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Crabtree effect

The Crabtree effect is a metabolic shift observed in certain eukaryotic cells, notably yeast and tumor cells, wherein high extracellular glucose concentrations repress mitochondrial respiration and promote fermentative metabolism, such as ethanol production in yeast or lactate production in mammalian cells, despite the availability of oxygen. First documented in 1929 by British biochemist Herbert Grace Crabtree through experiments on slices of mouse tumor tissue, the effect was characterized by a marked decrease in oxygen consumption upon glucose addition to aerobic suspensions, highlighting an inefficient yet rapid energy-yielding pathway. This phenomenon, analogous to the Warburg effect in proliferating mammalian cells, enables cells to prioritize glycolytic flux for quick ATP generation and biosynthetic precursors over efficient oxidative phosphorylation.^[1] In the model organism Saccharomyces cerevisiae, the Crabtree effect manifests in two distinct forms that underscore its regulatory complexity. The short-term Crabtree effect refers to the immediate onset of aerobic alcoholic fermentation triggered by a pulse of excess glucose in sugar-limited, respiring yeast cultures, resulting from an overflow of glycolytic intermediates that exceed mitochondrial processing capacity.^[2] In contrast, the long-term Crabtree effect involves the sustained repression of respiratory enzymes and mitochondrial biogenesis in glucose-limited chemostat cultures when the dilution rate surpasses a critical threshold, leading to a stable fermentative state even under aerobic conditions.^[3] These adaptations are mediated by glucose-sensing signaling pathways, including the Snf1/AMPK kinase and TOR complex, which downregulate genes for tricarboxylic acid cycle enzymes and oxidative phosphorylation while upregulating glycolytic and fermentative enzymes.^[1] The Crabtree effect has significant implications for cellular fitness, biotechnology, and disease. Evolutionarily, it likely arose as an advantage in nutrient-fluctuating environments, allowing Crabtree-positive yeasts like S. cerevisiae to outcompete respiring microbes by rapidly depleting glucose and producing the antimicrobial ethanol, a trait linked to ancient whole-genome duplications enhancing metabolic flexibility.^[4] In industrial contexts, such as ethanol production and baking, the effect is harnessed for high-yield fermentation but poses challenges in optimizing aerobic growth for biomass; recent metabolic engineering efforts as of 2025 have aimed to create Crabtree-negative strains to improve yields of other biochemicals.^[5]^[6]^[7] Furthermore, its parallels to the Warburg effect in cancer cells suggest shared mechanisms of metabolic reprogramming that support uncontrolled proliferation, making it a target for therapeutic interventions in oncology.^[1]

Definition and Overview

Core Phenomenon

The Crabtree effect refers to the metabolic shift in yeast cells, notably Saccharomyces cerevisiae, toward aerobic alcoholic fermentation when exposed to high glucose concentrations, resulting in the production of ethanol and carbon dioxide rather than complete oxidation of glucose through respiration, even though oxygen is plentiful.^[4] This phenomenon represents an overflow metabolism where excess carbon flux through glycolysis exceeds the capacity for respiratory processing, prioritizing rapid energy generation over maximal efficiency.^[8] Key features of the Crabtree effect include a respiratory quotient (RQ) exceeding 1, reflecting greater CO₂ production than O₂ consumption due to the decarboxylation of pyruvate to ethanol.^[9] The process yields only 2 ATP per glucose molecule via substrate-level phosphorylation in glycolysis, in contrast to approximately 18 ATP from oxidative phosphorylation in full respiration, underscoring the trade-off for faster growth rates.^[4] Associated byproducts extend beyond ethanol to include glycerol and acetate, which arise from redox balancing and minor pathway diversions during the fermentative overflow.^[10] Unlike strictly anaerobic fermentation, which requires oxygen absence, the Crabtree effect manifests under fully aerobic conditions, driven by glucose excess that represses respiratory enzymes and pathways.^[4] In typical batch cultures with initial glucose levels above 0.2 g/L, cells exhibit rapid glucose uptake, leading to prompt ethanol accumulation that persists until substrate depletion, often resulting in a biphasic growth pattern with an initial fermentative phase followed by respiratory diauxic shift.^[11]^[12]

Affected Organisms

The Crabtree effect is predominantly exhibited by certain unicellular fungi, particularly yeast species within the Ascomycota phylum. Saccharomyces cerevisiae, commonly known as baker's or brewer's yeast, displays a robust Crabtree-positive phenotype, characterized by the repression of respiration and induction of aerobic fermentation in the presence of high extracellular glucose concentrations. This leads to ethanol production as a major metabolic outcome under oxygen-replete conditions.^[8] Other Crabtree-positive yeasts include Schizosaccharomyces pombe, which secretes substantial ethanol (up to 42% of consumed glucose) during aerobic growth on excess glucose, and species from genera such as Zygosaccharomyces and Dekkera (e.g., Dekkera bruxellensis). In comparison, Crabtree-negative yeasts like Kluyveromyces marxianus, Debaryomyces hansenii, Scheffersomyces stipitis (formerly Pichia stipitis), and Candida utilis favor respiratory metabolism, fully oxidizing glucose with minimal byproduct formation even at elevated sugar levels, resulting in higher biomass yields.^[8]^[2]^[13] Beyond yeasts, the Crabtree effect, often termed overflow metabolism in this context, occurs in select bacteria such as Escherichia coli, where high glucose flux under aerobic conditions exceeds respiratory capacity, prompting acetate excretion instead of complete oxidation. It is infrequently observed in filamentous fungi, though examples exist in species like Rhizopus oryzae, which produces ethanol aerobically when glucose is abundant. While primarily observed in unicellular organisms such as yeasts, the Crabtree effect has also been reported in specific mammalian cell types, including tumor cells and kidney proximal tubule epithelial cells, though it remains uncommon across higher eukaryotes as a whole.^[14]^[15]^[16] For instance, a 2023 study demonstrated the Crabtree effect in normal kidney proximal tubule epithelial cells at physiological glucose levels.^[16] Distinctions in the Crabtree effect include long-term and short-term manifestations. The long-term variant arises during sustained growth in high-glucose media, enforcing persistent fermentative metabolism. The short-term variant represents a rapid, transient switch to aerobic ethanol production following glucose pulses in low-sugar-adapted cells, as seen in S. cerevisiae and related species.^[2] The onset of the Crabtree effect depends on a glucose concentration threshold that differs among strains; in S. cerevisiae, this is approximately 0.15 g/L for typical laboratory isolates, while industrial strains may trigger it at lower levels (around 0.05 g/L) due to enhanced glucose uptake capacities.^[4]

Historical Background

Discovery

The Crabtree effect was first described by English biochemist Herbert Grace Crabtree in 1929 as part of his investigations into the carbohydrate metabolism of tumor tissues. In experiments using slices of rat sarcoma and other malignant tissues suspended in buffered saline, Crabtree observed that adding glucose to the medium caused a marked decrease in oxygen consumption, despite ample oxygen availability, while simultaneously increasing lactic acid production through aerobic glycolysis. This repression of respiration by high sugar concentrations represented a key deviation from expected oxidative metabolism in normal tissues.^[17] Crabtree's early experiments quantified this phenomenon by measuring oxygen uptake and carbon dioxide output using manometric techniques on tumor preparations with varying glucose levels, typically ranging from 0 to 0.2% concentration. At low glucose, respiration proceeded efficiently with a respiratory quotient near 1, indicating complete oxidation; however, at higher levels, the quotient rose above 1, signaling a shift to fermentative breakdown and reduced overall respiratory efficiency. These findings highlighted how excess glucose could inhibit mitochondrial respiration, favoring rapid glycolytic flux even under aerobic conditions.^[17] The effect is named after Crabtree for his pioneering observations, though it built directly on Otto Warburg's 1920s studies of elevated glycolysis in tumors, which emphasized high lactate output but did not fully elucidate the glucose-mediated respiratory inhibition. While Crabtree's work focused on mammalian tumor cells, the phenomenon was soon recognized in microbial systems, particularly yeast, where analogous high-sugar repression of respiration leads to ethanol formation. Related early insights into yeast fermentation trace to Louis Pasteur's 19th-century demonstrations of sugar metabolism under aerobic conditions, but the Pasteur effect inversely describes how respiration suppresses fermentation at low sugar levels.^[17]

Subsequent Research

Following the initial observation of the Crabtree effect in the 1920s, research in the 1950s and 1960s advanced the understanding of glucose-mediated repression of respiratory enzymes in yeasts. Jacques Monod's work on diauxic growth and catabolite repression in bacteria during the 1940s and 1950s provided a conceptual framework that was applied to yeasts, where high glucose concentrations were shown to inhibit the synthesis of enzymes involved in alternative carbon source utilization. In 1966, R.H. De Deken demonstrated that the Crabtree effect functions as a regulatory system in Saccharomyces cerevisiae, where elevated glycolytic rates under aerobic conditions lead to repression of respiratory enzyme synthesis, thereby inhibiting oxygen consumption. During the 1970s, studies further delineated the temporal dynamics of the effect. Maria Lagunas and colleagues distinguished between short-term and long-term components: the short-term effect involves rapid inhibition of respiration upon glucose addition, often linked to transient ATP accumulation, while the long-term effect entails transcriptional repression of respiratory genes over hours. A key milestone was Helmut Holzer's 1967 work on catabolite repression in yeast, which highlighted the inactivation of enzymes like malate dehydrogenase in the presence of glucose, establishing a link between glucose signaling and metabolic enzyme turnover.^[18] Experimental approaches evolved during this period from respirometry, which measured oxygen uptake rates to quantify respiratory inhibition, to isotopic labeling techniques using radiolabeled glucose (e.g., ^{14}C-glucose) to trace carbon fluxes through glycolysis and the tricarboxylic acid cycle. These methods allowed researchers to quantify the diversion of carbon toward ethanol production rather than complete oxidation, providing evidence for flux partitioning in Crabtree-positive yeasts. In the 1980s and 1990s, attention shifted to key regulatory enzymes controlling glycolytic flux. Studies identified hexokinase isozymes, particularly hexokinase PII, as central to glucose repression, with mutants showing reduced repression and altered respiratory capacity. Phosphofructokinase was similarly implicated in flux control, where its activation under high glucose promotes glycolytic overflow and limits mitochondrial entry of pyruvate. By the 1990s, research confirmed the involvement of mitochondria, revealing that Crabtree-positive yeasts possess inherently limited respiratory chain capacity, making them prone to fermentation even under aerobic conditions. In the 2000s and beyond, advances in genomics and systems biology have further elucidated the molecular mechanisms, identifying key signaling pathways such as Snf1/AMPK and TOR that mediate glucose repression, as confirmed in studies up to 2025. These developments built on earlier genetic tools to enable precise manipulation and causal analysis of regulatory networks.^[1] Despite these advances, pre-2000 research highlighted persistent gaps, including the absence of genetic tools for direct manipulation of regulatory pathways, which hindered causal mechanistic studies. Early recognition of industrial implications emerged, particularly in ethanol production for brewing and bioenergy, where the effect's role in maximizing fermentative yields was noted but challenging to optimize without molecular interventions.

Biochemical Mechanism

Metabolic Pathways

The Crabtree effect prominently features an accelerated flux through glycolysis, the initial metabolic pathway for glucose breakdown. In this process, one molecule of glucose is phosphorylated and cleaved into two molecules of pyruvate through 10 sequential enzymatic reactions, including key steps catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase. This pathway generates a net yield of 2 ATP and 2 NADH per glucose molecule under standard conditions. During the Crabtree effect in organisms like Saccharomyces cerevisiae, the glycolytic flux increases substantially—often more than 5-fold—enabling rapid ATP production to support growth despite the presence of oxygen.^[10]^[19] Under high-glucose conditions, pyruvate is largely shunted away from oxidative metabolism toward fermentative pathways to maintain redox balance and high throughput. In yeast, the dominant route is alcoholic fermentation, where pyruvate is decarboxylated to acetaldehyde by pyruvate decarboxylase, releasing CO₂, and then reduced to ethanol by alcohol dehydrogenase using NADH as the electron donor. This step regenerates NAD⁺, which is essential for the continued operation of glycolysis at elevated rates. The net biochemical transformation, which dominates despite aerobic availability, can be represented as:

\ce{C6H12O6 + 2 [ADP](/page/ADP) + 2 P_i -> 2 CH3CH2OH + 2 CO2 + 2 ATP}

^[19]^[4] Concomitantly, respiratory pathways are repressed, limiting the entry of pyruvate into mitochondria and reducing overall oxygen consumption. A key restriction occurs at pyruvate dehydrogenase (PDH), where activity is curtailed, preventing efficient conversion of pyruvate to acetyl-CoA and subsequent flux through the tricarboxylic acid (TCA) cycle. Further downstream, diminished activity of cytochrome c oxidase in the electron transport chain contributes to lowered O₂ utilization, favoring fermentation over complete oxidation.^[19]^[20] Minor branches from glycolysis also contribute to byproduct formation during overflow metabolism. For instance, dihydroxyacetone phosphate can be diverted to glycerol via reduction by glycerol-3-phosphate dehydrogenase and dephosphorylation, aiding in NADH reoxidation under osmotic stress or redox imbalance. Additionally, a small fraction of acetaldehyde may be oxidized to acetate by aldehyde dehydrogenase, serving as an alternative sink for excess carbon. These pathways ensure metabolic flexibility but yield lower energy efficiency compared to full respiration.^[10]

Regulatory Mechanisms

The Crabtree effect in Saccharomyces cerevisiae is primarily governed by carbon catabolite repression (CCR), a regulatory system that represses the expression of over 100 genes involved in respiration and alternative carbon source utilization under high glucose conditions, favoring fermentative metabolism.^[21] This repression ensures prioritization of glycolysis and ethanol production, preventing competition from oxidative pathways. Glucose sensing occurs intracellularly through hexokinase PII (Hxk2), which acts as a conformational sensor: in high glucose, Hxk2 adopts a closed form that promotes nuclear localization and stabilizes repressor complexes.^[22] High glucose availability triggers increased cAMP production via activation of adenylate cyclase by Gpr1 and Ras pathways, elevating cAMP levels and activating protein kinase A (PKA).^[23] PKA, in turn, phosphorylates and activates the Glc7-Reg1 phosphatase complex, which dephosphorylates Hxk2 and the transcription factor Mig1, retaining them in the nucleus to enforce repression.^[22] At the transcriptional level, the zinc-finger repressor Mig1 binds to GC-rich motifs in the promoters of respiratory genes, such as COX5A (cytochrome c oxidase subunit) and CYC1 (iso-1-cytochrome c), inhibiting their expression in the presence of high glucose.^[21] This Mig1-mediated repression is counteracted in low glucose by the Snf1 kinase, which becomes activated through phosphorylation at Thr210 and subsequently phosphorylates Mig1 at Ser311, promoting its nuclear export and relieving repression of target genes.^[21] The Hap transcriptional complex, particularly through its glucose-repressed subunit Hap4, is also downregulated under high glucose via PKA and Mig1 pathways, further suppressing genes encoding TCA cycle and respiratory chain enzymes.^[24] Post-translational controls contribute to rapid modulation of flux. The pyruvate dehydrogenase (PDH) complex, which converts pyruvate to acetyl-CoA for mitochondrial entry, undergoes allosteric inhibition by accumulating acetyl-CoA and NADH under high glycolytic flux, diverting pyruvate toward fermentation.^[25] Similarly, the mitochondrial NAD+-dependent isocitrate dehydrogenase (Idh1/Idh2) activity is limited under high glucose, reinforcing overflow metabolism.^[26] The Crabtree effect manifests through short-term and long-term mechanisms. Short-term regulation arises from rapid glycolytic flux exceeding respiratory capacity, leading to NADH accumulation and redox imbalance that necessitates fermentative regeneration of NAD+ via alcohol dehydrogenase.^[12] Long-term effects involve sustained transcriptional changes, including the repression of numerous respiratory genes via the aforementioned pathways, ensuring persistent fermentative dominance.^[21]

Pasteur Effect

The Pasteur effect refers to the observation that exposure to oxygen reduces the rate of glucose consumption and ethanol fermentation in yeast cells, shifting metabolism toward more efficient aerobic respiration. This phenomenon ensures that cells prioritize the oxidative pathway, which yields substantially more ATP per glucose molecule compared to anaerobic glycolysis. In yeast such as Saccharomyces cerevisiae, aerobic conditions lead to a marked decrease in glycolytic flux, conserving glucose while maximizing energy production through mitochondrial oxidation.^[27] Discovered by Louis Pasteur in 1861 during his investigations into alcoholic fermentation, the effect was noted when yeast exposed to air fermented less sugar per unit of biomass than under anaerobic conditions, highlighting oxygen's role in suppressing fermentation. Pasteur's experiments demonstrated that oxygen not only inhibits the production of alcohol but also enhances overall cell growth efficiency by favoring respiration. This foundational insight, detailed in his studies on yeast metabolism, laid the groundwork for understanding oxygen's regulatory influence on microbial energy pathways.^[28] At the mechanistic level, oxygen facilitates the activation of pyruvate dehydrogenase (PDH), enabling pyruvate entry into the tricarboxylic acid (TCA) cycle and subsequent oxidative phosphorylation, which generates up to 18 times more ATP than glycolysis alone. The resulting elevation in ATP and citrate levels exerts feedback inhibition on phosphofructokinase (PFK), a rate-limiting enzyme in glycolysis, thereby slowing the upper glycolytic pathway and reducing lactate or ethanol output. This allosteric regulation by ATP and citrate ensures metabolic efficiency under aerobic conditions, preventing unnecessary glucose breakdown when respiration is viable.^[29] The Pasteur effect operates as the inverse of the Crabtree effect, where the former promotes respiratory metabolism in the presence of oxygen and low glucose, while the latter represses it under high glucose even aerobically; both phenomena modulate glucose flux to balance energy needs and biosynthetic demands. Experimental studies in yeast confirm this distinction, showing that glycolytic rates under anaerobic conditions can be several-fold (typically 2- to 5-fold) higher than aerobic rates without Crabtree interference, as measured by sugar uptake and ethanol production in controlled fermentations. This quantitative disparity underscores the Pasteur effect's role in optimizing ATP yield through oxygen-dependent pathway switching.^[30]^[31]

Warburg Effect

The Warburg effect, first described by Otto Warburg in the early 1920s, refers to the observation that cancer cells preferentially produce lactate through glycolysis even in the presence of oxygen and functional mitochondria, a process known as aerobic glycolysis. This metabolic shift allows tumor cells to generate energy rapidly despite the inefficiency of glycolysis compared to oxidative phosphorylation. Warburg's seminal work demonstrated that tumor tissues exhibit markedly higher rates of glycolysis and lactate formation under aerobic conditions than normal tissues, laying the foundation for understanding cancer metabolism.^[32] Key features of the Warburg effect include elevated glucose uptake facilitated by overexpressed glucose transporters such as GLUT1 and GLUT3, which enable cancer cells to acquire glucose at rates far exceeding those of normal cells. This supports rapid ATP production—approximately 2 ATP molecules per glucose molecule via glycolysis—prioritizing proliferation over energy efficiency. Additionally, the export of lactate via monocarboxylate transporters acidifies the tumor microenvironment, promoting invasion and immune evasion. These adaptations collectively favor biosynthetic demands, such as nucleotide and lipid synthesis, essential for uncontrolled cell growth.^[33] Mechanistically, the Warburg effect is driven by oncogenic signaling that reprograms metabolism. Activation of oncogenes like MYC and HIF-1 upregulates glycolytic enzymes, including hexokinase, phosphofructokinase, and lactate dehydrogenase A, enhancing flux through the glycolytic pathway. Furthermore, pyruvate dehydrogenase kinase (PDK) isoforms, induced by these oncogenes, phosphorylate and inhibit pyruvate dehydrogenase (PDH), blocking pyruvate conversion to acetyl-CoA and diverting it toward lactate production instead of mitochondrial respiration. This regulatory network ensures sustained aerobic glycolysis, even when oxygen is abundant.^[34]^[35] The Warburg effect shares parallels with the Crabtree effect observed in certain microorganisms, both representing overflow metabolism where fermentative pathways dominate under nutrient-rich, aerobic conditions to support rapid biomass accumulation. This suggests evolutionary convergence, though the Warburg effect operates in the multicellular context of tumors, potentially co-opting developmental or stress-response pathways for pathological growth. Evidence for the Warburg effect in clinical settings includes positron emission tomography (PET) imaging, which reveals high uptake of 18F-fluorodeoxyglucose (FDG) in tumors, reflecting increased glucose transport and reflecting the metabolic hallmark with high sensitivity for detection. In contrast to the ~36 ATP yield from complete glucose oxidation via respiration, the Warburg pathway's lower efficiency underscores its role in favoring speed over yield for proliferative advantage.^[19]^[36]^[33]

Evolutionary Perspectives

Origins and Evolution

The Crabtree effect is believed to have originated approximately 100 million years ago, coinciding with the diversification of angiosperms during the Early Cretaceous period, which introduced sugar-rich niches such as fruits and nectar that favored fermentative metabolism in yeasts.^[4] This timeline aligns with the emergence of ecological opportunities for yeasts to exploit high-glucose environments, marking a shift toward aerobic fermentation as a dominant strategy in certain microbial lineages.^[37] Phylogenetically, the Crabtree effect has evolved independently in multiple yeast lineages, particularly within the Ascomycota phylum, including species like Saccharomyces cerevisiae and Schizosaccharomyces pombe, but it is absent in bacteria and most unicellular algae.^[8] In contrast to prokaryotes, where overflow metabolism occurs under nutrient excess without full repression of respiration, the Crabtree effect in yeasts represents a more pronounced eukaryotic adaptation tied to compartmentalized cellular structures and regulatory networks.^[38] At the genetic level, the effect arose through duplications of key glycolytic genes, such as HXK2 encoding hexokinase 2, which enhances glucose phosphorylation and flux toward fermentation, coupled with reduced respiratory efficiency in Crabtree-positive lineages.^[39] Comparative genomic analyses reveal that Crabtree-positive yeasts in the Saccharomyces clade diverged following a whole-genome duplication event around 100 million years ago, which amplified copies of six out of thirteen glycolytic enzymes and increased hexose transporter abundance, solidifying fermentative dominance.^[40] These genomic signatures, absent in Crabtree-negative relatives like Kluyveromyces marxianus, underscore the role of gene dosage in the effect's emergence.^[8]

Adaptive Advantages

The Crabtree effect confers adaptive advantages to yeast species in nutrient-rich, competitive environments by prioritizing the rate of ATP production over yield. In high-glucose conditions, fermentation via glycolysis generates ATP more rapidly than respiration, allowing Crabtree-positive yeasts to achieve growth rates comparable to more efficient respiring species while quickly exploiting transient sugar resources. This rate/yield trade-off (RYT) enables rapid proliferation supported by high glycolytic fluxes, despite yielding only 2 ATP molecules per glucose versus approximately 18 from respiration.^[37] A key benefit is the competitive edge provided by ethanol production, which acts as a toxin against rival microorganisms, such as bacteria sensitive to alcohol, thereby securing dominance in sugar-abundant niches like ripening fruits. By employing a "make-accumulate-consume" strategy, yeasts first ferment glucose to ethanol under aerobic conditions and later respire the ethanol once sugars are depleted, deterring competitors in the interim and enhancing survival in ephemeral habitats.^[5]^[37] Furthermore, the Crabtree effect optimizes resource allocation by diverting carbon from biomass accumulation to ethanol synthesis, which mitigates oxidative stress associated with mitochondrial respiration and permits sustained proliferation amid fluctuating nutrient availability. Fitness models, including game-theoretical analyses, demonstrate that the Crabtree effect provides a selective advantage in dynamic ecosystems by enabling rapid resource depletion and inhibition of competitors. Ecologically, this mechanism bolsters persistence in high-sugar environments, such as fruit niches, where rapid colonization outweighs energetic efficiency.^[37]

Biological and Industrial Significance

Role in Natural Ecosystems

The Crabtree effect enables Crabtree-positive yeasts, such as Saccharomyces cerevisiae, to specialize in sugar-rich niches within natural ecosystems, including ripening fruits, floral nectars, and insect digestive tracts, where high glucose concentrations trigger fermentation over respiration. This metabolic strategy allows rapid proliferation and outcompetition of slower-growing, respiring microbial species, securing dominance in transient, high-carbon environments.^[4]^[41] In microbial communities, ethanol production via the Crabtree effect generates localized anaerobic micro-niches on fermenting substrates, altering community dynamics and facilitating succession patterns, such as the shift from aerobic bacteria to fermentative yeasts during fruit decay. For instance, initial bacterial colonization of fresh fruit gives way to yeast dominance as ethanol accumulation inhibits competitors and creates conditions favorable for anaerobic growth.^[42]^[41] This process contributes to biodiversity by supporting ethanol-tolerant fauna, including Drosophila species that exploit fermented fruits for nutrition and reproduction, while playing a pivotal role in terrestrial carbon cycling through efficient conversion of plant-derived sugars into volatile compounds and biomass.^[4]^[41] Environmental triggers like seasonal pulses of sugars from falling fruits in autumn activate the Crabtree effect, linking yeast metabolism to broader plant-microbe coevolutionary dynamics that have persisted since the rise of angiosperms.^[4] A notable case occurs in natural vineyard ecosystems, where wild S. cerevisiae strains leverage the Crabtree effect to dominate spontaneous fermentations on grape surfaces, establishing microbial consortia that initiate wild wine production without human intervention.^[43]^[41]

Applications and Challenges in Industry

In brewing and winemaking, the Crabtree effect is leveraged by Saccharomyces cerevisiae strains selected for their strong fermentative capacity, enabling rapid conversion of sugars to ethanol even under aerobic conditions, which outcompetes other microbes and achieves alcohol by volume (ABV) levels of 5-15% typical for beer and wine production.^[44]^[43] The effect is similarly central to industrial bioethanol production, where S. cerevisiae ferments glucose to ethanol with yields approaching 0.5 g ethanol per g glucose, supporting a global industry exceeding 110 billion liters annually from feedstocks like corn and sugarcane.^[45]^[46] However, byproduct accumulation, such as ethanol itself, inhibits further fermentation and limits overall efficiency.^[47] Key challenges arise from the Crabtree effect's prioritization of ethanol over other products, diverting only 10-20% of carbon to biomass in fermenting strains compared to up to 50% in respiring ones, which reduces yields of value-added metabolites like lipids and amino acids.^[37] In aerated industrial fermenters, partial respiration can induce oxidative stress through reactive oxygen species, complicating process control and cell viability.^[48] To address these, metabolic engineering has produced Crabtree-negative S. cerevisiae strains via CRISPR-mediated deletions of HXK2, which alleviates glucose repression and boosts respiratory flux for higher lipid and terpene yields (e.g., 2-fold increase in nerolidol to 3.4 g/L).^[49] Similarly, MIG1 knockout enhances respiration by derepressing oxidative genes, improving non-ethanol metabolite production.^[50] A 2025 innovation partitions sucrose metabolism through phosphorolysis and PGI1 deletion, coupled with redox balancing, to eliminate the Crabtree effect and recover 30% more carbon for biomass and products like lactic acid (0.22 g/g sucrose, 11-fold over controls).^[6] Recent advances include adaptive laboratory evolution (ALE) to generate hybrid Crabtree phenotypes, such as respiration-deficient strains with duplicated xylose pathways that achieve 55.9% theoretical ethanol yields from lignocellulosic sugars under aerobic conditions, expanding applications to sustainable biofuels and pharmaceuticals.^[51]

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This key trait, known as the Crabtree effect (Pronk, Steensma and Van Dijken 1996), is thought to be an adaptation to high sugar environments.
[38]
Why, when, and how did yeast evolve alcoholic fermentation? - NIH
Crabtree effect results in lower biomass production because a fraction of sugar is converted into ethanol. This means that more glucose has to be consumed to ...
[39]
Truth in wine yeast - PMC - NIH
While the Crabtree effect seems to clearly confer a selective advantage to S. cerevisiae over most other microorganisms during alcoholic fermentation, it poses ...
[40]
How did Saccharomyces evolve to become a good brewer?
Crabtree effect: alcoholic fermentation is a predominant pathway in the degradation of hexose sugars in the presence of oxygen, because of insufficient capacity ...Research Focus · Introduction · Is Ethanol Consumption...
[41]
Saccharomyces cerevisiae for lignocellulosic ethanol production
The target for the industry should be to achieve a minimum of 90% theoretical yields, which equates to around 0.511 g of ethanol per g of glucose consumed ( ...
[42]
Engineering Saccharomyces cerevisiae for ethanol production from ...
Global bioethanol production exceeds 110 billion liters annually, yet its expansion remains constrained by the limited range of carbon sources fermentable ...
[43]
Yeasts in sustainable bioethanol production: A review - ScienceDirect
Crabtree positive yeasts such as S. cerevisiae accumulate ethanol in the presence of oxygen, however Candia albicans which is a crabtree-negative yeast ...
[44]
Oxygen Response of the Wine Yeast Saccharomyces cerevisiae ...
Nov 8, 2012 · ... Crabtree effect. Accordingly, the respiratory quotients (RQ) were all higher than 1 under all oxygenated conditions (Table 1). Organic acid ...
[45]
Profiling proteomic responses to hexokinase-II depletion in terpene ...
In summary, inactivating HXK2 may relieve glucose repression on respiration and GAL promoters for improved bioproduction under aerobic conditions in S.
[46]
The advances in creating Crabtree-negative Saccharomyces ...
However, the overflow metabolism, known as the Crabtree effect, directs the majority of the carbon source toward ethanol production, in many cases, resulting in ...
[47]
Sucrose-driven carbon redox rebalancing eliminates the Crabtree ...
Jun 5, 2025 · This study describes an approach for overcoming the Crabtree effect in yeast, substantially improving energy metabolism, carbon recovery, and product yields.Missing: threshold | Show results with:threshold
[48]
Crabtree/Warburg-like aerobic xylose fermentation by engineered ...
The Crabtree/Warburg Effect in S. cerevisiae is a product of high glucose flux, which consequentially results in rapid glucose consumption aerobically and ...