Literature summary for 6.3.2.17 extracted from

Liani, E.; Rothem, L.; Bunni, M.A.; Smith, C.A.; Jansen, G.; Assaraf, Y.G.
Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines (2003), Int. J. Cancer, 103, 587-599.

Search for more literature for 6.3.2.17

Protein Variants

Protein Variants	Comment	Organism
C346F	MTXR5 antifolates-resistant cell subline	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
(2S)-2-(o-fluoro-p-(N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(prop-2-ynyl-amino)benzamido)-4-(tetrazol-5-yl)butyric acid	IC50 of 0.0000153 mM in the wild type cell line, IC50 of 0.000008 mM to 0.0016 mM in the antifolates-resistant sublines	Homo sapiens
(2S)-2-(o-fluoro-p-(N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(prop-2-ynyl-amino)benzamido)-4-(tetrazol-5-yl)butyric acid	IC50 of 0.0000125 mM in the wild type cell line, IC50 of 0.0000635 mM in the MTA-13 cell line	Mus musculus
(S)-2(5-(((1,2-dihydro-3-methyl-1-oxobenzo-(f)quinazolin-9-yl)methyl)-1-oxo-2-isoindolinyl))-glutaric acid	IC50 of 0.0000009 mM in the wild type cell line, IC50 of 0.0000012 mM to 0.000539 mM in the antifolates-resistant sublines	Homo sapiens
5,10-dideaza-5,6,7,8-tetrahydrofolic acid	IC50 of 0.0000277 mM in the wild type cell line, IC50 of 0.000143 mM to 0.0035 mM in the antifolates-resistant sublines	Homo sapiens
5,10-dideaza-5,6,7,8-tetrahydrofolic acid	IC50 of 0.0000591 mM in the wild type cell line, IC50 of 0.000205 mM in the MTA-13 cell line	Mus musculus
methotrexate-Glu	IC50 of 0.0000014 mM in the wild type cell line, IC50 of 0.000001 mM to 0.00095 mM in the antifolates-resistant sublines	Homo sapiens
methotrexate-Glu	IC50 of 0.00002 mM in the wild type cell line, IC50 of 0.0000545 mM in the MTA-13 cell line	Mus musculus
N-(4-(2(2-amino-3,4-dihydro-4-oxo-7H-pyrolo-(2,3-d)pyrimidine-5-yl)ethyl)-benzoyl)-L-glutamic acid	IC50 of 0.0000136 mM in the wild type cell line, IC50 of 0.000116 mM in the MTA-13 cell line	Mus musculus
N-(5-(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)L-glutamic acid	IC50 of 0.0000032 mM in the wild type cell line, IC50 of 0.00032 mM to 0.007168 mM in the antifolates-resistant sublines	Homo sapiens
N-(5-(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)L-glutamic acid	IC50 of 0.0000033 mM in the wild type cell line, IC50 of 0.000028 mM in the MTA-13 cell line	Mus musculus
Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine	IC50 of 0.000001 mM in the wild type cell line, IC50 of 0.000006 mM to 0.0017 mM in the antifolates-resistant sublines	Homo sapiens

KM Value [mM]

KM Value [mM]	KM Value Maximum [mM]	Substrate	Comment	Organism	Structure
0.063	-	methotrexate-Glu	pH 8.5, 37ºC, wild type cell line	Homo sapiens
0.074	-	methotrexate-Glu	pH 8.5, 37ºC, MTXR5 cell subline	Homo sapiens
1	-	L-glutamate	pH 8.5, 37ºC, wild type cell line	Homo sapiens
2	3	L-glutamate	pH 8.5, 37ºC, MTXR5 cell subline	Homo sapiens

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	-	human	-
Mus musculus	-	mouse	-

Purification (Commentary)

Purification (Comment)	Organism
crude total cell extracts are obtained by sonication followed by centrifugation	Homo sapiens

Source Tissue

Source Tissue	Comment	Organism	Textmining
CCRF-CEM cell	leukemia line, wild type line and various antifolate-resistant sublines	Homo sapiens	-
L-1210 cell	leukemia line, wild type cell line and pemetrexed-resistant MTA-13 cell line	Mus musculus	-

Specific Activity [micromol/min/mg]

Specific Activity Minimum [µmol/min/mg]	Specific Activity Maximum [µmol/min/mg]	Comment	Organism
additional information	-	the specific activity of the extract derived from MTXR5 cell subline is 7.1fold lower than that obtained with the wild type cell line	Homo sapiens

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
ATP + (2S)-2-(o-fluoro-p-(N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(prop-2-ynyl-amino)benzamido)-4-(tetrazol-5-yl)butyric acid + L-glutamate	-	Homo sapiens	ADP + (2S)-2-(o-fluoro-p-(N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(prop-2-ynyl-amino)benzamido)-4-(tetrazol-5-yl)butanoyl-L-Glu + phosphate	-	?
ATP + (2S)-2-(o-fluoro-p-(N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(prop-2-ynyl-amino)benzamido)-4-(tetrazol-5-yl)butyric acid + L-glutamate	-	Mus musculus	ADP + (2S)-2-(o-fluoro-p-(N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(prop-2-ynyl-amino)benzamido)-4-(tetrazol-5-yl)butanoyl-Glu + phosphate	-	?
ATP + (S)-2(5-(((1,2-dihydro-3-methyl-1-oxobenzo-(f)quinazolin-9-yl)methyl)-1-oxo-2-isoindolinyl))glutaric acid + L-glutamate	-	Homo sapiens	ADP + (S)-2(5-(((1,2-dihydro-3-methyl-1-oxobenzo-(f)quinazolin-9-yl)methyl)-1-oxo-2-isoindolinyl))glutaryl-L-Glu + phosphate	-	?
ATP + 5,10-dideaza-5,6,7,8-tetrahydrofolic acid + L-glutamate	lometrexol	Mus musculus	ADP + 5,10-dideaza-5,6,7,8-tetrahydrofolyl-L-Glu + phosphate	-	?
ATP + 5,10-dideaza-5,6,7,8-tetrahydrofolic acid + L-glutamate	lometrexol	Homo sapiens	ADP + 5,10-dideaza-5,6,7,8-tetrahydrofolyl-L-Glu + phosphate	-	?
ATP + methotrexate-Glu + L-glutamate	-	Mus musculus	ADP + methotrexate-Glu2 + phosphate	-	?
ATP + methotrexate-Glu + L-glutamate	-	Homo sapiens	ADP + methotrexate-Glu2 + phosphate	-	?
ATP + N-(4-(2(2-amino-3,4-dihydro-4-oxo-7H-pyrolo-(2,3-d)pyrimidine-5-yl)ethyl)-benzoyl)-L-glutamic acid + L-glutamate	-	Homo sapiens	ADP + N-(4-(2(2-amino-3,4-dihydro-4-oxo-7H-pyrolo-(2,3-d)pyrimidine-5-yl)ethyl)-benzoyl)-L-Glu2 + phosphate	-	?
ATP + N-(4-(2(2-amino-3,4-dihydro-4-oxo-7H-pyrolo-(2,3-d)pyrimidine-5-yl)ethyl)-benzoyl)-L-glutamic acid + L-glutamate	pemetrexed	Mus musculus	ADP + N-(4-(2(2-amino-3,4-dihydro-4-oxo-7H-pyrolo-(2,3-d)pyrimidine-5-yl)ethyl)-benzoyl)-L-Glu2 + phosphate	-	?
ATP + N-(5-(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)L-glutamic acid + L-glutamate	-	Homo sapiens	ADP + N-(5-(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)L-Glu2 + phosphate	-	?
ATP + N-(5-(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)L-glutamic acid + L-glutamate	raltitrexed	Mus musculus	ADP + N-(5-(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)L-Glu2 + phosphate	-	?
ATP + Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine + L-glutamate	-	Homo sapiens	?	-	?
additional information	depressed activity of the enzyme is the predominant mechanism of high level resistance to polyglutamylation-dependent antifolates	Mus musculus	?	-	?
additional information	depressed activity of the enzyme is the predominant mechanism of high level resistance to polyglutamylation-dependent antifolates	Homo sapiens	?	-	?

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor	Structure
0.000001	-	IC50 of 0.0000014 mM in the wild type cell line, IC50 of 0.000001 mM to 0.00095 mM in the antifolates-resistant sublines	Homo sapiens	methotrexate-Glu
0.0000012	-	IC50 of 0.0000009 mM in the wild type cell line, IC50 of 0.0000012 mM to 0.000539 mM in the antifolates-resistant sublines	Homo sapiens	(S)-2(5-(((1,2-dihydro-3-methyl-1-oxobenzo-(f)quinazolin-9-yl)methyl)-1-oxo-2-isoindolinyl))-glutaric acid
0.000006	-	IC50 of 0.000001 mM in the wild type cell line, IC50 of 0.000006 mM to 0.0017 mM in the antifolates-resistant sublines	Homo sapiens	Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine
0.000008	-	IC50 of 0.0000153 mM in the wild type cell line, IC50 of 0.000008 mM to 0.0016 mM in the antifolates-resistant sublines	Homo sapiens	(2S)-2-(o-fluoro-p-(N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(prop-2-ynyl-amino)benzamido)-4-(tetrazol-5-yl)butyric acid
0.000028	13	IC50 of 0.0000033 mM in the wild type cell line, IC50 of 0.000028 mM in the MTA-13 cell line	Mus musculus	N-(5-(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)L-glutamic acid
0.0000545	13	IC50 of 0.00002 mM in the wild type cell line, IC50 of 0.0000545 mM in the MTA-13 cell line	Mus musculus	methotrexate-Glu
0.0000635	13	IC50 of 0.0000125 mM in the wild type cell line, IC50 of 0.0000635 mM in the MTA-13 cell line	Mus musculus	(2S)-2-(o-fluoro-p-(N-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(prop-2-ynyl-amino)benzamido)-4-(tetrazol-5-yl)butyric acid
0.000116	13	IC50 of 0.0000136 mM in the wild type cell line, IC50 of 0.000116 mM in the MTA-13 cell line	Mus musculus	N-(4-(2(2-amino-3,4-dihydro-4-oxo-7H-pyrolo-(2,3-d)pyrimidine-5-yl)ethyl)-benzoyl)-L-glutamic acid
0.000143	-	IC50 of 0.0000277 mM in the wild type cell line, IC50 of 0.000143 mM to 0.0035 mM in the antifolates-resistant sublines	Homo sapiens	5,10-dideaza-5,6,7,8-tetrahydrofolic acid
0.000205	13	IC50 of 0.0000591 mM in the wild type cell line, IC50 of 0.000205 mM in the MTA-13 cell line	Mus musculus	5,10-dideaza-5,6,7,8-tetrahydrofolic acid
0.00032	-	IC50 of 0.0000032 mM in the wild type cell line, IC50 of 0.00032 mM to 0.007168 mM in the antifolates-resistant sublines	Homo sapiens	N-(5-(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)L-glutamic acid

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Release 2023.1 (January 2023)