Journal
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
Volume 89, Issue 6, Pages 1929-1938Publisher
SPRINGER
DOI: 10.1007/s00253-010-2983-7
Keywords
L-Isoleucine dioxygenase; 4-Hydroxyisoleucine; NAD(+)-dependent dehydrogenase; 2-Amino-3-methyl-4-ketopentanoic acid; Bacillus thuringiensis; TCA cycle
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Funding
- New Energy and Industrial Technology Development Organization (NEDO) of Japan [21780070]
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Grants-in-Aid for Scientific Research [21780070, 22658027] Funding Source: KAKEN
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4-Hydroxyisoleucine (HIL) found in fenugreek seeds has insulinotropic and anti-obesity effects and is expected to be a novel orally active drug for insulin-independent diabetes. Here, we show that the newly isolated strain Bacillus thuringiensis 2e2 and the closely related strain B. thuringiensis ATCC 35646 operate a novel metabolic pathway for L-isoleucine (L-Ile) via HIL and 2-amino-3-methyl-4-ketopentanoic acid (AMKP). The HIL synthesis was catalyzed stereoselectively by an a-ketoglutaric acid-dependent dioxygenase and to be useful for efficient production of a naturally occurring HIL isomer, (2S,3R,4S)HIL. The (2S,3R,4S)-HIL was oxidized to (2S,3R)-AMKP by a NAD(+)-dependent dehydrogenase. The metabolic pathway functions as an effective bypass pathway that compensates for the incomplete tricarboxylic acid (TCA) cycle in Bacillus species and also explains how AMKP, a vitamin B-12 antimetabolite with antibiotic activity, is synthesized. These novel findings pave a new way for the commercial production of HIL and also for AMKP.
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