Reactome | DHFR dimer binds DHFR inhibitors

DHFR dimer binds DHFR inhibitors

Stable Identifier

R-HSA-9709109

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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Dihydrofolates must be reduced to tetrahydrofolates by dihydrofolate reductases (DHFR) before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate, and therefore of DNA synthesis. Inhibitors of DHFR are anti-folates are used clinically as antiinfective, antineoplastic, and antiinflammatory drugs. They interfere with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa are sensitive to these drugs.

Methotrexate is the DHFR inhibitor used most often in a clinical setting as an anticancer drug and as an antiinflammatory and immunosuppressive agent (Koźmiński et al. 2020). Pemetrexed is used in combination with cisplatin for the treatment of malignant pleural mesothelioma (Chattopadhyay et al. 2007, Koda et al. 2020). Trimetrexate is a non-classical DHFR inhibitor used for the treatment of moderate-to-severe pneumocystis carinii pneumonia (Polshakov et al. 1999) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS) (Short et al. 2009). Pralatrexate is an antimetabolite for the treatment of relapsed or refractory peripheral T-cell lymphoma (Shimanovsky & Dasanu 2013, Peters et al. 2020).

Diflunisal, a salicylate derivative, is a nonsteroidal anti-inflammatory drug (NSAID) that primarily targets cyclooxygenase enzymes. It has recently been reported to competitively inhibit DHFR, opening the possibility of NSAID use in inflammatory processes by inhibiting different pathways (Duff et al. 2020).

Literature References

PubMed ID	Title	Journal	Year
33163492	Schedule-Dependent Synergy Between the Histone Deacetylase Inhibitor Belinostat and the Dihydrofolate Reductase Inhibitor Pralatrexate in T-and B-cell Lymphoma Cells in vitro van Gemert, FPA, Cillessen, SAGM, Peters, GJ, Jansen, G, Reddy, G, Kathmann, I	Front Cell Dev Biol	2020
33053560	Irinotecan and Gemcitabine as Second-Line Treatment in Patients with Malignant Pleural Mesothelioma following Platinum plus Pemetrexed Chemotherapy: A Retrospective Study Koda, Y, Nakajima, Y, Kitajima, K, Nakamura, A, Yokoi, T, Kijima, T, Kuribayashi, K, Doi, H, Minami, T, Takahashi, R, Ishigaki, H	Oncology	2020
17308042	Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications Moran, RG, Goldman, ID, Chattopadhyay, S	Mol Cancer Ther	2007
10091649	Structure and dynamics in solution of the complex of Lactobacillus casei dihydrofolate reductase with the new lipophilic antifolate drug trimetrexate Polshakov, VI, Feeney, J, Frenkiel, TA, Gargaro, AR, Birdsall, B	Protein Sci	1999
32658475	The Structural Basis for Nonsteroidal Anti-Inflammatory Drug Inhibition of Human Dihydrofolate Reductase DeRose, EF, Howell, EE, Pedersen, LC, Gabel, SA, London, RE, Krahn, JM, Duff, MR	J Med Chem	2020
23409799	Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma Dasanu, CA, Shimanovsky, A	Expert Opin Pharmacother	2013
19424049	Trimetrexate and folinic acid: a valuable salvage option for Pneumocystis jirovecii pneumonia Gilleece, YC, Churchill, DR, Short, CE, Fisher, MJ	AIDS	2009
32423175	Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers Koźmiński, P, Chesori, R, Halik, PK, Gniazdowska, E	Int J Mol Sci	2020