Why Does Pepsin Have a Negative Charge at Very Low pH? An Analysis of Conserved Charged Residues in Aspartic Proteinases
Pepsin has several properties which are markedly different from those common for other proteins. It has a very low pH optimum for the hydrolysis of different substrates and a high activity at pH 2. This implies a very stable tertiary structure under conditions in which many proteins are fully denatured. These properties of pepsin are critical for its physiological function which takes place in the extreme acid conditions of the gastric lumen. There the unfolded hydrophobic cores of the proteins to be cleaved are exposed to the first hydrolytic attack by pepsin. Another very specific property of pepsin is its extremely low isoelectric point. It has a net negative charge in the range of low pH values including the pH optimum for catalytic activity. The proteins to be cleaved have a net positive charge in this range of pH. These molecular features of pepsin are closely interdependent as all of them are the consequence of the specific arrangements and interaction of the charged groups in the three-dimensional fold of the enzyme. Data on the refined porcine pepsin A structure at 1.8 Å resolution (Sielecki et al., 1990) have pointed towards their explanation. Porcine pepsin has also been refined at 2.3 Å resolution in the monoclinic crystal form by Abad-Zapatero et al. (1990) and in the hexagonal crystal form by Cooper et al. (1990).
KeywordsAspartic Proteinase Aspartic Acid Residue Porcine Pepsin Individual Hydrogen Bonding Stable Tertiary Structure
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