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Genome-scale metabolic models of microorganisms are powerful frameworks to predict phenotypes from an organism’s genotype. While manual reconstructions are laborious, automated reconstructions often fail to recapitulate known metabolic processes. Here we present gapseq ( https://github.com/jotech/gapseq ), a new tool to predict metabolic pathways and automatically reconstruct microbial metabolic models using a curated reaction database and a novel gap-filling algorithm. On the basis of scientific literature and experimental data for 14,931 bacterial phenotypes, we demonstrate that gapseq outperforms state-of-the-art tools in predicting enzyme activity, carbon source utilisation, fermentation products, and metabolic interactions within microbial communities.

Psychiatric disorders are the leading cause of disability worldwide while the pathogenesis remains unclear. Genome-wide association studies (GWASs) have made great achievements in detecting disease-related genetic variants. However, functional information on the underlying biological processes is often lacking. Current reports propose the use of metabolic traits as functional intermediate phenotypes (the so-called genetically determined metabotypes or GDMs) to reveal the biological mechanisms of genetics in human diseases. Here we conducted a two-sample Mendelian randomization analysis that uses GDMs to assess the causal effects of 486 human serum metabolites on 5 major psychiatric disorders, which respectively were schizophrenia (SCZ), major depression (MDD), bipolar disorder (BIP), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). Using genetic variants as proxies, our study has identified 137 metabolites linked to the risk of psychiatric disorders, including 2-methoxyacetaminophen sulfate, which affects SCZ (P = 1.7 × 10–5) and 1-docosahexaenoylglycerophosphocholine, which affects ADHD (P = 5.6 × 10–5). Fourteen significant metabolic pathways involved in the 5 psychiatric disorders assessed were also detected, such as glycine, serine, and threonine metabolism for SCZ (P = .0238), Aminoacyl-tRNA biosynthesis for both MDD (P = .0144) and ADHD (P = .0029). Our study provided novel insights into integrating metabolomics with genomics in order to understand the mechanisms underlying the pathogenesis of human diseases.

Crop productivity is restricted by various abiotic stresses such as drought, salinity, heat, and cold. Many efforts have been taken to decrease the inhibition of plant growth by alleviating the abiotic stresses. Exogenous applications of hormones, plant growth regulators, and/or small signaling molecules have been reported as a means to enhance plant resistance to stress. One of the small signaling molecules utilized is 5-aminolevulinic acid (ALA) that has been shown to enhance plant growth under abiotic stress. As a metabolic intermediate in higher plants, ALA is a precursor of all tetrapyrroles such as chlorophyll, heme and siroheme. The pathway towards biosynthesis upstream and the metabolism downstream of ALA contains multiple regulatory points that are affected by positive/negative factors. However, report about the regulatory aspects of the ALA metabolic pathway and the role of ALA in stimulating physiochemical processes in higher plants under stress have not been collated and summarized systematically. In this regard, we summarize recent developments in understanding the mechanisms of plant responses to abiotic stress which are affected by ALA as well as new information on the metabolic pathway of ALA. We find that exogenous application of ALA can enhance some key physiological and biochemical processes in plants such as photosynthesis, nutrient uptake, antioxidant characteristics and osmotic equilibrium, however, more in-depth research on the specific mechanisms are needed.

Numerous studies have been focusing on breeding tomato plants with enhanced lycopene accumulation, considering its positive effects of fruits on the visual and functional properties. In this study, we used a bidirectional strategy: promoting the biosynthesis of lycopene, while inhibiting the conversion from lycopene to β- and α-carotene. The accumulation of lycopene was promoted by knocking down some genes associated with the carotenoid metabolic pathway. Finally, five genes were selected to be edited in genome by CRISPR/Cas9 system using -mediated transformation. Our findings indicated that CRISPR/Cas9 is a site-specific genome editing technology that allows highly efficient target mutagenesis in multiple genes of interest. Surprisingly, the lycopene content in tomato fruit subjected to genome editing was successfully increased to about 5.1-fold. The homozygous mutations were stably transmitted to subsequent generations. Taken together, our results suggest that CRISPR/Cas9 system can be used for significantly improving lycopene content in tomato fruit with advantages such as high efficiency, rare off-target mutations, and stable heredity.

Major depressive disorder (MDD) is a common mental illness characterized by persistent low mood and anhedonia, normally accompanied with cognitive impairment. Due to its rising incidence and high rate of recurrence and disability, MDD poses a substantial threat to patients’ physical and mental health, as well as a significant economic cost to society. However, the etiology and pathogenesis of MDD are still unclear. Chronic inflammation may cause indoleamine-2,3-dioxygenase (IDO) to become overactive throughout the body and brain, resulting in excess quinolinic acid (QUIN) and less kynuric acid (KYNA) in the brain. QUIN’s neurotoxicity damages glial cells and neurons, accelerates neuronal apoptosis, hinders neuroplasticity, and causes depression due to inflammation. Therefore, abnormal TRP-KYN metabolic pathway and its metabolites have been closely related to MDD, suggesting changes in the TRP-KYN metabolic pathway might contribute to MDD. In addition, targeting TRP-KYN with traditional Chinese medicine showed promising treatment effects for MDD. This review summarizes the recent studies on the TRP-KYN metabolic pathway and its metabolites in depression, which would provide a theoretical basis for exploring the etiology and pathogenesis of depression.

Phthalic acid esters (PAEs) have long been known as the most widely used plasticizer with a broad range of industrial application. PAEs are ubiquitous in different environments and our daily life due to their large and widespread application. Recent PAEs research mainly focused on their environmental fate (including leaching, migration, transformation) and toxicology and risk assessment. With the comprehensive recognition of their potential hazard, the elimination of PAEs has attracted worldwide concerns. Although many factors may contribute to the degradation of PAEs, the dominant role of biodegradation was widely reported. Many PAEs-degrading bacteria were isolated, metabolites and metabolic pathways were proposed, and enzymes involved in the degradation were identified. The current paper presents an overview of available reports about PAEs-degrading bacteria and related molecular mechanisms. The metabolic pathways deduced from the identified intermediates were presented. The upstream and downstream pathways of PAEs metabolism were summarized, including the aerobic and anaerobic pathways of phthalic acid (PA) degradation. Known enzymes involved in the hydrolysis of ester bonds were characterized according to their properties. Based on phylogenetic analysis, all these enzymes were distributed in four families of esterases and one unknown family. For these five families, conserved sequence motifs were identified and the biological properties of these motifs were characterized. Challenges and emerging opportunities are also discussed.

Epilepsy is one of the most common diseases of the central nervous system. The diagnosis of epilepsy mainly depends on electroencephalograms and symptomatology, while diagnostic biofluid markers are still lacking. In addition, approximately 30% of patients with epilepsy (PWE) show a poor response to the currently available anti-seizure medicines. An increasing number of studies have reported alterations in the blood, brain tissue, cerebrospinal fluid and urine metabolome in PWE and animal models of epilepsy. The aim of this review was to identify potential metabolic biomarkers and pathways that might facilitate diagnostic, therapeutic and prognostic determination in PWE and the understanding of the pathogenesis of the disease. The PubMed and Embase databases were searched for metabolomic studies of PWE and epileptic models published before December 2020. The study objectives, types of models and reported differentially altered metabolites were examined and compared. Pathway analyses were performed using MetaboAnalyst 5.0 online software. Thirty-five studies were included in this review. Metabolites such as glutamate, lactate and citrate were disturbed in both PWE and epileptic models, which might be potential biomarkers of epilepsy. Metabolic pathways including alanine, aspartate and glutamate metabolism; glycine, serine and threonine metabolism; glycerophospholipid metabolism; glyoxylate and dicarboxylate metabolism; and arginine and proline metabolism were involved in epilepsy. These pathways might play important roles in the pathogenesis of the disease. This review summarizes metabolites and metabolic pathways related to epilepsy and provides a novel perspective for the identification of potential biomarkers and therapeutic targets for epilepsy.

Metabolic reprogramming fulfils increased nutrient demands and regulates numerous oncogenic processes in tumors, leading to tumor malignancy. Branched-chain amino acids (BCAAs, i.e., valine, leucine, and isoleucine) function as nitrogen donors to generate macromolecules such as nucleotides and are indispensable for human cancer cell growth. The cell-autonomous and non-autonomous roles of altered BCAA metabolism have been implicated in cancer progression and the key proteins in the BCAA metabolic pathway serve as possible prognostic and diagnostic biomarkers in human cancers. Here we summarize how BCAA metabolic reprogramming is regulated in cancer cells and how it influences cancer progression.

Abstract Underground metabolic pathways—leaks in the metabolic network caused by promiscuous enzyme activities and nonenzymatic transformations—can provide the starting point for emergence of novel protopathways if a mutation or environmental change increases flux to a physiologically significant level. This early stage in pathway evolution, in which promiscuous enzymes are still serving their native functions and proper regulation has not yet emerged, is typically hidden from our view. We previously used laboratory evolution to evolve a novel four-step protopathway in ΔpdxB E. coli, which lacks an enzyme required for synthesis of pyridoxal 5′-phosphate (PLP). By sequencing population genomic DNA from samples archived during the evolution experiment, we have identified mutations that rose and fell in abundance in the population leading to JK1, the dominant clone after 150 population doublings. We have identified the order in which the four mutations arose in JK1 and the physiological effect of each mutation. The first mutation increases the rate of PLP synthesis. The second mutation did not impact PLP synthesis but rather created a cheater that thrived in the population by scavenging nutrients released from the fragile parental cells. Notably, the dominant lineages at the end of the experiment all derived from this cheater strain. The third mutation in JK1 destroyed a PLP phosphatase, which preserves precious PLP. Finally, the fourth mutation improved growth in glucose after the PLP synthesis problem had been solved. Together, these mutations resulted in restoration of PLP synthesis and a 32-fold increase in growth rate.

Glucose and xylose are the major components of lignocellulose. Effective utilization of both sugars can improve the efficiency of bioproduction. Here, we report a method termed parallel metabolic pathway engineering (PMPE) for producing shikimate pathway derivatives from glucose–xylose co-substrate. In this method, we seek to use glucose mainly for target chemical production, and xylose for supplying essential metabolites for cell growth. Glycolysis and the pentose phosphate pathway are completely separated from the tricarboxylic acid (TCA) cycle. To recover cell growth, we introduce a xylose catabolic pathway that directly flows into the TCA cycle. As a result, we can produce 4.09 g L −1 cis , cis -muconic acid using the PMPE Escherichia coli strain with high yield (0.31 g g −1 of glucose) and produce l -tyrosine with 64% of the theoretical yield. The PMPE strategy can contribute to the development of clean processes for producing various valuable chemicals from lignocellulosic resources. In lignocellulose biomass, microbes prefer consuming glucose over xylose, which affects target compound production. Here, the authors achieve simultaneous utilization of glucose and xylose for target chemical production and cell growth, respectively, and realize high-level production of shikimate pathway derivatives.