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Adenylate Cyclase Inhibitors: Definition & Overview

Instructor: Darla Reed

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

This lesson will remind you what adenylate cyclase is and what it does. Then you will further discover what kind of inhibitors block its action and their potential uses in medicine.

What is Adenylate Cyclase?

What is the difference between a knife and a ring if they're both made of metal? Their shape gives them different functions. Molecules in a cell also have different shapes and therefore different functions. Adenylate cyclase (AC) is an enzyme that helps in these changes.

One molecule, adenosine triphosphate(ATP), is the main energy source for cells. However, ATP structure can be altered so that the bonds between some of the atoms form a kind of circle. When this happens, the function of the molecule also changes. It goes from becoming a main energy source to a messenger for the cell called cyclic adenosine monophosphate(cAMP). This is where adenylate cyclase, or AC, comes in, it is the enzyme that changes ATP from an energy source to a messenger. This change happens super fast, ATP to cAMP is like Clark Kent changing to Superman.

AC is an enzyme that changes ATP to cAMP
AC changes ATP to cAMP

There are nine different isoforms, or types, of AC. Isoforms are kind of like twins. Each looks similar and does the same thing but each one is just a little bit different in their own way. AC has nine of them, all found in different kinds of cells. For example, AC1 and 8 can be found in brain tissue, while AC3 is found in your nose.

AC is anchored to the cell's membrane; similar to how a ship is anchored at shore (although one type of AC does float around like a ship). The part of the enzyme that changes ATP to cAMP, the active site, is inside the cell.

Isoforms have same function but different features
Isoforms have the same function but different features

AC Inhibition

Normally AC has to be turned on, like a light switch, in order to function. And just like a light switch, there are molecules that can turn off or block AC function called inhibitors.

One type of inhibitor is inhibitory G-protein (Gi). G-proteins have three parts, an alpha, beta, and gamma part. The beta and gamma often act together like best friends, but the alpha part is by far the most active.

Gi has 3 parts, alpha inhibits AC1 and AC5, while beta/gamma inhibits AC1
G-proteins have 3 subunits: alpha, beta and gamma

When it comes to inhibition, the alpha part can inhibit AC isoforms 1, 5, and 6, while the beta-gamma duo is known to inhibit AC1. There is still some uncertainty on just how Gi blocks AC function, whether it actually flips it off itself by binding to the active site, or affects a different part of the cell, like someone turning off the breaker so that even if you flip the switch on, it won't work.

Gi inhibits AC function, though we
Gi inhibits AC function

There are also competitive inhibitors of AC, molecules that compete with ATP for the active site, rather like two people trying to get the last popular toy left on the shelf. Competitive inhibitors of AC often have very complicated scientific names such as MANT-ITP (2'3'-O-(N-methylanthraniloyl)-Inosine 5'triphosphate).

competitive inhibitors block AC function
Competitive inhibitors block AC function

Another form of AC inhibition is non-competitive and includes allosteric inhibitors, which means molecules bind somewhere other than the active site and in doing so change the active site so that it doesn't work. Imagine the shopper rushing to nab the last toy gets to the store only to find it closed and is left to stare pitifully at the lone toy on the shelf, unable to get it. Like competitive inhibition, non-competitive and allosteric inhibitors often have long and complicated names like SQ22,536 (9-(tetrahydrofuryl)-adenine).

Non-competitive inhibitors block AC function
Non-competitive/allosteric inhibitors block AC function

One type of non-competitive AC inhibitors are purine site (P-site) inhibitors. They are analogs of the molecule adenosine. Analogs are kind of like distant cousins, they're related in some way to adenosine by structure and chemical composition, but aren't the same thing.

P-site inhibitors are analogs of adenosine; similar in composition
Analogs of adenosine have molecules in common

Other inhibitors working via competitive or non-competitive inhibition include: calcium (Ca2+) , known inhibitor of AC 5 and 6 and hydrogen sulfate(H2 S) which attacks AC at the genetic level. This means H2 S goes into the nucleus and tells it to stop making AC so there's less AC to function.

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