The Saccharomyces cerevisiae acetyl-coenzyme A synthetase encoded by the ACS1 gene, but not the ACS2-encoded enzyme, is subject to glucose catabolite inactivation

Jong-Gubbels, Patricia de; Berg, M. A.; Steensma, H. Yde; Dijken, Johannes P. van; Pronk, Jack T.

doi:10.1111/j.1574-6968.1997.tb10466.x

Cited by 37 publications

(13 citation statements)

References 26 publications

(43 reference statements)

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“…For example, the acetate permease gene ADY2 (51) directly feeds acetate into the system for acetyl-CoA production. We also tested mRNA expression of ACS2, which encodes another nucleocytoplasmic acetyl-CoA synthetase that is not a Cat8/Adr1 target gene and has the opposite expression pattern of ACS1 (49). As expected, ACS2 expression decreased during the diauxic shift under the NR condition and was unaffected by deletion of CAT8 and ADR1 (Fig.…”

Section: Resultsmentioning

confidence: 96%

“…ACH1 encodes a mitochondrial enzyme that produces acetyl-CoA by transferring the CoA moiety of succinyl-CoA onto acetate (47,48). ACS1, on the other hand, encodes a nucleocytoplasmic acetyl-CoA synthetase that utilizes acetate and free CoA as the substrates (49). Both are glucose repressed and activated during the diauxic shift (49,50).…”

Section: Resultsmentioning

confidence: 99%

“…ACS1, on the other hand, encodes a nucleocytoplasmic acetyl-CoA synthetase that utilizes acetate and free CoA as the substrates (49). Both are glucose repressed and activated during the diauxic shift (49,50). ACH1 was activated during the diauxic shift, as expected, but there was not much difference between the NR and CR conditions other than the earlier activation in CR cultures (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway

Wierman

Maqani

Strickler

et al. 2017

Molecular and Cellular Biology

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AMP-activated protein kinase (AMPK) and the homologous yeast SNF1 complex are key regulators of energy metabolism that counteract nutrient deficiency and ATP depletion by phosphorylating multiple enzymes and transcription factors that maintain energetic homeostasis. AMPK/SNF1 also promotes longevity in several model organisms, including yeast. Here we investigate the role of yeast SNF1 in mediating the extension of chronological life span (CLS) by caloric restriction (CR). We find that SNF1 activity is required throughout the transition of log phase to stationary phase (diauxic shift) for effective CLS extension. CR expands the period of maximal SNF1 activation beyond the diauxic shift, as indicated by Sak1-dependent T210 phosphorylation of the Snf1 catalytic ␣-subunit. A concomitant increase in ADP is consistent with SNF1 activation by ADP in vivo. Downstream of SNF1, the Cat8 and Adr1 transcription factors are required for full CR-induced CLS extension, implicating an alternative carbon source utilization for acetyl coenzyme A (acetyl-CoA) production and gluconeogenesis. Indeed, CR increased acetyl-CoA levels during the diauxic shift, along with expression of both acetyl-CoA synthetase genes ACS1 and ACS2. We conclude that CR maximizes Snf1 activity throughout and beyond the diauxic shift, thus optimizing the coordination of nucleocytosolic acetyl-CoA production with massive reorganization of the transcriptome and respiratory metabolism. KEYWORDS Snf1, AMPK, aging, yeast, caloric restriction, ADP, diauxic shift, acetyl-CoA A lthough each eukaryotic species suffers from its own set of age-related maladies, characteristics of the aging process at a cellular level are well conserved, including mitochondrial dysfunction, inefficient turnover of damaged proteins and organelles, accumulated reactive oxygen species (ROS) damage, and gradual breakdown of chromatin structure (reviewed in reference 1). Given the variety of the cellular components involved, it is astounding that any single intervention can alleviate the deterioration of all these processes. Caloric restriction (CR), however, slows the onset of aging-related pathologies and extends life span in almost every model organism tested, ranging from yeast to mammals (reviewed in reference 2). Some mechanistic commonalities for CR have emerged, including upregulation of cellular autophagy, increased mitochondrial respiration, protective oxidative stress responses, and decreased protein synthesis (reviewed in reference 3). The majority of these processes are regulated by a series of highly conserved nutrient signaling pathways, including the AMP-activated protein kinase (AMPK) signaling pathway (4).AMPK is the eukaryotic cell's primary energy sensor, regulating metabolism and other downstream processes while interacting with other signaling pathways (5). Experimental evidence for AMPK as a mediator of the CR longevity response is mounting. In Caenorhabditis elegans, AMPK is activated and required for life span extension under certain CR regimens (6, 7). I...

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway

Wierman

Maqani

Strickler

et al. 2017

Molecular and Cellular Biology

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“…Acetyl-CoA synthetase has been shown to be essential in C. albicans (13) and S. cerevisiae (54). Although studies in other pathogens have not been carried out, deletion of one of the three isoforms in C. neoformans has been shown to reduce virulence in vivo (14).…”

Section: Discussionmentioning

confidence: 99%

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

Koselny

Green

DiDone

et al. 2016

Antimicrob Agents Chemother

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gOnly one new class of antifungal drugs has been introduced into clinical practice in the last 30 years, and thus the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib derivative which has been tested in a phase I clinical trial as an anticancer agent. AR-12 inhibits fungal acetyl coenzyme A (acetyl-CoA) synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma. AR-12 has a broad spectrum of activity, including activity against yeasts (e.g., Candida albicans, non-albicans Candida spp., Cryptococcus neoformans), molds (e.g., Fusarium, Mucor), and dimorphic fungi (Blastomyces, Histoplasma, and Coccidioides) with MICs of 2 to 4 g/ml. AR-12 is also active against azole-and echinocandin-resistant Candida isolates, and subinhibitory AR-12 concentrations increase the susceptibility of fluconazole-and echinocandin-resistant Candida isolates. Finally, AR-12 also increases the activity of fluconazole in a murine model of cryptococcosis. Taken together, these data indicate that AR-12 represents a promising class of small molecules with broad-spectrum antifungal activity.T he treatment of life-threatening invasive fungal infections (IFIs) remains a significant challenge to modern medicine (1, 2). Two primary factors contribute to the difficult nature of IFI therapy. First, most IFIs affect people with compromised immune function, and therefore, IFI patients are more reliant on the efficacy of the antifungal drug than immunocompetent patients. Second, the development of effective antifungal drugs is difficult, because many fundamental biological processes are highly conserved between fungi and humans (3). Consequently, identifying molecules that kill the pathogen and spare the host is very challenging. Currently, only three primary classes of antifungal drugs are in clinical use: (i) azole ergosterol biosynthesis inhibitors (e.g., fluconazole [FLU]), (ii) polyene ergosterol binding agents (e.g., amphotericin B), and (iii) echinocandin 1,3-␤-D-glucan synthase inhibitors (e.g., caspofungin). The number of antifungal drugs pales in comparison to the number of distinct classes of antimicrobial agents, and, in fact, there are currently more classes of antiretroviral agents available for the treatment of HIV/AIDS than classes of antifungal drugs (2).The pace of antifungal drug development has been extremely slow. For example, the most recent addition to the antifungal pharmacopeia, the echinocandins, was discovered in the early 1970s and introduced into clinical practice in the early 2000s (3). Furthermore, no new drugs for the treatment of cryptococcal meningitis, one of the most important causes of infectious disease-related deaths in HIV/AIDS patients (4), have been introduced into clinical practice in more than 20 years. In fact, the current gold standard therapy is based on drugs (amphotericin B an...

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“…ACS has been a target in multiple metabolic engineering strategies with S. cerevisiae for overproduction of acetyl-CoA-derived products (40)(41)(42), as well as for overproduction of NADPH for aerobic xylitol production (43). We chose to overexpress ACS2, which unlike ACS1 is not subject to glucose catabolite inactivation (44). Overexpression of ACS2 in strain M6951 resulted in strain M7890.…”

Section: Construction Of a Gpdmentioning

confidence: 99%

Increasing Anaerobic Acetate Consumption and Ethanol Yields in Saccharomyces cerevisiae with NADPH-Specific Alcohol Dehydrogenase

Henningsen

Hon

Covalla

et al. 2015

Appl Environ Microbiol

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Saccharomyces cerevisiae has recently been engineered to use acetate, a primary inhibitor in lignocellulosic hydrolysates, as a cosubstrate during anaerobic ethanolic fermentation. However, the original metabolic pathway devised to convert acetate to ethanol uses NADH-specific acetylating acetaldehyde dehydrogenase and alcohol dehydrogenase and quickly becomes constrained by limited NADH availability, even when glycerol formation is abolished. We present alcohol dehydrogenase as a novel target for anaerobic redox engineering of S. cerevisiae. Introduction of an NADPH-specific alcohol dehydrogenase (NADPH-ADH) not only reduces the NADH demand of the acetate-to-ethanol pathway but also allows the cell to effectively exchange NADPH for NADH during sugar fermentation. Unlike NADH, NADPH can be freely generated under anoxic conditions, via the oxidative pentose phosphate pathway. We show that an industrial bioethanol strain engineered with the original pathway (expressing acetylating acetaldehyde dehydrogenase from Bifidobacterium adolescentis and with deletions of glycerol-3-phosphate dehydrogenase genes GPD1 and GPD2) consumed 1.9 g liter ؊1 acetate during fermentation of 114 g liter ؊1 glucose. Combined with a decrease in glycerol production from 4.0 to 0.1 g liter ؊1 , this increased the ethanol yield by 4% over that for the wild type. We provide evidence that acetate consumption in this strain is indeed limited by NADH availability. By introducing an NADPH-ADH from Entamoeba histolytica and with overexpression of ACS2 and ZWF1, we increased acetate consumption to 5.3 g liter ؊1and raised the ethanol yield to 7% above the wild-type level. Saccharomyces cerevisiae is the principal microorganism used to produce ethanol, of which 93 billion liters were globally produced in 2014 (1). However, new strains are needed for the production of second-generation biofuels. Pretreatment and monomerization of lignocellulosic substrates produce complex sugar mixtures, including the C 5 sugars xylose and arabinose that are poorly fermented by most wild-type S. cerevisiae strains (2, 3). In addition, a variety of inhibitory compounds are released, such as furfural, hydroxymethylfurfural, methylglyoxal, and acetate (4-6). It is therefore desirable not only to expand the substrate range of S. cerevisiae (3, 7-9) but also to increase its inhibitor tolerance (10-13).Acetate is released during deacylation of hemicellulose and lignin and can be present in concentrations of Ͼ10 g liter Ϫ1 in cellulosic hydrolysates (4,14). At low pH particularly, this weak organic acid is a potent inhibitor of S. cerevisiae metabolism (15-17). Unfortunately, wild-type S. cerevisiae strains are poorly equipped to eliminate acetate from the medium under anoxic conditions. S. cerevisiae can grow on acetate as the sole carbon source under oxic conditions by converting acetate to acetyl coenzyme A (acetyl-CoA) with acetyl-CoA synthetase (ACS) (EC 6.2.1.1) and by either respiring acetyl-CoA in the tricarboxylic acid (TCA) cycle or upgrading acetyl-CoA to four-...

show abstract

The Saccharomyces cerevisiae acetyl-coenzyme A synthetase encoded by the ACS1 gene, but not the ACS2-encoded enzyme, is subject to glucose catabolite inactivation

Cited by 37 publications

References 26 publications

Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway

Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

Increasing Anaerobic Acetate Consumption and Ethanol Yields in Saccharomyces cerevisiae with NADPH-Specific Alcohol Dehydrogenase

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