Thread by @ssfarouk

1/

Here's another #immunosuppression #tweetorial. This time, a focus on mycophenolic acid (MPA). #MMF #Mycophenolate

The main mechanism of action of MPA is inhibition of which of the following:

2/ Let's meet the players. Mycophenolate mofetil (MMF, left) is a prodrug of MPA while mycophenolate sodium (MPS, right) is an enteric-coated salt of MPA.

MMF administration releases MPA in the stomach, while mycophenolate sodium (MPS) releases it in the small intestine.

3/ MPA is often referred to as an "anti-metabolite", which means a substance that interrupts a metabolic process within cells.

The process that MPA interrupts here: PURINE SYNTHESIS

4/ Purines can be either synthesized de novo or salvaged from nucleotide degradation products.

Which purine synthesis pathway does MPA inhibit?

5/ MPA inhibits the DE NOVO purine synthesis pathway.

Lymphocytes don't really use the salvage pathway, which uses bases/nucleosides from degraded DNA/RNA to build nucleotides.

T & B cells like to build their nucleotides DE NOVO (i.e. from scratch) from simple molecules.

6/ Now some alphabet soup...

Inosine monophosphate dehydrogenase (IMP-DH) a DE NOVO purine synthesis pathway enzyme that converts IMP to guanosine monophosphate (GMP).

MPA 🛑 IMPDH and ultimately ⬇️ stores of guanine, leading to ⬇️

ncbi.nlm.nih.gov/pubmed/19436616

7/ Gastrointestinal adverse effects are common and include diarrhea, nausea, and vomiting. Enteric-coated MPS was developed to try to help with these, though GI side effects have been shown to be similar in clinical studies.

https://www.ncbi.nlm.nih/pubmed/21486609

8/ Enterocytes, like lymphocytes, use the DE NOVO purine synthesis pathway and thus are susceptible to MPA-induced injury.

MMF-induced colitis has been described and endoscopic biopsies may reveal inflammatory changes that mimic IBD.

ncbi.nlm.nih.gov/pubmed/24025088

9/ Let's stop there. The take home messages:

1. T + B cells use the DE NOVO purine synthesis pathway
2. MPA is an anti-metabolite, 🛑 an important enzyme in the de novo pathway, IMPDH
3. GI adverse effects are common + may be related to 🛑 of the de novo pathway in enterocytes