NDLI: Substrate specificity of Rv3378c, an enzyme from Mycobacterium tuberculosis, and the inhibitory activity of the bicyclic diterpenoids against macrophage phagocytosis

Content Provider	Royal Society of Chemistry (RSC)
Author	Hoshino, Tsutomu Shinohara, Yosuke Hara, Takashi Ootsuka, Takahiro Nakano, Chiaki
Copyright Year	2011
Abstract	The Rv3378c gene product from Mycobacterium tuberculosis encodes a diterpene synthase to produce tuberculosinol (3), 13R-isotuberculosinol (4a), and 13S-isotuberculosinol (4b) from tuberculosinyl diphosphate (2). The product distribution ratios are 1 : 1 for 3 to 4 and 1 : 3 for 4a to 4b. The substrate specificity of the Rv3378c-encoded enzyme was examined. The 3 labdadienyl diphosphates, copalyl diphosphate (CDP) (7), ent-CDP (8), and syn-CDP (9), underwent the conversion reaction, with good yields (67–78%). Copalol (23) and manool (24) were produced from 7, ent-copalol (25) and ent-manool (26) from 8, and syn-copalol (27) and vitexifolin A (28) from 9. The ratio of 23 to 24 was 40 : 27, that of 25:26 was 22 : 50, and that of 27:28 was 16 : 62. Analysis on a GC-MS chromatograph equipped with a chiral column revealed that 24, 26, and 28 consisted of a mixture of 13R- (a) and 13S-stereoisomers (b) in the following ratio: ca. 1 : 1 for 24a to 24b, ca. 1 : 5 for 26a to 26b, and ca. 1 : 19 for 28a to 28b. The structures of these products indicate that the reactions of the 3 CDPs proceeded in the same fashion as that of 2. This is the first report on the enzymatic synthesis of natural diterpenes manool, ent-manool, and vitexifolin A. Both Rv3377c and Rv3378c genes are found in virulent Mycobacterium species, but not in avirulent species. We found that 3 and 4 inhibited the phagocytosis of opsonized zymosan particles by human macrophage-like cells. Interestingly, the inhibitory activity was synergistically increased by the coexistence of 3 and 4b. Other labdane-related diterpenes, 13–16 and 23–28, had little or no inhibitory activity. This synergistic inhibition by 3 and 4 may provide further advantage to the impairment of phagocyte function, which might contribute to pathogenicity of M. tuberculosis.
Starting Page	2156
Ending Page	2165
Page Count	10
File Format	HTM / HTML PDF
ISSN	14770520
Volume Number	9
Issue Number	7
Journal	Organic & Biomolecular Chemistry
DOI	10.1039/c0ob00884b
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Zymosan Gas chromatography\u2013mass spectrometry Mycobacterium Terpene Gene Mycobacterium tuberculosis Enzyme Opsonin Pyrophosphate Phagocytosis Phagocyte
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Biochemistry Physical and Theoretical Chemistry

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