Purine Catabolism & Disorders

Purine Catabolism & Related Disorders

Here, we'll learn about purine catabolism and its related disorders.

Overview

Adenosine deaminase deficiency deficiency leads to severe combined immunodeficiency disorder (SCID).
In the purine salvage pathway, the absence of hypoxanthine-guanine phosphoribosyltransferase leads to Lesch-Nyhan syndrome.
Hyperuricemia (excess uric acid production) leads to gout (aka, gouty arthritis).

*Purine Catabolism (overview)*

Next, show that an important intermediary in purine catabolism is xanthine, which we show, now:

We draw it out like AMP but without the amine group from the C6 (which tells us that AMP must get deaminated (lose its amine group))
& instead include oxygen molecules double bonded to the C6 and C2 carbons (which tells us that the AMP ultimately undergoes oxidation reactions).
We also exclude the ribose molecule (which, as we'll see is removed in the conversion from inosine to hypoxanthine).

which is much like xanthine but has undergone further oxidation and is also deprotonated (which we'll see is relevant to the relationship between uric acid and urate).

Purine catabolism

Now, let's learn the individual steps in purine catabolism.

Show that via a nucleotidase catalyzed reaction, water is introduced and AMP loses its phosphate.

See if you can draw out the end-result knowing that adenosine is a ribonucleoside. Remember a nucleoside is the nucleic acid without the phosphate (whereas the nucleotide contains the phosphate). So the molecule we've drawn is the same as AMP but without the phosphate at the 5' end of the ribose.

So redraw adenosine but show that the C6 loses its amino group, which is instead replaced with an oxygen from a water molecule. This step accounts for the fact that xanthine was deaminated. We'll see that guanine does not require this kind of conversion (its breakdown is much simpler).

severe combined immunodeficiency disorder (SCID)

We show an image of David Vetter (the original "Bubble Boy") to remember the severe environmental protection needed to ward off pathogens in this disorder.

Purine catabolism (cont.)

Next, show that inosine converts to hypoxanthine (we show it, now, as insonine but without the ribose group*).

The ribose group is removed and added to a phosphate to form ribose 1-phosphate, which is catalyzed by nucleotide phosphorylase.
Importantly, show that ribose 1-phosphate is isomerized to ribose 5-phosphate by phosphopentomutase.
Then forms 5-phosphoribosyl-1-pyrophosphate, which we saw was critical to pyrimidine and purine nucleic acid biosynthesis.

Show that guanine passes directly to xanthine (after first being broken down from the nucleotide (GMP) to the nucleoside (guanosine) to the purine base (guanine)).
Next, introduce Lesch-Nyhan syndrome, which results from a deficiency of hypoxanthine-guanine phosophoribosyltransferase (HGPRT), a fundamental enzyme in the purine salvage pathway.

Purine Salvage Pathway

Indicate guanine and hypoxanthine (the byproduct of adenine).
Show that hypoxanthine-guanine phosophoribosyltransferase is responsible for the conversion of these free nucleic acid bases to their nucleotide counterparts: GMP and IMP, respectively.
Then, show that IMP goes on to convert to AMP (the nucleotide), which is the product of adenine (the free nucleic base).

Lesch-Nyhan syndrome

There are high levels of urate from a deficiency of hypoxanthine-guanine phosophoribosyltransferase (HGPRT).
Indicate that it notably results in a neurocognitive disorder that consists of:

Cognitive dysfunction
Self-mutilation (we show an image of dermatophagia, an obsessive gnawing of the skin to remember the self-mutilation).

Purine catabolism (cont.)

Show that it's similar to xanthine but is further oxidated and show that uric acid is deprotonated to to form urate.

So, let's introduce xanthine oxidase, which is key to the conversion of hypoxanthine to xanthine and also the conversion of xanthine to uric acid.
Show that these oxidation reactions require the addition of oxygen and water, which result in the formation of hydrogen peroxide.
Importantly, indicate that the drug allopurinol, a key medication in gout management, inhibits the conversion of hypoxanthine to xanthine and also xanthine to uric acid.
Allopurinol acts as a substrate for xanthine oxidase (it usurps it) to convert itself to alloxanthine. Then, the alloxanthine acts as an inhibitor of xanthine oxidase because it remains tightly bound to the enzyme's active site, called suicide inhibition.
Indicate that allopurinol is also used in the management of Lesch-Nyhan syndrome.
Now, introduce the pathological condition of gout.
Indicate that in this condition there are chronic levels of hyperuricemia, typically from overproduction of uric acid (rather than under excretion).

We show an XRay of a great toe and encircle gouty arthritis.
Urate crystals supersaturate (from reduced urate solubility), and then nucleate (cluster) and grow. Because not all patients with hyperuricemia develop gout, much study has gone to determine what physiological conditions enhance its pathological development.
Indicate that the following conditions are believed to enhance the promotion of crystallization of uric acid in the setting of hyperuricemia: pH of 7—9, colder temperatures, and higher sodium concentrations.

Gout

Now, take a moment to write out that gout results from high levels of urate.
Indicate that urate's sodium salt crystallizes and causes painful accumulation in the joints.
We show a gouty tophus under H&E section.
And we show a slide of needle-shaped gouty crystals.

Gout Treatments

Finally, let's consider some of the treatment strategies for gout.

In acute gout, it's common to administer anti-inflammatories, such as colchicine.
In chronic gout, other treatment approaches are taken:

Uricosuric agents, such as probenecid, are used to decrease the reabsorption of uric acid in the renal tubule.
Uric acid inhibitors, such as allopurinol, inhibit uric acid production.
Pegloticase is a uricase that converts uric acid to allantoin.

Special Thanks (Images)

Dermatophagia in Lesch-Nyhan Syndrome: 6th Happiness* Gouty Tophus: Hellerhoff* Gouty Crystals: Ed Uthman (from Houston, TX, USA)*