Researchers unlock mystery of immunosuppressive drug's biosynthesis

Mycophenolic acid (MPA), discovered in 1893, was the first natural antibiotic to be isolated and crystallized in human history. Today, this fungal metabolite has been developed into multiple first-line immunosuppressive drugs to control immunologic rejection during organ transplantation and treat various autoimmune diseases.

However, the biogenesis of such an old and important molecule was an unsolved mystery for more than a century.

Recently, scientists from the Qingdao Institute of Bioenergy and Bioprocess Technology (QIBEBT) of the Chinese Academy of Sciences cracked this intriguing black box by fully elucidating the biosynthetic pathway of MPA. The results were published in Proceedings of the National Academy of Sciences of the United States of America (PNAS).

The researchers revealed that MPA biogenesis requires very unique cooperation between biosynthetic enzymes and β-oxidation catabolic machinery.

Interestingly, the involved enzymes were observed to be compartmentalized in different organelles including cytoplasm, the endoplasmic reticulum, the Golgi apparatus, and peroxisomes.

In this pathway, the oxygenase MpaB', which is intriguingly homologous to a latex-clearing enzyme, was identified as the long-sought key enzyme responsible for oxidative cleavage of the farnesyl side chain that is structurally similar to rubber.

The resultant carboxylic acid intermediate allows it to be recognized by the fungal β-oxidation machinery located in the peroxisomes. The following successive β-oxidation chain-shortening process is elegantly gated by the peroxisomal acyl-CoA hydrolase MpaH', thus leading to efficient and specific production of MPA.

The scientists concluded that compartmentalized biosynthesis is likely a very important characteristic of natural product biosynthesis in higher organisms such as fungi and plants.

They hope their work will prompt more research on this phenomenon since there is only very limited knowledge about the subcellular localization of fungal biosynthetic enzymes and their involvement in product formation and intermediate trafficking.

The researchers also hope the insights gained from this study will encourage industrial strain improvements that would lower the cost of this popular immunosuppressive drug as well as novel drug development based on MPA structural derivatization.

Ultimately, we wish that millions of patients will benefit from this basic research"

Li Shengying, corresponding author of the study

Source:
Journal reference:

Shengying, L. et al. (2019) Compartmentalized biosynthesis of mycophenolic acid. PNAS. doi.org/10.1073/pnas.1821932116.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment
Post

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
Chemical genetics uncovers promising anti-COVID compounds