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Zymogen: Granules & Activation

Instructor: Darla Reed

Darla has taught undergraduate Enzyme Kinetics and has a doctorate in Basic Medical Science

In this lesson you will be reminded what a zymogen is, and discover what zymogen granules are: where they are found and how they and zymogens can be activated.

What Is a Zymogen?

Have you ever eaten a candy bar? Can you just pop it in your mouth? No, because first you have to remove the wrapper.

A zymogen is like a wrapped candy bar. In order to get to the good stuff, you need to tear away what's keeping you from it. Zymogens, or proenzymes, are enzymes that aren't functioning yet because their action is blocked by a 'wrapper'. The 'wrapper' can be a link between two amino acids (the building blocks of proteins), like a piece of string keeping a box closed. Or it can be an extra section of protein, like a jar lid.

Zymogens are inactive enzymes.
Zymogens are inactive enzymes with a single peptide bond or group of amino acids blocking function.

But what are enzymes? Enzymes are proteins that help chemical reactions happen faster via special places called active sites.

Enzymes have active sites.
Enzymes have active sites.

Imagine you want to make a fruit smoothie. You could hand-mush the fruit or put the fruit in a blender. The blender is like an enzyme; the active site is like the blades of the blender. The fruit becomes a fruit smoothie faster in the blender than if you squish it by hand.

Enzymes help make many things in the cell, but they can also unmake them. Enzymes that chop up proteins are called proteases.

Enzymes that degrade other proteins are proteases.
Some enzymes are proteases

When cells make enzymes, especially proteases, they often make them as zymogen, an inactive form of the enzyme. This is so they don't go crazy and are only used when needed. Imagine your reaction if your blender suddenly hopped about on the counter, out of control, spewing half-chopped fruit everywhere. The counter would be a mess, and so would the cell.

Zymogens also ensure the enzyme folds properly (has the correct 3-D form), make the enzyme stable in unfavorable environments, and allow the enzyme to go to the proper place so that it doesn't function where it's not supposed to.

You can recognize most zymogens by their name. Enzymes that begin with 'pro-' or end with '-gen' are often the zymogen form. For example: PROthrombin is the zymogen form of thrombin, an enzyme involved in blood clotting. PepsinoGEN is the zymogen form of pepsin, the enzyme found in your stomach that helps digest food.

Zymogen Activation

Zymogens are activated by snipping the bonds between two or more amino acids, rather like cutting a balloon string so that it floats away. When the bonds are cut, the enzyme changes its conformation, its 3-D structure, so that the active site is free or able to become active.

Activated zymogens change their 3-D structure.
Zymogens change their 3-D structure when they are activated

Upon activation, sometimes pieces of the protein completely leave the enzyme, like taking the wrapper off a candy bar. Other times, the pieces of protein fold in and become part of the enzyme, like a catapult being pulled back.

Zymogens can be activated by proteases that cut the amino acid bonds. They can also be activated by the environment and become autocatalytic. Autocatalysis is self-activation, and happens when something in the environment allows the zymogen to cut its own chemical bonds.

Environment can activate zymogen autocatalysis
Environmental factors aid in initiating autocatalysis of zymogens

Pepsinogen, for example, does not become pepsin until the pH is around 2-3. The extra hydrogens found in the lower pH makes the molecule cut its own bonds that are preventing it from functioning as a digestive enzyme.

What Are Zymogen Granules?

Inside the cells of your pancreas and salivary glands are proteases that can activate digestive enzymes. To make sure the proteases inside the cell can't change into the zymogen form before they are released into your digestive system, the cell uses special holding rooms called granules.

Zymogen granules are places in the cell that keep zymogens safe from the proteases inside the cell. They are like little rooms, or little bubbles, full of different types of zymogens.

Zymogen granule inside a cell
Zymogen granule

They are mostly found in acinar cells. Acinar cells are cells found in the pancreas and salivary glands that group together like the bumps on a raspberry.

Acinar cells
Acinar cell, histology and rendered example

Most zymogen granules begin formation where the zymogens are first formed - the endoplasmic reticulum (ER). The ER is like the cell's factory; it's where proteins are made. From there, they are sent to the Golgi. The Golgi is like the cell's post office; it's where finished products are packed and shipped to different parts of the cell. From the Golgi, fully formed zymogen granules begin to gather at the apex, or the top of the cell.

Zymogen granules move from the ER, to the Golgi, and then to the apex.
Zymogen granules move from ER to apex

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