An overview of rapamycin: from discovery to future perspectives.
Rapamycin is an immunosuppressive metabolite produced from several actinomycete species. Besides its immunosuppressive activity, rapamycin and its analogs have additional therapeutic potentials, including antifungal, antitumor, neuroprotective/neuroregenerative, and lifespan extension activities. The core structure of rapamycin is derived from (4R,5R)-4,5-dihydrocyclohex-1-ene-carboxylic acid that is extended by polyketide synthase. The resulting linear polyketide chain is cyclized by incorporating pipecolate and further decorated by post-PKS modification enzymes. Herein, we review the discovery and biological activities of rapamycin as well as its mechanism of action, mechanistic target, biosynthesis, and regulation. In addition, we introduce the many efforts directed at enhancing the production of rapamycin and generating diverse analogs and also explore future perspectives in rapamycin research. This review will also emphasize the remarkable pilot studies on the biosynthesis and production improvement of rapamycin by Dr. Demain, one of the world's distinguished scientists in industrial microbiology and biotechnology.
Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, 120-750, Republic of Korea.
Young Ji
YJ
Yoo
Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, 48109, USA.
Hanseong
H
Kim
Natural Products Discovery Institute, The Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, PA, 18902, USA. sung.park@bblumberg.org.
Sung Ryeol
SR
Park
Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, 120-750, Republic of Korea. joonyoon@ewha.ac.kr.
Yeo Joon
YJ
Yoon
D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D020123:Sirolimus / Q000737:chemistry* / Q000494:pharmacology*; D013302:Streptomyces / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D007166:Immunosuppressive Agents; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
Biological activity; Biosynthesis; Mechanism of action; Production enhancement; Rapamycin