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ACS Synth Biol ; 9(7): 1813-1822, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32470291

RESUMO

l-Histidine is a functional amino acid with numerous therapeutic and ergogenic properties. It is one of the few amino acids that is not produced on a large scale by microbial fermentation due to the lack of an efficient microbial cell factory. In this study, we demonstrated the engineering of wild-type Escherichia coli to overproduce histidine from glucose. First, removal of transcription attenuation and histidine-mediated feedback inhibition resulted in 0.8 g/L histidine accumulation. Second, chromosome-based optimization of the expression levels of histidine biosynthesis genes led to a 4.75-fold increase in histidine titer. Third, strengthening phosphoribosyl pyrophosphate supply and rerouting the purine nucleotide biosynthetic pathway improved the histidine production to 8.2 g/L. Fourth, introduction of the NADH-dependent glutamate dehydrogenase from Bacillus subtilis and the lysine exporter from Corynebacterium glutamicum enabled the final strain HW6-3 to produce 11.8 g/L histidine. Finally, 66.5 g/L histidine was produced under fed-batch fermentation, with a yield of 0.23 g/g glucose and a productivity of 1.5 g/L/h. This is the highest titer and productivity of histidine ever reported from an engineered strain. Additionally, the metabolic strategies utilized here can be applied to engineering other microorganisms for the industrial production of histidine and related bioproducts.


Assuntos
Escherichia coli/genética , Escherichia coli/metabolismo , Glucose/metabolismo , Histidina/biossíntese , Engenharia Metabólica/métodos , Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Bacillus subtilis/enzimologia , Proteínas de Bactérias/metabolismo , Técnicas de Cultura Celular por Lotes/métodos , Corynebacterium glutamicum/metabolismo , Fermentação , Glutamato Desidrogenase/metabolismo , Lisina/metabolismo , Fosforribosil Pirofosfato/metabolismo , Nucleotídeos de Purina/biossíntese
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