Abstract
A putative three-gene cluster for asperterpenoid A was identified. Step-wise reconstitution of this gene cluster in Aspergillus oryzae reveals that astC encodes a sesterterpene cyclase to synthesize preasperterpenoid A, which is dually oxidized by a P450 enzyme AstB to give asperterpenoid A along with a minor product asperterpenoid B, and asperterpenoid A is further oxidized by another P450 eznyme AstA to afford a new sesterterpenoid asperterpenoid C. Unexpectedly, asperterpenoids A and B, but not the final product asperterpenoid C, exhibit potent inhibitory activity against Mycobacterium tuberculosis protein tyrosine phosphatase B with IC50 values of 3-6 μM.
MeSH terms
-
Antitubercular Agents / metabolism*
-
Antitubercular Agents / pharmacology*
-
Aspergillus oryzae / enzymology
-
Aspergillus oryzae / genetics
-
Aspergillus oryzae / metabolism*
-
Biosynthetic Pathways
-
Cytochrome P-450 Enzyme System / metabolism
-
Enzyme Inhibitors / metabolism
-
Enzyme Inhibitors / pharmacology
-
Fungal Proteins / genetics
-
Fungal Proteins / metabolism
-
Humans
-
Lyases / metabolism
-
Multigene Family
-
Mycobacterium tuberculosis / drug effects
-
Mycobacterium tuberculosis / enzymology*
-
Protein Tyrosine Phosphatases / antagonists & inhibitors*
-
Sesquiterpenes / metabolism*
-
Sesquiterpenes / pharmacology*
-
Tuberculosis / drug therapy
Substances
-
Antitubercular Agents
-
Enzyme Inhibitors
-
Fungal Proteins
-
Sesquiterpenes
-
asperterpenoid A
-
Cytochrome P-450 Enzyme System
-
Protein Tyrosine Phosphatases
-
Lyases