Regulation of Cellular Metabolism by Protein Lysine Acetylation

Zhao, Shimin; Xu, Wei; Jiang, Wenqing; Yu, Wei; Lin, Yan; Zhang, Tengfei; Yao, Jun; Zhou, Li; Zeng, Yue; Li, Hong; Li, Yixue; Shi, Jiong; An, Wenlin; Hancock, Susan M.; He, Fuchu; Qin, Lun‐Xiu; Chin, Jason W.; Yang, Pengyuan; Chen, Xian; Lei, Qun-Ying; Xiong, Yue; Guan, Kun Liang

doi:10.1126/science.1179689

Cited by 1,649 publications

(1,702 citation statements)

References 16 publications

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“…Indeed, computational and experimental studies show that T. gondii ACL is essential when accompanied by deletion of the other source of cytosolic acetyl-CoA, acetyl-CoA synthase (ACS) [83]. It follows that reduced levels of mitochondrial [BCKDH E1/ knockout (KO)] or cytoplasmic (ACL-ACS double KO) acetyl-CoA may have implications for the activities and balance of fatty acid biosynthesis and/or acetylation [84][85][86][87][88].…”

Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

“…In other organisms, some metabolic enzymes are controlled by their acetylation state [86][87][88]. For example, phosphoenolpyruvate carboxykinase (PEPCK, classically catalyzing the reverse reaction of PEPC) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) can catalyze gluconeogenesis when deacetylated in humans and Salmonella, respectively [87,89].…”

Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

See 1 more Smart Citation

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Jacot

Waller

Soldati‐Favre

et al. 2016

Trends in Parasitology

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Pages 15apicomplexan mitochondrion in energy generation has remained unclear, given the glucosereplete intracellular nature of the environmental niches of these parasites and the apparent reduction of mitochondrial metabolic pathways [4][5][6][7]. For example, apicomplexan mitochondria lack 'type I' NADH dehydrogenase (NDH, complex I of the ETC) and many apparently lack the enzymes and transporters required for fatty acid b-oxidation [8,9]. Furthermore, the pyruvate dehydrogenase complex (PDH) responsible for conversion of pyruvate into acetyl-CoA -an obligate fuel for the TCA cycle -is only present in the apicoplast [10]. Consequently, there was no obvious entry point to allow catalysis of glycolytic pyruvate by the TCA cycle [10][11][12][13][14]. Despite this, there is overwhelming evidence that apicomplexans rely on a functional and canonical TCA cycle (as reviewed [4,5,15]), and apicomplexan genome annotations indicate the presence of all enzymes of the TCA cycle. Only one clade of apicomplexans, Cryptosporidium spp., show evidence of outright loss of the TCA cycle, but these taxa retain only a highly reduced mitochondrion, the mitosome, and have also lost their apicoplast [5,8,16].This review highlights how metabolomics technologies coupled to genetic manipulation have helped in unraveling apicomplexan parasite plasticity in carbon source utilization through different life stages, revealing a complex and sometimes counter-intuitive pattern of metabolic gains, losses, and reassignments. These changes have presumably been tailored to allow these parasites to thrive within their various host niches, but may constitute some much-needed Achilles' heels in the fight against these devastating diseases. Plasmodium falciparum and the Glycolytic DeceitGlycolysis has long appeared to be the main source of ATP and NAD(P)H in the erythrocytic stages of the malaria parasites, [5,[17][18][19][20][21]. Indeed, glucose uptake in P. falciparum-infected red blood cells (RBCs) has been observed to increase 75-100-fold compared to uninfected RBC [22][23][24][25]. Up to 93% of glucose is converted directly to lactate in asexual stages [26][ 4 _ T D $ D I F F ] and is ultimately excreted into the surrounding host cell. Perturbation of glucose uptake is detrimental to parasite growth [27,28], suggesting that glycolysis is an important part of the parasite's strategy for rapid proliferation. In a manner analogous to the Warburg effect observed in highly-proliferative cancer lines and other rapidly-growing cells (e.g., yeast and bloodstream Trypanosoma spp.), Plasmodium (in erythrocytic stages) has opted for fast generation of ATP through substrate-level phosphorylation and secretion of lactate as an end-product (aerobic fermentative glycolysis), as opposed to the 'slow but efficient' mitochondrial oxidative phosphorylation and complete oxidation [29]. Reasons for this dependence on glycolytic fermentation remain unclear -after all, blood stages of Plasmodium certainly have access to oxygen -but it may be a way of avoiding excessiv...

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Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Jacot

Waller

Soldati‐Favre

et al. 2016

Trends in Parasitology

View full text Add to dashboard Cite

show abstract

“…On the other hand, acetylation, which is a post-transcriptional modification of many proteins, is influenced by glucose levels, as acetyl groups are derived from glucose metabolism. Histones, which regulate gene expression, and several metabolic enzymes are regulated by acetylation and are thus responsive to the presence of glucose (Wellen et al, 2009;Zhao et al, 2010).…”

Section: Sensing Glucose Deprivationmentioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

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Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials. Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels. Enforcement of glycolysis inhibits apoptosis induced by cytokine deprivation. Conversely, antiglycolytic agents enhance cell death induced by radio-and chemotherapy. Synergistic effects are likely due to regulation of the apoptotic machinery, as glucose regulates activation and levels of proapoptotic BH3-only proteins such as Bim, Bad, Puma and Noxa, as well as the antiapoptotic Bcl-2 family of proteins. Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death, which can proceed through necrosis or through mitochondrial or caspase-8-mediated apoptosis. We will discuss how oncogenic pathways involved in metabolic stress signaling, such as p53, AMPK (adenosine monophosphate-activated protein kinase) and Akt/mTOR (mammalian target of rapamycin), influence sensitivity to inhibition of glucose metabolism. Finally, we will analyze the rationale for the use of antiglycolytic inhibitors in the clinic, either as single agents or as a part of combination therapies.

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“…Histone acetyltransferases catalyze the addition of acetyl groups to lysine residues, and histone deacetylases remove acetyl groups from lysine residues. Although histones are the classic target of histone acetyltransferases and HDACs, thousands of proteins are acetylated in tissue‐specific manner, including the majority of skeletal muscle contractile proteins (Lundby et al ., 2012) as well as most metabolic enzymes (Zhao et al ., 2010). …”

Section: Introductionmentioning

confidence: 99%

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Walsh¹,

et al. 2015

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SummarySarcopenia, the loss of skeletal muscle mass and function during aging, is a major contributor to disability and frailty in the elderly. Previous studies found a protective effect of reduced histone deacetylase activity in models of neurogenic muscle atrophy. Because loss of muscle mass during aging is associated with loss of motor neuron innervation, we investigated the potential for the histone deacetylase (HDAC) inhibitor butyrate to modulate age‐related muscle loss. Consistent with previous studies, we found significant loss of hindlimb muscle mass in 26‐month‐old C57Bl/6 female mice fed a control diet. Butyrate treatment starting at 16 months of age wholly or partially protected against muscle atrophy in hindlimb muscles. Butyrate increased muscle fiber cross‐sectional area and prevented intramuscular fat accumulation in the old mice. In addition to the protective effect on muscle mass, butyrate reduced fat mass and improved glucose metabolism in 26‐month‐old mice as determined by a glucose tolerance test. Furthermore, butyrate increased markers of mitochondrial biogenesis in skeletal muscle and whole‐body oxygen consumption without affecting activity. The increase in mass in butyrate‐treated mice was not due to reduced ubiquitin‐mediated proteasomal degradation. However, butyrate reduced markers of oxidative stress and apoptosis and altered antioxidant enzyme activity. Our data is the first to show a beneficial effect of butyrate on muscle mass during aging and suggests HDACs contribute to age‐related muscle atrophy and may be effective targets for intervention in sarcopenia and age‐related metabolic disease.

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Regulation of Cellular Metabolism by Protein Lysine Acetylation

Cited by 1,649 publications

References 16 publications

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Sugar-free approaches to cancer cell killing

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

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