Year: 2024
Type: article
Abstract: Akira Endo, a scientist whose discovery saved millions of lives, died on June 5, 2024, at the age of 90.In 1972, while working as a biochemist at the Sankyo Pharmaceutical Company in Tokyo, Endo discovered a natural product that blocked the synthesis of cholesterol in animal cells.Isolated from a bluegreen mold, Endo's chemical was the first statin, a class of drugs that lower plasma cholesterol and prevent heart attacks.Ingested daily by more than 40 million Americans, statins rank with penicillin as among the most beneficial advances in human health.Born in 1933, Endo grew up on a farm in northern Japan.His interest in natural products was aroused when he read a biography of Alexander Fleming, who discovered penicillin, an antibacterial molecule produced by a blue-green mold.After graduating from Tohoku University in 1957, Endo joined the Sankyo Company as a biochemist.In the tradition of Fleming, Endo worked on a project that aimed to isolate useful products from molds.He was so successful that Sankyo provided a fellowship for him to study for two years in the United States.He was accepted into the laboratory of the noted biochemist Bernard Horecker at the Albert Einstein College of Medicine in New York.Although he had already developed an interest in cholesterol, this was not Horecker's interest, so Endo worked on enzymes involved in the synthesis of bacterial cell walls.Nevertheless, the training in enzymology was crucial to his future success in identifying the target of the first statin ( 1 ).Upon his return to Sankyo in 1968, Endo was given the rare opportunity to attack a pure science problem that had no immediate commercial application.Stimulated by the mounting evidence that high blood cholesterol causes heart attacks, Endo chose to search for an inhibitor of cholesterol synthesis.Over the previous two decades, the biochemists Konrad Bloch, Feodor Lynen, and John Cornforth had brilliantly elucidated the complex pathway by which organisms synthesize 27-carbon cholesterol from 2-carbon acetate.Of the 26 enzymatic steps in the pathway, the rate-limiting one had been identified as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), which catalyzes the first committed step. Screening 3800 Fungal Extracts: The First StatinUnable to measure HMG CoA reductase activity directly, Endo adopted an assay to measure the incorporation of radioactive 14 C-acetate into 14 C-cholesterol in homogenates of rat liver.Inspired by Fleming's experience, Endo screened through Sankyo's extensive collection of 3800 fungal species to find a chemical that inhibited 14 C-acetate incorporation.In the summer of 1972, he hit paydirt-both literally and figuratively.The active compound was produced by a blue-green mold, Penicillium citrinum, that grew in the rice fields near Kyoto.Remarkably, this mold belongs to the same Penicillium genus that had yielded Fleming's penicillin.Endo named his compound ML-236B.The statin field was born ( 1 , 2 ).Endo soon showed that ML-236B blocks cholesterol synthesis by inhibiting HMG CoA reductase, and he soon found out why.ML-236B contains a side chain that is identical to mevalonate, the product of HMG CoA reductase, and it acts
Authors: Joseph L. Goldstein, Michael S. Brown
Institution: The University of Texas Southwestern Medical Center
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4402697917