Overview of RNase A Structure/Function Relationships
Ribonuclease A (RNase A) is a small (124 amino acids) digestive enzyme secreted by the pancreas and is an endonuclease specifically designed to hydrolyze RNA (but not DNA) phosphodiester bonds which covalently link ribonucleotides particularly those linked to pyrimidine bases such as uracil.
Two His residues -- His12 and His119 -- are implicated in the catalytic mechanism of this enzyme. The imidazole ring of His12 has an anonymously low pK value (pk < 6.0) suggesting it must be deprotonated for catalysis. Conversely, the imidazole ring of His119 has an anonymously high pK value (pk > 6.0) suggesting it must be protonated for catalysis.
A two-step reaction is proposed for hydolysis of RNA.
Uridine vanadate is a potent competitive inhibitor of RNase A. What makes it so potent is the fact that its structure mimicks a transition state intermediate in the reaction. Specifically, the oxidized vanadium atom is pentavalent ion with five coordinated oxygen atoms whose stable structure is believed to mimic the bipyramid structure of an unstable pentavalent phosphodiester intermediate that transiently forms in the active site of the enzyme.
Legend: 2',3'-cyclic uridine vanadate complex with RNase A active site. The pentacovalently coordinated vanadium (V) atom of the inhibitor forms metal bonds with 5 oxygen atoms (redspheres) creating a bipyramidal 2',3' cyclic ribonucleotide (black wireframe) linked to uracil. Specific active site residue contacts with His 119, His12, Lys41, and Thr45 are shown with distance measurements indicated in Ångstroms.
Additional information concerning the properties of RNase A and its interaction with another inhibitor (TBU), 2-methyl-2-proponol (t-butyl alcohol), can be also found at the following world-wide web sites:
Go to the MCDB 108AL RNase A web page for further examination of the properties of this enzyme.
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|©|| Duane W. Sears|
Revised: July 27, 1998