Details of the Drug Metabolized by Drug-Metabolizing Enzyme (DME)

General Information of Drug (ID: DR1045)
Drug Name
Methotrexate
Synonyms
Metatrexan; Methotextrate; Methotrexat; Methotrexat-Ebewe; Methotrexate, L-; Methotrexatum; Methoxtrexate; Methylaminopterin; Methylaminopterinum; Metotressato [DCIT]; Metotrexato; Mexate; Mexate-Aq; N-Bismethylpteroylglutamic acid; A-Methopterin; A-Methpterin; Amethopterin; Amethopterin L-; Amethopterine; Antifolan; Emtexate; Folex-Pfs; L-Amethopterin; Maxtrex; Rasuvo; Rheumatrex; Trexall; methotrexate; (S)-2-(4-(((2,4-Diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)pentanedioic acid; Abitrexate; Folex; Hdmtx; MTX; NCI-C04671
Indication Breast cancer [ICD11: 2C60] Approved [1]
Structure
3D MOL 2D MOL
Pharmaceutical Properties Molecular Weight 454.4 Topological Polar Surface Area 211
Heavy Atom Count 33 Rotatable Bond Count 9
Hydrogen Bond Donor Count 5 Hydrogen Bond Acceptor Count 12
Cross-matching ID
PubChem CID
126941
ChEBI ID
CHEBI:44185
CAS Number
59-05-2
TTD Drug ID
D0SV8E
Formula
C20H22N8O5
Canonical SMILES
CN(CC1=CN=C2C(=N1)C(=NC(=N2)N)N)C3=CC=C(C=C3)C(=O)NC(CCC(=O)O)C(=O)O
InChI
1S/C20H22N8O5/c1-28(9-11-8-23-17-15(24-11)16(21)26-20(22)27-17)12-4-2-10(3-5-12)18(31)25-13(19(32)33)6-7-14(29)30/h2-5,8,13H,6-7,9H2,1H3,(H,25,31)(H,29,30)(H,32,33)(H4,21,22,23,26,27)/t13-/m0/s1
InChIKey
FBOZXECLQNJBKD-ZDUSSCGKSA-N
The Metabolic Roadmap of This Drug
The Full List of Drug Metabolites (DM) of This Drug
DM Name DM ID PubChem ID Reaction DM Level REF
2, 4-diamino-N(10)-methylpteroic acid (DAMPA) DM015062
72441
Unclear - Unclear 1 [7]
Methotrexate?polyglutamates DM018110 N. A. Unclear - Unclear 1 [8] , [9]
MTX-7-OH DM015454
5385077
Oxidation - Hydroxylation 1 [10] , [11]
The Full List of Metabolic Reaction (MR) of This Drug
MR ID Reactant Product MR Type DME REF
MR010009 Methotrexate MTX-7-OH Oxidation - Hydroxylation Unclear [10], [11]
MR010010 Methotrexate Methotrexate?polyglutamates Unclear - Unclear FPGS [8], [9]
MR010011 Methotrexate 2, 4-diamino-N(10)-methylpteroic acid (DAMPA) Unclear - Unclear Unclear [7]
Drug-Metabolizing Enzyme(s) (DME) Metabolizing This Drug
DME Name DME Info Species Uniprot ID EC Number REF
Dihydrofolate reductase (DHFR) DME0141 Homo sapiens
DYR_HUMAN
1.5.1.3
[2]
Folylpolyglutamate synthase (FPGS) DME0191 Homo sapiens
FOLC_HUMAN
6.3.2.17
[2]
Gamma-Glu-X carboxypeptidase (GGH) DME0142 Homo sapiens
GGH_HUMAN
3.4.19.9
[2]
Glutamate carboxypeptidase II (FOLH1) DME0579 Homo sapiens
FOLH1_HUMAN
3.4.17.21
[3]
Methylenetetrahydrofolate reductase (MTHFR) DME0083 Homo sapiens
MTHR_HUMAN
1.5.1.20
[2]
Thiopurine methyltransferase (TPMT) DME0014 Homo sapiens
TPMT_HUMAN
2.1.1.67
[4]
Thymidylate synthase (TYMS) DME0137 Homo sapiens
TYSY_HUMAN
2.1.1.45
[2]
Unclear metabolic mechanism (DME-unclear) DME1469 Variovorax paradoxus Not Available Not Available [5] , [6]
⏷ Show the Full List of 8  DME(s)
References
1 Methotrexate was approved by FDA. The 2020 official website of the U.S. Food and Drug Administration.
2 The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4.
3 Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006 Jun;11(6):694-703.
4 Genetics of rheumatoid arthritis. Mayo Clin Proc. 2006 Jan;81(1):94-101.
5 The 46 kDa dimeric protein from Variovorax paradoxus shows faster methotrexate degrading activity in its nanoform compare to the native enzyme. Enzyme Microb Technol. 2016 Apr;85:38-43.
6 Isolation and molecular detection of methylotrophic bacteria occurring in the human mouth. Environ Microbiol. 2005 Aug;7(8):1227-38.
7 Pharmacokinetics and metabolism of the methotrexate metabolite 2, 4-diamino-N(10)-methylpteroic acid
8 Measuring methotrexate polyglutamates
9 Hepatotoxic potentials of methotrexate: Understanding the possible toxicological molecular mechanisms
10 Clinical and Laboratory Associations with Methotrexate Metabolism Gene Polymorphisms in Rheumatoid Arthritis
11 Leflunomide Increases Hepatic Exposure to Methotrexate and Its Metabolite by Differentially Regulating Multidrug Resistance-Associated Protein Mrp2/3/4 Transporters via Peroxisome Proliferator-Activated Receptor Activation

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