The Role of Digestive Enzymes and Their Inhibitors in Human Digestion

so before digestive enzymes can begin digesting the proteins that we ingest into our body they have to be activated

VI the process of proteolytic activation proteolytic cleavage now the problem with proteolytic cleavage is once that

enzyme under goes proteolytic cleavage proteolytic cleavage cannot be reversed so once we break that peptide bond in

that uh zymogen to form the active form of that Digest of enzyme that process cannot be reversed so that implies that

proteolytic cleavage is a one-way Street the question is once we activate our digestive enzymes and once our digestive

enzymes actually carry out their function what happens to those digestive enzymes that actually turns off the

activity of those enzymes because once we break down all the macromolecules that we ingest we want to be ble to

actually turn off the activity of all the digestive enzymes because if we don't turn off the activity of these

digestive enzymes they will continue breaking down the proteins and that includes the proteins found surrounding

our cells in the extracellular environment so the question is because we don't want this to actually take

place we don't want our digestive enzymes to basically damage our own tissue what we do is our cells use

Inhibitors irreversible Inhibitors to basically turn off and inhibit the activity of these functional enzym so

our body utilizes irreversible inhibition to switch off the functionality and the activity of many

different types of digestive enzymes and the ones we're going to focus on in this lecture is Trion and elast days so these

Inhibitors basically they bind into the active side of the enzyme and once they bind into the active side they block the

substrate molecule from actually entering the active side and by this manner because that inhibitor binds

irreversibly to the active side of the enzyme it basically blocks and inhibits the activity of that digestive enzyme so

let's begin by focusing on tripson and how our body actually regulates and turns off the activity of trip now

remember Trion is a very important digestive enzyme it's probably the most important one and that's because what

tripson does is it acts as a master activator and what that means is it basically activates all the different

types of digestive enzymes from their xymogen form into their active form in fact tripon not only activates Pro

elastase into elastase into carboxypeptidase kimat cinogen into

trogen it also activates it it also activates itself it activates trinen into Tron and it also activates prol

liase into lipase our digestive enzyme that is responsible for breaking down the light the lipids that we ingest into

our body so tripson is a very important digestive enzyme it's it's responsible for essentially coordin ating the

activation of all the different types of enzymes at the same exact time and that's precisely why it's very important

that our body has a very effective way of switching off the activity of tripon when it needs to so there's a special

type of inhibitor that our cell produce known as the pancreatic Tron inhibitor and this is basically what it looks like

so we have some Alpha chains we have the bit well actually we have one alpha chain and we have these two beta chains

now notice we have this single amino acid lysine 15 and it's lysine 15 that has a negative charge that is

responsible for binding to the positively charged Amino Acid found in the active side of Tron remember Tron is

a protease and inside the active side of Tron we have a specific type of residue that has a negative charge that plays

the role of catalyzing that reaction and so because the lysine 15 contains a negative charge it can interact very

well with that positively charged Amino Acid found in that active side of Trion so what pancreatic trips inhibitor does

is it acts as an affinity label a substrate analog and this is one example of irreversible inhibition this molecule

basically looks very much like the substrate molecule that binds into the active side of Tron in fact the

structure of this pancreatic Tron inhibitor is complementary to the structure found inside the active side

and that's exactly why upon binding to the active side this molecule doesn't actually change in uh it doesn't

actually change in shape because the shape of this molecule is already complementary to the shape of that

active side and once it binds onto that active side because of that perfect fit it does not dissociate it does not let

go and so it blocks the entrance of substrate molecules and in this manner it basically inhibits the activity of

Trion so pancreatic Tron inhibitor is an example of a highly potent irreversible inhibitor of Tron it binds very tightly

to trion's active side and blocks its activity and as I mentioned earlier pancreatic Tron inhibitor is a substrate

analog also known as an affinity label and it resembles the structure of that substrate molecule in fact the inhibitor

has a structure that is essentially complementary to that active side of tripson now inside our body we actually

have a relatively low concentration of pancre trips and inhibitor compared to the concentration of the actual

digestive enzyme Tron the question is if we have so much more Trion inside our body compared to the pancreatic tripon

inhibitor how is this inhibitor actually able to turn off the activity of digestion the breakdown of proteins and

lipids and other macromolecules well essentially because Tron plays such an important role in the activation of all

these different enzymes digestive enzymes basically inhibiting a small amount of

tripon really goes a long way because of the importance the role that tripson plays in the overall activation of our

digestion so pancreatic tripon inhibitor binds to Tron in the pancreas and in the ducts and even though the concentration

of Tron inhibitor is much lower than the concentration of Tron itself the inhibition of even a tiny number of

these Trion molecules goes a long way because of trion's role as this master activat because it plays such a crucial

role in activating the entire digestion process because it activates all the different types of digestion digestive

enzymes that exist inside our digestive system now the next question I'd like to ask is what exactly happened to our body

if the pancreatic trips inhibitor is either mutated in some way or we produce an inadequate amount of the pancreatic

trips inhibitor well if we don't have enough of this inhibitor what that means is we'll overproduce the Tron and we'll

have too many active Tron molecules inside our pancreas and if we have too many active tripon molecules what that

means is these active tripon molecules will begin to break down the extracellular proteins found surrounding

our cells inside the pancreas and this will cause the destruction of the tissue found in the pancreas and this condition

is a medical condition it has a name of acute pancreatitis so our inability to produce

adquate pancreatic tripson Inhibitors can lead to Serious tissue damage in the pancreas and this can lead to

inflammation of the pancreas a medical condition we call acute pancreatitis now remember Tron itself in

its zymogen form called uh proton is produced in the pancreas and so as it travels through the pancreatic ducts if

it's activated in those ducts it will basically begin to digest and break down the extracellular environment found

surround the cells in the pancreas if we don't have enough of this inhibitor to actually inhibit the activity of that

Trion now let's move on to another type of digestive enzyme and let's see how this enzyme is actually inactivated so

this enzyme we're going to focus on is elastase now elastase can be produced essentially in two major regions Al

lastas is either produced by the asinar cells found in the pancreas these are the ex cells that we spoke about

previously and this type of elastase is known as pancreatic elastase and the other source of elastase are wide blood

cells known as nutrifil and these are basically those uh cells that are able to actually engulf bacterial cells that

invade our body so we have pancreatic gastas and we also have neutrophilic gastas now pancreatic gastas it is used

to break down those um proteins that we ingest into our body but neutrophilic eles can be used by these wi blood cells

to actually break down and kill off bacterial cells but sometimes as we'll see in just a moment the neutrophilic

elastase can can also actually cause damage to our own extracellular tissue as we'll see in just a moment so we

conclude that elastase can be used to break down the proteins we ingest via food molecules and we can also use it to

basically destroy bacterial cells and in some case we can use it to basically destroy our own host

tissue now just like we have pancreatic Tron inhibitor that inhibits Tron we also have an irreversible inhibitor that

basically inhibits the activity of a last days and this type of inhibitor is known as alpha 1 anti-in now the reason

it's called antirion is because this also actually inhibits the activity of Tron so this inhibitor alpha1 anti-ron

can also bind into the active side of Tron and inhibit the activity of Tron but as it turns out although it does

bind to tripsin and inhibit trion's activity it binds much more effectively and it inhibits much more effectively

the activity of a last stas and so Alpha One anti-ps and binds into the active pocket the active side of the last days

it binds irreversibly doesn't dissociate from the active side and it blocks other substrate molecules from entering the

active site and therefore it inhibits the catalytic activity of el lastas now the next question is what

happens if this inhibitor alpha 1 anti-ron is actually inactivated so if we mutate the inhibitor in some way or

if our body simply isn't able to produce an adequate supply of this inhibitor what exactly happen so in the case of

inhibiting or destroying the pancreatic tripson inhibitor we saw that this can lead to acute

pancreatitis but in the case of destroying or mutating this inhibitor we essentially will have an excess amount

of el lastas now what exactly will that lead to well these nutrifil are found

predominantly in the boundary region between the outside and the inside environment and this means the lungs

because remember the alveoli of the lungs basically create that boundary between the outside environment the air

and the inside environment and so these nutrifil are going to be found predominantly in the alveoli of our

lungs and if we somehow inhibit the activity of the alpha1 antirion if our body doesn't produce enough alpha1

antirion or if you if we mutate alpha1 antirion in some fashion what that means is these nutrifil will essentially

produce too many of these elastase molecules and if we have too many active elastase molecules inside our alveoli

these elastase will begin to Break Down The alvioli Walls of our lungs and by breaking down the extracellular tissue

inside the alveoli of the lungs what that does is it basically decreases the elasticity of those alvioli and what

that means is we're going to have a much harder time breathing so we have to breathe harder to basically Exchange

change the same volume of air as in the normal case and this condition is known as Anisa so pulmonary empyema is the

process by which we have the breakdown of the tissue found in the lungs and that basically leads to change in the

property of those alveoli and that makes it much more difficult to actually breathe so we see that mutation or

inadequate concentration of alpha1 anti-ri can lead to tissue damage particularly the tissue found in the

lungs and that's because those nutrifil are found at the boundary between the outside and the inside that is the lungs

and so if the nutrifil release too many elast days and those eles are not deactivated are not inhibited by this

alpha 1 antirion that can basically lead to destruction of the tissue found in those Alvar walls and that can lead to a

pulmonary physa or simply anasma this is known as destructive lung disease now since we're on the topic of

enyma let's actually talk about how smoking can lead to this condition known as enyma and what smoking actually does

to this particular inhibitor so basically when we're smoking we're creating a bunch of different types of

oxidizing agents and so when we smoke when we inhale that smoke all these different types of oxidizing