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Multiple folate enzyme inhibition: mechanism of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA)
Authors:
Chuan Shih
Lillian L Habeck
Laurane G Mendelsohn
Victor J Chen
Richard M Schultz
Institution:
a
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285,USA
Abstract:
Keywords:
Abbreviations:
r
recombinant
h
human
m
murine
TS
thymidylate synthase
DHFR
dihydrofolate reductase
GARFT
glycinamide ribonucleotide formyltransferase
AICARFT
aminoimidazole carboxamide ribonucleotide formyltransferase (EC 2
1
2
3)
C1-S
C1 tetrahydrofolate synthase
D/C
the protein domain of C1-S containing the 5
10-methylenetetrahydrofolate dehydrogenase (EC 1
5
1
5) and 5
10-methenyltetrahydrofolate cyclohydrolase activities
D/C/S
the full length enzyme of C1-S containing 5
10-methylenetetrahydrofolate dehydrogenase
5
10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activities (EC 6
3
4
3)
FPGS
folylpolyglutamate synthetase
HEPES
N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]
MTT
3-[4
5-dimethylthiazol-2yl]-2
5-diphenyltetrazolium bromide
DDATHF
5
10-dideazatetrahydrofolic acid
Lometrexol
6R-DDATHF
ME
mercaptoethanol
NADPH
β-nicotinamide adenine dinucleotide phosphate
reduced form
ATP
adenosine 5′-triphosphate
6R-MTHF
6[R]-5
10-methylene-5
6
7
8-tetrahydrofolate
LY231514
N-[4-[2-(2-amino-3
4-dihydro-4-oxo-7H-pyrrolo[2
3-d]pyrimidin-5-yl)ethyl]-benzoyl]-L-glutamic acid
MTA
multitargeted antifolate
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