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Pepsin is a protease that operates in the acid pH of the stomach. Many proteins are denatured at low pH, and most enzymes — whether or not they denature — require a higher pH for activity.

Why is pepsin not denatured at low pH, and has catalytic activity at low pH, but not at higher pH?

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  • $\begingroup$ Are you confusing inactivity with denaturation? Have you investigated how high and low pH can denature proteins (or inactivate enzymes without denaturing them)? Don't just say "if this happens to X why doesn't it happen to Y?", but show you understand why it happens to Y. $\endgroup$ – David Jun 4 '18 at 18:53
  • $\begingroup$ I think i may be referring to inactivity, why does pepsin become more inactive in more basic environments? $\endgroup$ – BioKid Jun 5 '18 at 7:41
  • $\begingroup$ OK. I have edited your question so that it does not mix up activity and structural native state, and focussed particularly on pepsin so perhaps it is no longer a duplicate. You can revert if you wish. $\endgroup$ – David Jun 5 '18 at 13:23
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The aspects of this question relating to the effect of pH on enzyme activity have been dealt with previously on SE Biology questions and answers:

  1. Why does pH have an effect on enzymes?
  2. How can ionized amino acid form be important for the catalytic activity?

Their relevance to the situatio of pepsin can be summarized:

  • The forces stabilizing the native three-dimensional (tertiary) structure of proteins include ionic and partial ionic (hydrogen-) bonds. It is thought that high concentrations of charged hydrogen ions or hydroxyl ions compete for the ionic or polar residues involved in these interactions disrupting the structure — denaturing it.
    The effect of such ions will vary from protein to protein depending on the number and strength of these interactions. One presumes pepsin has evolved a structure with interactions that are less susceptible to a high concentration of hydrogen ions and therefore does not denature at low pH.
  • Catalysis often involves ionization of groups on the enzyme, not merely to bind substrates, but also to participate in the reaction. Typically the reaction mechanism involves flipping from ionized to deionized state or vice versa. Hence, the optimum pH for an enzymic reaction is often at the pKa of the ionizing group (in the environment of the protein), as this is the pH of half ionization.
    The reaction mechanism of pepsin, an aspartic protease, involves two aspartate residues, each of which has a low pKa, explaining why pepsin works optimally at low pH.

Mechanism of action of aspartic proteases

The catalytic mechanisms of other proteases (serine proteases and cysteine proteases) do not involve ionization changes in aspartic acid, which is why they operate at higher pHs.

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A good question. As you have accurately described, pepsin is indeed a protein, more specifically, a protease enzyme - a catalyst which assists the break-down of protein at certain amino-acid markers such as tryptophan and phenylalanine. As you are likely aware, proteins are composed from approximately 20 amino-acids, as shown below.

Amino-acids

However, the chemical properties of a protein are constituted by its folding - its three-dimensional shape. This answer describes some superficial differences between protein families and the mechanism and function whereby pepsin is capable of functioning at a low pH.

Protein structures

Disregarding any post-translational modifications - the alterations made to a protein following translation from mRNA - proteins are made from a determined sequence of amino-acids, named its primary structure. Different classes of proteins shall have a different sequence and proportion of various amino-acids. For example, collagen fibrils are composed from a greater proportion of the amino-acids glycine-proline-hydroxyproline.

A sample of pepsin extracted from a pig (Porcine pepsin) demonstrated a higher yield of asparagine.

Secondary structure - the inter-molecular bonding between amino-acid side-chains including hydrogen-bonding and disulfide bridge. As you correctly described a protein denaturing, it is these bonds which are broken, thereby altering the protein's shape.

Although there be four principal protein structures - primary, secondary, tertiary and quaternary - the first two are most critical to understanding the ability for pepsin to withstand low pH. Pepsin is originally secreted into the stomach as a proenzyme - an inactive precursor to an enzyme - called pepsinogen. When food is ingested, both pepsinogen and hydrochloric acid are released into the stomach. Returning to our primary structure, pepsinogen possesses 44 additional amino-acids compared with the active enzyme. During acidic conditions, the pepsinogen auto-catalyses its own cleavage from the additional strand, folding into the correct form.

Therefore, other proteins in high acidic conditions lose their unique three-dimensional structure due to the breaking of these inter-molecular bonds. In a sense, denaturing only specifies a transformation into an inactive protein but could be stated for pepsinogen which is 'denatured' into pepsin which attains its activity in this 'denatured' form.

For more information regarding pepsin, I would advise the following Wikipedia page as an initial resource: https://en.wikipedia.org/wiki/Pepsin For information regarding collagen and porcine-pepsin composition, the following sources respectively may help: https://www.ncbi.nlm.nih.gov/books/NBK21582/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC427253/?page=2

I wish you good digestion!

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  • $\begingroup$ So after all that I have indigestion because I don't see any answer to the question in what you have written. Can you summarize in one or two sentences? $\endgroup$ – David Jun 4 '18 at 18:47
  • $\begingroup$ @David It appeared that the Original Poster needed to discriminate digested proteins from the enzyme pepsin itself. So, proteins have primary and secondary structure which provide the protein with its shape. Dietary proteins are denatured because of the breaking of secondary structure while pepsin (pepsinogen) is activated at low pH. Admittedly, because I did not explicitly refer to high pH, I will edit the post and insert this additional response. Thank you. $\endgroup$ – Epistemonaut Jun 4 '18 at 19:14

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