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Construction of an Alternative NAD⁺ De Novo Biosynthesis Pathway.

ABSTRACT: Nicotinamide adenine dinucleotide (NAD⁺) is a life essential molecule involved in versatile biological processes. To date, only two de novo biosynthetic routes to NAD⁺ are described, both of which start from a proteinogenic amino acid and are tightly controlled. Here, a de novo quinolinic acid pathway starting from chorismate, which provides an alternative route (named as the C3N pathway) to NAD⁺ biosynthesis, is established. Significantly, the C3N pathway yields extremely high cellular concentrations of NAD(H) in E. coli. Its utility in cofactor engineering is demonstrated by introducing the four-gene C3N module to cell factories to achieve higher production of 2,5-dimethylpyrazine and develop an efficient C3N-based whole-cell bioconversion system for preparing chiral amines. The wide distribution and abundance of chorismate in most kingdoms of life implies a general utility of the C3N pathway for modulating cellular levels of NAD(H) in versatile organisms.

SUBMITTER: Ding Y

PROVIDER: S-EPMC8097395 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Construction of an Alternative NAD+ De Novo Biosynthesis Pathway.

Ding Yong Y Li Xinli X Horsman Geoff P GP Li Pengwei P Wang Min M Li Jine J Zhang Zhilong Z Liu Weifeng W Wu Bian B Tao Yong Y Chen Yihua Y

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20210301 9

Nicotinamide adenine dinucleotide (NAD+) is a life essential molecule involved in versatile biological processes. To date, only two de novo biosynthetic routes to NAD+ are described, both of which start from a proteinogenic amino acid and are tightly controlled. Here, a de novo quinolinic acid pathway starting from chorismate, which provides an alternative route (named as the C3N pathway) to NAD+ biosynthesis, is established. Significantly, the C3N pathway yields ...[more]

PMID: 33977072

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Project description:BackgroundInflammatory bowel disease is an incurable and idiopathic disease characterized by recurrent gastrointestinal tract inflammation. Tryptophan metabolism in mammalian cells and some gut microbes comprise intricate chemical networks facilitated by catalytic enzymes that affect the downstream metabolic pathways of de novo nicotinamide adenine dinucleotide (NAD+) synthesis. It is hypothesized that a correlation exists between tryptophan de novo NAD+ synthesis and chronic intestinal inflammation.MethodsTranscriptome analysis was performed using high-throughput sequencing of mRNA extracted from the distal colon and brain tissue of Winnie mice with spontaneous chronic colitis and C57BL/6 littermates. Metabolites were assessed using ultra-fast liquid chromatography to determine differences in concentrations of tryptophan metabolites. To evaluate the relative abundance of gut microbial genera involved in tryptophan and nicotinamide metabolism, we performed 16S rRNA gene amplicon sequencing of fecal samples from C57BL/6 and Winnie mice.ResultsTryptophan and nicotinamide metabolism-associated gene expression was altered in distal colons and brains of Winnie mice with chronic intestinal inflammation. Changes in these metabolic pathways were reflected by increases in colon tryptophan metabolites and decreases in brain tryptophan metabolites in Winnie mice. Furthermore, dysbiosis of gut microbiota involved in tryptophan and nicotinamide metabolism was evident in fecal samples from Winnie mice. Our findings shed light on the physiological alterations in tryptophan metabolism, specifically, its diversion from the serotonergic pathway toward the kynurenine pathway and consequential effects on de novo NAD+ synthesis in chronic intestinal inflammation.ConclusionThe results of this study reveal differential expression of tryptophan and nicotinamide metabolism-associated genes in the distal colon and brain in Winnie mice with chronic intestinal inflammation. These data provide evidence supporting the role of tryptophan metabolism and de novo NAD+ synthesis in IBD pathophysiology.

Dataset Information

Construction of an Alternative NAD⁺ De Novo Biosynthesis Pathway.

Publications

Construction of an Alternative NAD<sup>+</sup> De Novo Biosynthesis Pathway.

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