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Ionization behavior of the histidine residue in the catalytic triad of serine proteases

Hunkapiller, Michael W. and Smallcombe, Stephen H. and Whitaker, Don R. and Richards, John H. (1973) Ionization behavior of the histidine residue in the catalytic triad of serine proteases. Journal of Biological Chemistry, 248 (23). pp. 8306-8308. ISSN 0021-9258.

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α-Lytic protease is a homologue of the mammalian serine proteases such as trypsin, chymotrypsin, and elastase, and its single histidine residue belongs to the Asp-His-Ser catalytic triad. This single histidine residue has been selectively enriched in the C-2 carbon with 13C. Magnetic resonance studies of the chemical shift and coupling constant (1Jch) behavior of this nucleus as a function of pH suggest that the imidazole ring is neutral above pH 5 and therefore that the group which is known to ionize with pKa near 6.7 must be the aspartic acid residue. Implications of these new pKa assignments for the catalytic mechanism of serine proteases are discussed and include the absence of any need to separate charge during catalysis. The histidine residue plays two roles. (a) It insulates the aspartic acid from an aqueous environment and accordingly raises its pKa. (b) It serves as a bidentate base to accept a proton from the serine at one of its nitrogens and concertedly transfer a proton from its other nitrogen to the buried carboxylate anion during formation of the tetrahedral intermediate.

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Additional Information:© 1973 by the American Society for Biochemistry and Molecular Biology. Submitted on June 13, 1973. This work was supported by Grants NIGMS-16424 and NIGMS-10218 from the United States Public Health Service and Grant MA-4409 from the Medical Research Council of Canada. Contribution 4712 from the Church Laboratory of Chemical Biology, California Institute of Technology. [M.W.H. was a] [r]ecipient of a National Institutes of Health Traineeship Award.
Funding AgencyGrant Number
Medical Research Council of CanadaMA-4409
United States Public Health ServiceNIGMS-10218
United States Public Health ServiceNIGMS-16424
National Institutes of HealthUNSPECIFIED
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Church Laboratory of Chemical Biology4712
Issue or Number:23
Record Number:CaltechAUTHORS:HUNjbc73
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11458
Deposited By: Tony Diaz
Deposited On:28 Aug 2008 03:37
Last Modified:03 Oct 2019 00:19

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