PMID- 23869564
OWN - NLM
STAT- MEDLINE
DCOM- 20130930
LR  - 20211021
IS  - 1520-4995 (Electronic)
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 52
IP  - 30
DP  - 2013 Jul 30
TI  - Biological and structural evaluation of 10R- and 10S-methylthio-DDACTHF reveals a 
      new role for sulfur in inhibition of glycinamide ribonucleotide transformylase.
PG  - 5133-44
LID - 10.1021/bi4005182 [doi]
AB  - Glycinamide ribonucleotide transformylase (GAR Tfase) is a folate-dependent 
      enzyme in the de novo purine biosynthesis pathway, which has long been considered 
      a potential target for development of anti-neoplastic therapeutics. Here we 
      report the biological and X-ray crystallographic evaluations of both independent 
      C10 diastereomers, 10S- and 10R-methylthio-DDACTHF, bound to human GAR Tfase, 
      including the highest-resolution apo GAR Tfase structure to date (1.52 A). Both 
      diastereomers are potent inhibitors (Ki = 210 nM for 10R, and Ki = 180 nM for 
      10S) of GAR Tfase and exhibit effective inhibition of human leukemia cell growth 
      (IC(5)(0) = 80 and 50 nM, respectively). Their inhibitory activity was surprisingly 
      high, and these lipophilic C10-substituted analogues show distinct advantages 
      over their hydrophilic counterparts, most strikingly in retaining potency in 
      mutant human leukemia cell lines that lack reduced folate carrier protein 
      activity (IC(5)(0) = 70 and 60 nM, respectively). Structural characterization reveals 
      a new binding mode for these diastereoisomers, in which the lipophilic thiomethyl 
      groups penetrate deeper into a hydrophobic pocket within the folate-binding site. 
      In silico docking simulations of three other sulfur-containing folate analogues 
      also indicate that this hydrophobic cleft represents a favorable region for 
      binding lipophilic substituents. Overall, these results suggest sulfur and its 
      substitutions play an important role in not only the binding of anti-folates to 
      GAR Tfase but also the selectivity and cellular activity (growth inhibition), 
      thereby presenting new possibilities for the future design of potent and 
      selective anti-folate drugs that target GAR Tfase.
FAU - Connelly, Stephen
AU  - Connelly S
AD  - Department of Integrative Structural and Computational Biology, The Scripps 
      Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, 
      United States.
FAU - DeMartino, Jessica K
AU  - DeMartino JK
FAU - Boger, Dale L
AU  - Boger DL
FAU - Wilson, Ian A
AU  - Wilson IA
LA  - eng
SI  - PDB/4EW1
SI  - PDB/4EW2
SI  - PDB/4EW3
GR  - P01 CA063536/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20130719
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (10-methylthio-DDACTHF)
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Apoproteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Peptide Fragments)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tetrahydrofolates)
RN  - EC 2.1.2.2 (Phosphoribosylglycinamide Formyltransferase)
RN  - EC 2.1.2.3 (Phosphoribosylaminoimidazolecarboxamide Formyltransferase)
RN  - EC 6.3.- (Carbon-Nitrogen Ligases)
RN  - EC 6.3.4.13 (GART protein, human)
SB  - IM
MH  - Antimetabolites, Antineoplastic/*chemistry/metabolism/pharmacology
MH  - Apoproteins/antagonists & inhibitors/chemistry/metabolism
MH  - Binding Sites
MH  - Carbon-Nitrogen Ligases/antagonists & inhibitors/*chemistry/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Enzyme Inhibitors/*chemistry/metabolism/pharmacology
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Leukemia/drug therapy/enzymology
MH  - *Models, Molecular
MH  - Molecular Conformation
MH  - Molecular Docking Simulation
MH  - Neoplasm Proteins/antagonists & inhibitors/chemistry/genetics/metabolism
MH  - Peptide Fragments/antagonists & inhibitors/chemistry/metabolism
MH  - Phosphoribosylaminoimidazolecarboxamide Formyltransferase/antagonists & 
      inhibitors/chemistry/genetics/metabolism
MH  - Phosphoribosylglycinamide Formyltransferase/antagonists & 
      inhibitors/*chemistry/genetics/metabolism
MH  - Recombinant Proteins/antagonists & inhibitors/chemistry/metabolism
MH  - Stereoisomerism
MH  - Structure-Activity Relationship
MH  - Tetrahydrofolates/*chemistry/metabolism/pharmacology
PMC - PMC3823235
MID - NIHMS508342
EDAT- 2013/07/23 06:00
MHDA- 2013/10/01 06:00
PMCR- 2014/07/30
CRDT- 2013/07/23 06:00
PHST- 2013/07/23 06:00 [entrez]
PHST- 2013/07/23 06:00 [pubmed]
PHST- 2013/10/01 06:00 [medline]
PHST- 2014/07/30 00:00 [pmc-release]
AID - 10.1021/bi4005182 [doi]
PST - ppublish
SO  - Biochemistry. 2013 Jul 30;52(30):5133-44. doi: 10.1021/bi4005182. Epub 2013 Jul 
      19.