Kinetic and molecular modeling of nucleoside and nucleotide inhibition of malate dehydrogenase.
We studied the inhibition of mitochondrial malate dehydrogenase (mMDH) by the nucleotides cAMP, AMP, ADP, ATP. The experimental kinetic studies showed that the nucleotides were competitive inhibitors and that cAMP was probably the most potent inhibitor. To explain these observations, we used molecular modeling to determine the location, orientation, and relative binding energy of the nucleotides to mMDH. The order of the calculated binding energies, from lowest (most favorable) to highest, was cAMP, AMP, ADP, and ATP, which corresponded somewhat to the order of the experimentally determined inhibition constants.
Harris
Douglas G
DG
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602-5700, USA.
Marx
Douglas P
DP
Anderson
Jonathan M
JM
McCune
Ronald W
RW
Zimmerman
S Scott
SS
D000249:Adenosine Monophosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D000242:Cyclic AMP / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D009705:Nucleosides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation
D004791:Enzyme Inhibitors; D009705:Nucleosides; D009711:Nucleotides; D009243:NAD; D000249:Adenosine Monophosphate; D000242:Cyclic AMP; D008291:Malate Dehydrogenase