PMID- 19719322
OWN - NLM
STAT- MEDLINE
DCOM- 20091203
LR  - 20211020
IS  - 1520-4995 (Electronic)
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 48
IP  - 40
DP  - 2009 Oct 13
TI  - Functional energetic landscape in the allosteric regulation of muscle pyruvate 
      kinase. 3. Mechanism.
PG  - 9466-70
LID - 10.1021/bi900281s [doi]
AB  - Mammalian pyruvate kinase exists in four isoforms with characteristics tuned to 
      specific metabolic requirements of different tissues. All of the isoforms, except 
      the muscle isoform, exhibit typical allosteric behavior. The case of the muscle 
      isoform is a conundrum. It is inhibited by an allosteric inhibitor, Phe, yet it 
      has traditionally not been considered as an allosteric enzyme. In this series of 
      study, an energetic landscape of rabbit muscle pyruvate kinase (RMPK) was 
      established. The phenomenon of inhibition by Phe is shown to be physiological. 
      Furthermore, the thermodynamics for the temperature fluctuation and concomitant 
      pH change as a consequence of muscle activity were elucidated. We have shown that 
      (1) the differential number of protons released or absorbed with regard to the 
      various linked reactions adds another level of control to shift the binding 
      constants and equilibrium of active <--> inactive state changes (the latter 
      controls quantitatively the activity of RMPK); (2) ADP plays a major role in the 
      allosteric mechanism in RMPK under physiological temperatures (depending on the 
      temperature, ADP can assume dual and opposite roles of being an inhibitor by 
      binding preferentially to the inactive form and a substrate); and (3) simulation 
      of the RMPK behavior under physiological conditions shows that the net results of 
      the 21 thermodynamic parameters involved in the regulation are well-tuned to 
      allow the maximal response of the enzyme to even minute changes in temperature 
      and ligand concentration.
FAU - Herman, Petr
AU  - Herman P
AD  - Faculty of Mathematics and Physics, Institute of Physics, Charles University, Ke 
      Karlovu 5, 121 16 Prague, Czech Republic. herman@karlov.mff.cuni.cz
FAU - Lee, J Ching
AU  - Lee JC
LA  - eng
GR  - R01 GM077551/GM/NIGMS NIH HHS/United States
GR  - R01 GM077551-04/GM/NIGMS NIH HHS/United States
GR  - GM 77551/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Ligands)
RN  - 47E5O17Y3R (Phenylalanine)
RN  - 61D2G4IYVH (Adenosine Diphosphate)
RN  - EC 2.7.1.40 (Pyruvate Kinase)
SB  - IM
MH  - Adenosine Diphosphate/chemistry/metabolism
MH  - Allosteric Regulation
MH  - Animals
MH  - Computer Simulation
MH  - Energy Metabolism
MH  - Enzyme Activation
MH  - Ligands
MH  - Models, Chemical
MH  - Muscle, Skeletal/*enzymology
MH  - Phenylalanine/chemistry
MH  - Protein Binding
MH  - Pyruvate Kinase/*antagonists & inhibitors/chemistry/*metabolism/physiology
MH  - Rabbits
MH  - Thermodynamics
PMC - PMC2758332
MID - NIHMS146296
EDAT- 2009/09/02 06:00
MHDA- 2009/12/16 06:00
PMCR- 2010/10/13
CRDT- 2009/09/02 09:00
PHST- 2009/09/02 09:00 [entrez]
PHST- 2009/09/02 06:00 [pubmed]
PHST- 2009/12/16 06:00 [medline]
PHST- 2010/10/13 00:00 [pmc-release]
AID - 10.1021/bi900281s [doi]
PST - ppublish
SO  - Biochemistry. 2009 Oct 13;48(40):9466-70. doi: 10.1021/bi900281s.