PMID- 10659854
OWN - NLM
STAT- MEDLINE
DCOM- 20000211
LR  - 20180815
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 403
IP  - 6767
DP  - 2000 Jan 20
TI  - Regulation of carbamoyl phosphate synthetase by MAP kinase.
PG  - 328-32
AB  - The de novo synthesis of pyrimidine nucleotides is required for mammalian cells
      to proliferate. The rate-limiting step in this pathway is catalysed by carbamoyl 
      phosphate synthetase (CPS II), part of the multifunctional enzyme CAD. Here we
      describe the regulation of CAD by the mitogen-activated protein (MAP) kinase
      cascade. When phosphorylated by MAP kinase in vitro or activated by epidermal
      growth factor in vivo, CAD lost its feedback inhibition (which is dependent on
      uridine triphosphate) and became more sensitive to activation (which depends upon
      phosphoribosyl pyrophosphate). Both these allosteric regulatory changes favour
      biosynthesis of pyrimidines for growth. They were accompanied by increased
      epidermal growth factor-dependent phosphorylation of CAD in vivo and were
      prevented by inhibition of MAP kinase. Mutation of a consensus MAP kinase
      phosphorylation site abolished the changes in CAD allosteric regulation that were
      stimulated by growth factors. Finally, consistent with an effect of MAP kinase
      signalling on CPS II activity, epidermal growth factor increased cellular uridine
      triphosphate and this increase was reversed by inhibition of MAP kinase. Hence
      these studies may indicate a direct link between activation of the MAP kinase
      cascade and de novo biosynthesis of pyrimidine nucleotides.
FAU - Graves, L M
AU  - Graves LM
AD  - Department of Pharmacology, Comprehensive Cancer Center, University of North
      Carolina at Chapel Hill, 27599-7365, USA. lmg@med.unc.edu
FAU - Guy, H I
AU  - Guy HI
FAU - Kozlowski, P
AU  - Kozlowski P
FAU - Huang, M
AU  - Huang M
FAU - Lazarowski, E
AU  - Lazarowski E
FAU - Pope, R M
AU  - Pope RM
FAU - Collins, M A
AU  - Collins MA
FAU - Dahlstrand, E N
AU  - Dahlstrand EN
FAU - Earp, H S 3rd
AU  - Earp HS 3rd
FAU - Evans, D R
AU  - Evans DR
LA  - eng
GR  - R01 GM060371/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (CAD trifunctional enzyme)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Flavonoids)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Pyrimidine Nucleotides)
RN  - 7540-64-9 (Phosphoribosyl Pyrophosphate)
RN  - EC 2.1.3.2 (Aspartate Carbamoyltransferase)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.5.2.3 (Dihydroorotase)
RN  - EC 6.3.5.5 (Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing))
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
RN  - UT0S826Z60 (Uridine Triphosphate)
SB  - IM
CIN - Nature. 2000 Jan 20;403(6767):255-6. PMID: 10659830
MH  - Allosteric Regulation
MH  - Amino Acid Sequence
MH  - Animals
MH  - Aspartate Carbamoyltransferase/antagonists &
      inhibitors/chemistry/genetics/*metabolism
MH  - Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)/antagonists &
      inhibitors/chemistry/genetics/*metabolism
MH  - Cell Line
MH  - Cricetinae
MH  - Dihydroorotase/antagonists & inhibitors/chemistry/genetics/*metabolism
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Flavonoids/pharmacology
MH  - *MAP Kinase Signaling System
MH  - Mesocricetus
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
MH  - Molecular Sequence Data
MH  - Multienzyme Complexes/antagonists & inhibitors/chemistry/genetics/*metabolism
MH  - Mutagenesis, Site-Directed
MH  - Phosphoribosyl Pyrophosphate/metabolism
MH  - Phosphorylation
MH  - Pyrimidine Nucleotides/biosynthesis
MH  - Rats
MH  - Uridine Triphosphate/metabolism
EDAT- 2000/02/05 09:00
MHDA- 2000/02/19 09:00
CRDT- 2000/02/05 09:00
PHST- 2000/02/05 09:00 [pubmed]
PHST- 2000/02/19 09:00 [medline]
PHST- 2000/02/05 09:00 [entrez]
AID - 10.1038/35002111 [doi]
PST - ppublish
SO  - Nature. 2000 Jan 20;403(6767):328-32. doi: 10.1038/35002111.