Covalent Modification Control – Metabolic Control of Enzyme Activity

by Kevin Ahern, PhD

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    00:01 Another consideration for the control of metabolic pathways is covalent modification of enzymes and I am going to give a couple of examples here; because, they each illustrate important principles.

    00:11 The first is this reaction that you can see on the screen.

    00:14 Trypsinogen is an inactive form of a proteolytic enzyme that we have in our digestive system called trypsin.

    00:23 Now our digestive system has some enzymes that are designed to do some really nasty things to the food that we eat.

    00:28 Nasty in the sense that they just rip them apart.

    00:31 These proteases take proteins, that are in our diet, and break them into smaller pieces.

    00:37 And they work very very efficiently and they are very very powerful in doing what they do.

    00:44 The problem is if they are not controlled properly, they can attack the very tissues that make them.

    00:50 And that's a problem. So for that reason when we have very powerful enzymes that could act chaos within a cell. Many times those proteins are made in an inactive form and that's the zymogen form that I referred to.

    01:04 Well, how is it that these proteins become active? One of the ways it happens for the proteases that we can see here is by action of another protease that has to break a bond to convert the zymogen, which is the inactive form, into the active form.

    01:21 Now as you might imagine that enteropeptidase that's seen here is located some place away from the place where the trypsinogen is made.

    01:29 The trypsinogen is made in our pancreas as are many proteolytic enzymes.

    01:36 Now if trypsin were active at the pancreas where the trypsinogen is synthesized, then trypsin being a protease could attack the proteins in the pancreas.

    01:44 Now, that actually does happen sometimes.

    01:48 There is a sickness called pancreatitis that is very painful and happens when the zymogens that are made in the pancreas get activated too soon.

    01:57 When that happens they attack the pancreas and some severe problems can result as a result of that including fatality. So, managing this zymogen activity is very important.

    02:09 Well, this is only one of several different zymogens that are made in the pancreas and we can see some others and we can also see some hierarchy here.

    02:18 Trypsin becomes activated by enteropeptidase and when it's active, it starts activating other proteases.

    02:25 One of those proteases is chymotrypsinogen which become chymotrypsin upon activation.

    02:31 Trypsin can also activate another protease called proelastase into the active form called elastase.

    02:37 Now these activations are typically happening inside of the digestive system where those proteases are really aim to work in the first place.

    02:47 A third zymogen that trypsin can activate is procarboxypeptidase and again this is involved in breaking down proteins in the digestive system.

    02:55 And last trypsin can activate an enzyme that breaks down fat as well and that enzyme that breaks down fat is called lipase.

    03:05 So managing where that lipase is active is important just like managing where the proteases are active as well.

    03:13 Now I show you this scheme; because, there is a very important principle and that's known as cascading affects.

    03:18 Cascading affects happen in a circumstance like what you see here where an enzyme on the left activates an enzyme in the middle, in this case, trypsin.

    03:29 Well, enzymes are very rapid in their function.

    03:32 So the enzyme in the left isn't activating just one trypsin. Let's imagine it's activating 10,000.

    03:39 Well, each of those 10,000 trypsins was able to go and activate another 10,000 of the individual molecules on the other side.

    03:47 The result of cascading affects like this is the enormous amplification of the signal very very quickly.

    03:54 So, by this doing cascading scheme that you see here what happens is, a few enteropeptidases can activate a lot of proteases and lipases ultimately.

    04:07 Now, I mentioned chymotrypsinogen and I wanna bring up its activation as well; because, it puts an additional ring to the process that I haven't talk about.

    04:17 Chymotrypsinogen is synthesized obviously in an inactive form. That's what the "ogen" on the end of the molecule's name says.

    04:26 Trypsin activates it by cutting a bond between amino acids 15 and 16. So you can see going on from the top line to the second line that there is a gap between 15 and 16.

    04:38 You also notice that the piece between 1 and 15 doesn't go flying away but it's held in place by that S-S bond.

    04:45 Now in a different presentation, I talked about the importance of disulphide bonds in terms of maintaining protein structure and here we can see a very graphic example of the value of a disulphide bond.

    04:57 Now chymotrypsin, in fact, the form of it's shown on the second line is called π-chymotrypsin.

    05:03 π-chymotrypsin is only partly active.

    05:06 It only works on a very select substrate and the select substrate it works on, is itself.

    05:14 The catalytic action of π-chymotrypsin is to make additional cuts in the chymotrypsin, as you see here, such that a fully active chymotrypsin is synthesized known as the α-chymotrypsin.

    05:29 The additional cuts include cutting off a two amino acid piece at amino acid number 13 and cutting out off three amino acid segment between amino acids 146 and 149.

    05:43 Now the result of those actions is to actually open up the active site of the enzyme.

    05:49 Prior to that final cleavage, the active site of the enzyme is not fully open but after that happens it is fully open and substrates can then get in and the enzyme can work on them.

    05:59 So in the very top form the enzyme is completely closed, or as I described earlier, sealed for your protection in a previous presentation and in the bottom line the enzyme is open for business.

    About the Lecture

    The lecture Covalent Modification Control – Metabolic Control of Enzyme Activity by Kevin Ahern, PhD is from the course Metabolic Control.

    Included Quiz Questions

    1. They are activated by cleaving of peptide bonds
    2. They are inactivated by cleaving of peptide bonds
    3. They are inactivated by phosphorylation
    4. They are created by phosphorylation
    1. It is activated by trypsin
    2. It partly activates itself by cleaving disulfide bonds
    3. It is made in an active form and inactivated by enteropeptidase
    4. It activates all of the other proteases by cleaving peptide bonds
    1. Enteropeptidase
    2. Chymotrypsinogen
    3. Proelastase
    4. Procarboxypeptidase
    5. Prolipase

    Author of lecture Covalent Modification Control – Metabolic Control of Enzyme Activity

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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