Homodimericin A: A Complex Hexacyclic Fungal Metabolite.
Microbes sense and respond to their environment with small molecules, and discovering these molecules and identifying their functions informs chemistry, biology, and medicine. As part of a study of molecular exchanges between termite-associated actinobacteria and pathogenic fungi, we uncovered a remarkable fungal metabolite, homodimericin A, which is strongly upregulated by the bacterial metabolite bafilomycin C1. Homodimericin A is a hexacyclic polyketide with a carbon backbone containing eight contiguous stereogenic carbons in a C20 hexacyclic core. Only half of its carbon atoms have an attached hydrogen, which presented a significant challenge for NMR-based structural analysis. In spite of its microbial production and rich stereochemistry, homodimericin A occurs naturally as a racemic mixture. A plausible nonenzymatic reaction cascade leading from two identical achiral monomers to homodimericin A is presented, and homodimericin A's formation by this path, a six-electron oxidation, could be a response to oxidative stress triggered by bafilomycin C1.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 240 Longwood Avenue, Boston, Massachusetts 02115, United States.
Emily
E
Mevers
Process Research and Development, NMR Structure Elucidation Group, Merck & Co., Inc. , Mail Stop RY800-C163, 126 East Lincoln Avenue, Rahway, New Jersey 07065 United States.
Josep
J
Saurí
Process Research and Development, NMR Structure Elucidation Group, Merck & Co., Inc. , Mail Stop RY800-C163, 126 East Lincoln Avenue, Rahway, New Jersey 07065 United States.
Yizhou
Y
Liu
Advanced Chemistry Development, Inc. (ACD/Laboratories) Toronto Department, 8 King Street East, Suite 107, Toronto, ON M5C 1B5, Canada.
Arvin
A
Moser
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 240 Longwood Avenue, Boston, Massachusetts 02115, United States.
Timothy R
TR
Ramadhar
Advanced Chemistry Development, Inc. (ACD/Laboratories) Toronto Department, 8 King Street East, Suite 107, Toronto, ON M5C 1B5, Canada.
Maria
M
Varlan
Process Research and Development, NMR Structure Elucidation Group, Merck & Co., Inc. , Mail Stop RY800-C163, 126 East Lincoln Avenue, Rahway, New Jersey 07065 United States.
R Thomas
RT
Williamson
Process Research and Development, NMR Structure Elucidation Group, Merck & Co., Inc. , Mail Stop RY800-C163, 126 East Lincoln Avenue, Rahway, New Jersey 07065 United States.
Gary E
GE
Martin
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 240 Longwood Avenue, Boston, Massachusetts 02115, United States.
Jon
J
Clardy
D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology*; D043224:Deoxyribonuclease (Pyrimidine Dimer) / Q000737:chemistry* / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D061065:Polyketides / Q000737:chemistry* / Q000378:metabolism*; D014242:Trichoderma / Q000737:chemistry* / Q000378:metabolism; D015854:Up-Regulation; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism*
D000935:Antifungal Agents; D061065:Polyketides; D014764:Viral Proteins; C470698:endonuclease V, phage T4; D043224:Deoxyribonuclease (Pyrimidine Dimer)