Advance Glycated End Products (AGEs)

We learnt a lot about High Blood sugar, Insulin Resistance, inflammation, and then its impact on atherosclerosis. All these are very closely intertwined.

?But one of the important physiological processes, that remain silently behind these processes, which also need to be discussed is called Advance Glycated End products or AGEs.

?AGEs are molecules that are formed, when protein binds with a covalent bond to a molecule of glucose. We can also say, protein gets glycated chemically. Let’s first understand, how they're formed and then some of the biological effects they have.

?Glucose has three major forms. The two most prominent ones are the cyclic forms; alpha isomer and beta isomer. They form a ring like structure. Therefore, they are also called as cyclic form of glucose. Then there is a very small concentration of the linear or straight chain form, also called acyclic form, as it doesn't form a ring.

However, in biological systems the alpha and beta isomers are constantly interconverting between one another. But for the alpha isomer to get to the beta & beta isomer to alpha, first it must decyclize into the linear form and then it can recycle into the other cyclic isomer.

?At any given time, the linear acyclic isomers are very small in numbers but there is some of these acyclic, linear form of glucose, the aldehyde functional group, labeled as position 1 is very reactive, particularly to the amino acid lysine.

When come in contact, the lone pair of the nitrogen in the amino acid lysine, can nucleophilically attack the carbon of that aldehyde, and this forms a covalent bond.

?The next step is a Schiff base formation, an intermediate rearrangement of the double bonds between nitrogen & carbon. The double bond formation, results in the loss of one (H2O) water molecule.

?In this entire process, there is no requirement of any enzyme & this happens spontaneously. Therefore, these are non-enzymatic reactions.

?The last step is the Amadori rearrangement, which is again a rearrangement of the bonds. There is a nitrogen carbon single bond & carbon oxygen double bond, and this is the most stable of all these forms.

?The protein here is different, as it is now chemically bonded to the glucose. Meaning the protein has now become glycated.

Why is this relevant?

Well, number one – this new molecule, a form of the original protein, is now bound to the glucose molecule, and it cannot reverse itself to its original structure. It’s an irreversible reaction. And number two - this new molecule, where we have a protein-glucose-adduct, and this is termed an advance glycated end product or an AGE. ?Now, we have this protein that's been glycated.

?There is always glucose in the blood at any given time. Every single person has blood glucose, that’s what our cells run on.?With normal healthy blood glucose, in a healthy individual, the AGE formation process happens always in a small extent. And there are mechanisms in place within our body, to get rid of these AGEs and keep them at bay. It is the extent of their formation that dictates health versus disease.

?In a healthy individual, the fasting blood sugar value should be somewhere between 70 and 100 mg/DL.?That's a low & healthy value. Therefore, the number of AGEs that will form, will be very small & they're not really going to produce harmful effects in the body, as our body have the mechanism in place to counteract on them.

?However, it's when their production becomes excessive, that exceed the body's ability to get rid of them, then we start seeing their accumulation and their physiological effects.

?Diabetes & AGEs

?Hyperglycemia or chronic hyperglycemia is a condition where there's a lot of blood glucose, that’s what we see in individuals who consume high sugar diets and people with type2 diabetes.

So, with excess sugar in the blood, there is excess glycation of proteins. And you get an accumulation of these advanced glycation end products.

?So, what is their biological Effects?

?RAGE stands for “receptor of advance glycated end product”.??These receptors are present on certain immune cells, nerve cells, bone tissue & lungs cells.?

We're going to look at two major pathways.

?This is a macrophage and in the plasma membrane it has this protein called RAGE. The AGEs can bind to this protein and when they do, it activates certain pathways inside the cell.

The first pathway we're going to look at is the NOX pathway.?NOX is a membrane-bound protein called NADPH phagosome oxidase.?

?NADPH phagosome oxidase enzyme is a committed step in reactive oxidative species (ROS) synthesis.

But NADPH phagosome oxidase enzyme to get Activated, AGE must bind to its RAGE receptor. And when that happens there's an intracellular signalling cascade that occurs. And immediately, the activation of NOX NADPH Phagosome oxidase takes place.

?This enzyme catalyzes the irreversible conversion of molecular oxygen (O2) into the superoxide radical, which is a free radical. it is a reactive oxidative species.

?Recall body’s 3 enzymatic natural antioxidants: SOD- Superoxide Dismutase, Catalase & Glutathione

?The superoxide radical can be converted to hydrogen peroxide by SOD - superoxide dismutase. The resulting Hydrogen peroxide is not a free radical, but it is a reactive oxidative species (ROS).

?Hydrogen peroxide can react in one of two ways. One, it can react with this antioxidant enzyme Catalase.?Catalase is known as a protective Antioxidant enzyme. So, Catalase will get rid of hydrogen peroxide by converting it into water and molecular oxygen.?both of which are harmless.

?Alternately, hydrogen peroxide can react with iron in the (Ferrous state) Fe+2 state.?Fe+2 can reduce hydrogen peroxide into a molecule of water and a hydroxyl radical.

?Hydroxyl radicals are extremely dangerous. They're the most reactive of any of the reactive oxidative species. Hydroxyl radicals can damage membrane lipids, can damage DNA, can damage proteins and they can cause cellular damage.

In addition, they can also oxidize and damage LDL particles. And these Oxidised LDLs can cause a horrendous amount of damage especially when their production is excessive.

?So, activation of this NOX enzyme pathway will lead to the production of superoxide, hydrogen peroxide and hydroxyl radicals.

?It's also worth noting, that LDLs can also be glycated by glucose & itself be an AGE, which can also activate the RAGE receptor and move in a vicious cycle.

?These Glycated & oxidized LDLs that contribute to atherosclerosis, going to be up taken by macrophages which causes them to release inflammatory cytokines, differentiate into foam cells and that contributes to plaque formation.

The second pathway of the AGEs is NF kappa B.

?We have the advance glycated end product that binds to its receptor RAGE and RAGE can indirectly activate NF kappa b.??

RAGE activates the protein called IKK. IKK is a kinase protein & phosphorylates certain proteins.?Inside, we have a complex protein here, called I kappa B alpha. I kappa B alpha inhibits the function of RelA and p50.

?These two proteins ( RelA and p50) combined are actually NF kappa B.?As long as I kappa B alpha is bound to these two proteins, it keeps them inhibited. So, when RAGE activates IKK, IKK phosphorylates I kappa B alpha which lose grip on RelA & P50 and it floats away. The two phosphates then degraded via the proteasomal pathway & leaves a free RelA and p50.

?Collectively these two proteins are this NF kappa B which itself is a transcription factor. It comes into the nucleus through the nuclear pore complex and binds to specific elements on the DNA.

?NF kappa B requires other proteins like a co-activator & RNA polymerase. Also, it recruits RNA polymerase to a target gene, results in its transcription to mRNA. Then mRNA leaves the nucleus, into the cytoplasm where it's picked up by Ribosomes and translated into a protein.

?What are those proteins?

?It all started with an Advance Glycated product, which activated RAGE.?Do you think it's going to be pro-inflammatory or anti-inflammatory?

Well, it's going to be pro-inflammatory.

So, what we see here is, the AGEs bind to RAGE that activate the NF kappa B pathway, that changes the gene expression. It results in the production of inflammatory cytokines & a whole host of such proteins that are generated.

They also trigger the production of all sorts of other inflammatory molecules including production of oxidized LDL. These inflammatory cytokines & oxidized LDLs are going to contribute to inflammation and contribute to the progression of atherosclerosis.

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