Abstract
A rare stereoisomer of inositol, scyllo-inositol, is a therapeutic agent that has shown potential efficacy in preventing Alzheimer’s disease. Mycobacterium tuberculosis ino1 encoding myo-inositol-1-phosphate (MI1P) synthase (MI1PS) was introduced into Bacillus subtilis to convert glucose-6-phosphate (G6P) into MI1P. We found that inactivation of pbuE elevated intracellular concentrations of NAD+·NADH as an essential cofactor of MI1PS and was required to activate MI1PS. MI1P thus produced was dephosphorylated into myo-inositol by an intrinsic inositol monophosphatase, YktC, which was subsequently isomerized into scyllo-inositol via a previously established artificial pathway involving two inositol dehydrogenases, IolG and IolW. In addition, both glcP and glcK were overexpressed to feed more G6P and accelerate scyllo-inositol production. Consequently, a B. subtilis cell factory was demonstrated to produce 2 g L−1scyllo-inositol from 20 g L−1 glucose. This cell factory provides an inexpensive way to produce scyllo-inositol, which will help us to challenge the growing problem of Alzheimer’s disease in our aging society.
Highlights
A rare stereoisomer of inositol, scyllo-inositol, is a therapeutic agent that has shown potential efficacy in preventing Alzheimer’s disease
The cofactor NAD+·NADH has been shown to be localized in the Rossmann-fold domain of MI1P synthase (MI1PS), a domain which is conserved throughout the evolutionary history of this family of enzymes[27]
When pbuE was inactivated in B. subtilis, MI1PS became active as a functional enzyme (Fig. 3a)
Summary
A rare stereoisomer of inositol, scyllo-inositol, is a therapeutic agent that has shown potential efficacy in preventing Alzheimer’s disease. There is no cure for Alzheimer’s disease, but numerous attempts have been made to develop molecules capable of targeting these aggregations of amyloid β-proteins Among these molecules, a rare stereoisomer of inositol, scyllo-inositol, has been shown to be promising. Other studies, where scyllo-inositol treatment has been combined with other treatments, such as antibodies against amyloid β-proteins[5], or using a guanidine-appended scyllo-inositol derivative[6] have shown great potential of scyllo-inositol or its derivatives to treat Alzheimer’s disease in animal models Such trials and the possible development of treatments require a large quantity of scyllo-inositol, which rarely occurs in nature. B. subtilis possesses the iolABCDEFGHIJ operon, which encodes the enzymes responsible for the metabolism of inositol This metabolism includes IolG, an inositol dehydrogenase that couples the reduction of NAD+ with the oxidation of myo-inositol to give scyllo-inosose (Fig. 1). This cell factory provides an inexpensive way to produce scyllo-inositol
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