1976: a mould yields the first cholesterol inhibitor

In 1976 Akira Endo, Masao Kuroda and Yoshio Tsujita described in The Journal of Antibiotics three new inhibitors of cholesterogenesis produced by the mould Penicillium citrinum: ML-236A, ML-236B and ML-236C. The same year, Endo and Kuroda published a result in FEBS Letters explaining the mechanism: ML-236A and ML-236B competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, the enzyme that sets the pace of the whole cholesterol synthesis pathway.

The starting point was ecological reasoning rather than pharmacology. Fungi compete with bacteria and other microorganisms by producing compounds that block their growth. If some microorganisms need sterols to build their membranes, then somewhere among fungal metabolites there should be substances that stop those sterols being made. Endo screened thousands of strains along that line of thought before arriving at Penicillium citrinum.

Three years later, in 1979, Endo described in the same journal monacolin K, produced by a fungus of the genus Monascus — the same one that has been used in East Asia for centuries to ferment red rice. The compound turned out to be identical to lovastatin, the first statin later approved for treatment. A drug and a traditional foodstuff met in a single molecule.

The story has two sides and both are worth naming. Statins are now among the most widely prescribed medicines in the world, and the path from a mould culture to a pharmacy is one of the best documented answers to the question of why anyone studies fungal secondary metabolites. At the same time ML-236B, compactin, never became a drug — its development was halted and other molecules reached the market first. Discovery and deployment are two different histories in medicine.

From three laboratory codes to a mechanism

In 1976 Akira Endo, Masao Kuroda and Yoshio Tsujita described three metabolites from cultures of Penicillium citrinum: ML-236A, ML-236B and ML-236C. This was the isolation of defined compounds, not merely an observation that a mould extract “lowered cholesterol.” Parallel enzyme experiments showed that ML-236A and ML-236B competitively inhibited HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, without comparably blocking the other tested steps in that pathway.

Endo’s separate 1979 paper reported monacolin K from Monascus ruber strain No. 1005, isolated from a food sample collected in Thailand. It records a ten-day culture, extraction from five litres of culture filtrate and recovery of 87 mg of crystals. That is a later stage in the chemical story. The 1976 papers establish the fungal metabolites and their enzyme target; they do not by themselves describe a finished clinical medicine.