Aug 2026· Scientific Reports· Vol 16· 0 citations· 49 references
Medicine
TL;DR
A suite of multi-omic data is collected to dissect how carbon source availability reshapes the metabolic network, lipid allocation, and regulatory architecture of Lipomyces starkeyi and enhances the understanding of Lipomyces molecular rearrangements.
Abstract
Lipomyces is a genus of oleaginous yeasts with potential for contributing to reliable biomanufacturing supply chains. However, progress in advanced strain designs and engineering efforts are still constrained by a lack of understanding of the underlying molecular drivers of Lipomyces phenotypes. To address this gap, we collected a suite of multi-omic data to dissect how carbon source availability reshapes the metabolic network, lipid allocation, and regulatory architecture of Lipomyces starkeyi. We observed that glucose promotes biosynthetic and proliferative processes supported by abundant energy and carbon intermediates, xylose enhances redox-balancing mechanisms centered on the pentose phosphate pathway, and glycerol activates respiratory metabolism, β-oxidation, and the glyoxylate cycle. Lipid species distributions remained consistent in both nitrogen replete and depleted conditions across the carbon sources, indicating robust production mechanisms. Regulatory protein identification and network analysis revealed glycerol-driven respiratory growth favors regulatory programs integrating stress tolerance, redox balance, and lipid-associated metabolism, whereas xylose growth activates compensatory transcriptional responses aimed at maintaining mitochondrial function. Nitrogen limitation modulates the strength of these responses but does not fundamentally alter their direction, reinforcing carbon source as the dominant driver of regulatory architecture. Taken together, this data enhances the understanding of Lipomyces molecular rearrangements and provides a foundation for further development of predictive phenotypic tools in this genus.
This review addresses current knowledge on the regulatory networks controlling glycerol metabolism in yeasts, compassing transport mechanisms, metabolic pathways, transcriptional control and enzyme regulation, and pointed out promising avenues for future research and biotechnological innovation.
Juliana Silva Carneiro Fonseca, W. B. da Silveira· World Journal of Microbiolog...· 0 citations
ABSTRACT Megasphaera cerevisiae is a well‐known beer spoilage organism, capable of producing undesirable flavours and turbidity. Although the biosynthesis of medium‐chain fatty acids (MCFAs) has been extensively studied in different Megasphaera species, the metabolic behaviour of M. cerevisiae in controlled environments remains largely unexplored. This study examines the MCFAs production from diverse substrates and reports flux analyses of core metabolism for the first time using a genome‐scale model. The results suggest that acetate stimulates butyrate production but not caproic acid production. Butyrate supplementation, either alone or in combination with acetate, promoted CA synthesis. Lactate supplementation primarily led to the formation of propionic acid and acetic acid. The metabolic network model was manually curated and validated against the different experimental data. The metabolic flux results showed that butyrate production facilitated via the reverse β‐oxidation (RBO) pathway, with a minor contribution from the fatty acid synthesis (FAS) pathway. Conversely, CA synthesis was mainly synthesised through the FAS pathway, irrespective of the substrate used. The pathway analyses results highlighted the critical role of hydrogen production in M. cerevisiae metabolism, particularly under conditions where lactate is utilised. Collectively, these findings offer novel insights into the metabolic versatility and pathway preferences of M. cerevisiae .
W. Sabra, Sonia Villotti, Joachim Fensterle et al.· Environmental Microbiology R...· 0 citations
Carbon catabolite repression (CCR) is a widespread regulatory strategy across diverse microorganisms that prioritises the utilisation of preferred carbon sources. In industrial bioprocesses, however, CCR-mediated substrate hierarchy can delay the utilisation of secondary carbon sources in mixed feedstock, thereby extending fermentation time and limiting carbon conversion efficiency toward target products. Existing reviews have largely addressed CCR in a microorganism-specific manner, potentially obscuring conserved principles, limiting cross-species comparisons, and constraining generalisable engineering; computational modelling and engineering applications also remain underrepresented. This review therefore first summarises CCR mechanisms across diverse microorganisms through a common systems-level framework, in which transport-linked sensing converts carbon flux into intracellular signals, transcriptional regulators reprogramme genome-wide expression, RNA-based mechanisms fine-tune the timing and magnitude of responses, and protein stability shapes their persistence. Multi-omics approaches, particularly interactomics and single-cell omics, are then highlighted for revealing CCR as a dynamic and multilayered regulatory system by resolving interaction networks, temporal changes, and cell-to-cell heterogeneity beyond bulk measurements. Quantitative computational modelling is also discussed, with emphasis on kinetic and constraint-based frameworks that connect regulatory mechanisms to metabolic flux and predict system behaviour under changing carbon substrates. Engineering strategies, including adaptive laboratory evolution, transcription factor engineering, transporter and promoter engineering, and pathway rewiring, are further compared for the relief of CCR and improvement of substrate co-utilisation and production performance. Finally, these advances are presented within a Design-Build-Test-Learn framework, through which mechanistic discovery and omics-scale analysis are used to inform model development, and modelling and engineering are iteratively coupled to improve microbial performance. We propose that such an integrative paradigm is emerging as a unifying direction for CCR research, and provides a foundation for rational strain design and more efficient, sustainable biomanufacturing.
Mengtian Lu, Haoran Ding, Hong-Yu Zhang et al.· Synthetic and Systems Biotec...· 0 citations
Summary The metabolic pathways that sustain bacterial persistence during nutrient limitation remain poorly understood. Using stationary-phase Escherichia coli as a model of antibiotic tolerance, we used proteomics, genetics, metabolic phenotyping, and single-cell imaging to define a metabolic framework underlying persistence. Perturbation of tricarboxylic acid cycle function reprogrammed stationary-phase physiology, suppressing lipid and glycerol metabolism, altering energy homeostasis and proteostasis, and reducing antibiotic tolerance. Systems-level analyses identified phospholipid-derived glycerol catabolism as a critical metabolic pathway linking carbon recycling to persistence. Genetic disruption of key nodes within this pathway impaired proton motive force homeostasis, reduced large polar protein aggregate formation, altered division-associated remodeling, and sensitized cells to antibiotic-induced lysis. Metabolic assays further revealed that persisters retain a selective capacity to utilize glycerol for rapid proton motive force restoration. Together, these findings support a model in which stationary-phase persisters are sustained through metabolic rewiring that coordinates energy maintenance, proteostasis, and antibiotic tolerance.
Han G. Ngo, S. G. Mohiuddin, Mehmet A. Orman· iScience· 0 citations
Muconic acid is a versatile platform chemical that can be biologically produced from lignocellulosic substrates, including from lignin-related aromatic compounds. Pseudomonas putida has been previously engineered to convert lignin-related aromatic compounds to muconate at quantitative molar yields. This high atom efficiency requires a supplemental carbon and energy source to support bacterial growth, and central carbon metabolic efficiency and its interaction with aromatic catabolism are underexplored. Here, we applied proteomics, metabolomics, and 13C-fluxomics to quantitatively compare central carbon and energy metabolism in wild-type P. putida KT2440 and a muconate-producing strain, P. putida CJ781. During cultivation on glucose and 4-hydroxybenzoate, CJ781 showed increased glucose uptake, reconfigured central fluxes, and increased extracellular leakage of aliphatic acids relative to wild type. These altered fluxes supported a 3-fold higher ATP pool, in excess of demand. Pyruvate and acetate secretion in CJ781 was mitigated by debottlenecking TCA-cycle entry via citrate synthase overexpression. Furthermore, tuned expression of the catechol dioxygenase and protocatechuate decarboxylase enabled the production of 36.3 g L-1 muconate at 1.1 g L-1 h-1. Overall, this work reveals how P. putida redirects carbon and energy fluxes to support aromatic bioconversion for improved bioproduction from renewable feedstocks.
R. Wilkes, P. Suthers, A. Borchert et al.· bioRxiv· 3 citations
Two-stage bioprocesses which decouple cell growth from product synthesis are an attractive approach to biomanufacturing. However high levels of production in stationary phase cultures often suffer from a progressive decline in metabolism. We demonstrate that in E. coli pyruvate accumulation, an inevitable consequence of high-flux metabolism, acts as a major inhibitor of stationary-phase glucose uptake. To address this limitation, we introduce a redesigned central metabolic architecture, the gluconate-bypass (GBP), which reroutes carbon flux around glucose-6-phosphate to sustain metabolic activity during stationary phase production. This architecture provides two key advantages: it decouples glucose uptake from pyruvate mediated inhibition, enabling prolonged stationary phase productivity, and glucose oxidation intrinsically co-generates the reducing cofactor NADPH to support biosynthetic pathways that require NADPH. We validated this architecture using the NADPH dependent production of L-alanine as a representative case study. Implementation of the GBP metabolism generated a self regulating host that achieved a record alanine titer of 197 g L-1 and extended production longevity by 1.6 fold, resulting in an improved production yield of 94%. Together, these results demonstrate that the GBP metabolism supports robust stationary phase biosynthesis and provides a versatile framework for efficient production of pyruvate derived chemicals.
Utsuki Yano, Payel Sarkar, M. Lynch· Metabolic Engineering· 0 citations
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