;48(11):4301-5. doi: 10.1128/AAC.48.11.4301-4305.2004.
• Ref 2: Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells. Mol Cancer. 2010 Apr 30;9:96. doi: 10.1186/1476-4598-9-96.