In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 18, No. 7 ( 2022-7-11), p. e1010615-
Abstract:
Tuberculosis (TB) is one of the leading infectious diseases of global concern, and one quarter of the world’s population are TB carriers. Biotin metabolism appears to be an attractive anti-TB drug target. However, the first-stage of mycobacterial biotin synthesis is fragmentarily understood. Here we report that three evolutionarily-distinct BioH isoenzymes (BioH1 to BioH3) are programmed in biotin synthesis of Mycobacterium smegmatis . Expression of an individual bioH isoform is sufficient to allow the growth of an Escherichia coli Δ bioH mutant on the non-permissive condition lacking biotin. The enzymatic activity in vitro combined with biotin bioassay in vivo reveals that BioH2 and BioH3 are capable of removing methyl moiety from pimeloyl-ACP methyl ester to give pimeloyl-ACP, a cognate precursor for biotin synthesis. In particular, we determine the crystal structure of dimeric BioH3 at 2.27Å, featuring a unique lid domain. Apart from its catalytic triad, we also dissect the substrate recognition of BioH3 by pimeloyl-ACP methyl ester. The removal of triple bioH isoforms (Δ bioH1 / 2 / 3 ) renders M . smegmatis biotin auxotrophic. Along with the newly-identified Tam/BioC, the discovery of three unusual BioH isoforms defines an atypical ‘BioC-BioH(3)’ paradigm for the first-stage of mycobacterial biotin synthesis. This study solves a long-standing puzzle in mycobacterial nutritional immunity, providing an alternative anti-TB drug target.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1010615
DOI:
10.1371/journal.ppat.1010615.g001
DOI:
10.1371/journal.ppat.1010615.g002
DOI:
10.1371/journal.ppat.1010615.g003
DOI:
10.1371/journal.ppat.1010615.g004
DOI:
10.1371/journal.ppat.1010615.g005
DOI:
10.1371/journal.ppat.1010615.g006
DOI:
10.1371/journal.ppat.1010615.g007
DOI:
10.1371/journal.ppat.1010615.g008
DOI:
10.1371/journal.ppat.1010615.t001
DOI:
10.1371/journal.ppat.1010615.s001
DOI:
10.1371/journal.ppat.1010615.s002
DOI:
10.1371/journal.ppat.1010615.s003
DOI:
10.1371/journal.ppat.1010615.s004
DOI:
10.1371/journal.ppat.1010615.s005
DOI:
10.1371/journal.ppat.1010615.s006
DOI:
10.1371/journal.ppat.1010615.s007
DOI:
10.1371/journal.ppat.1010615.s008
DOI:
10.1371/journal.ppat.1010615.s009
DOI:
10.1371/journal.ppat.1010615.s010
DOI:
10.1371/journal.ppat.1010615.s011
DOI:
10.1371/journal.ppat.1010615.s012
DOI:
10.1371/journal.ppat.1010615.s013
DOI:
10.1371/journal.ppat.1010615.s014
DOI:
10.1371/journal.ppat.1010615.s015
DOI:
10.1371/journal.ppat.1010615.s016
DOI:
10.1371/journal.ppat.1010615.s017
DOI:
10.1371/journal.ppat.1010615.s018
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2205412-1
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