Acetylation of Metabolic Enzymes Coordinates Carbon Source Utilization and Metabolic Flux

Wang, Qijun; Zhang, Yakun; Yang, Chen; Xiong, Huiming; Lin, Yan; Yao, Jun; Li, Hong; Xie, Lu; Zhao, Wei; Yao, Yufeng; Ning, Zhi Bin; Zeng, Rong; Xiong, Yue; Guan, Kun Liang; Zhao, Shimin; Zhao, Guo Ping

doi:10.1126/science.1179687

Cited by 915 publications

(1,018 citation statements)

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“…The acetylation modification is reversed by a deacetylase, and the bacterial CobB sirtuin was identified as responsible for this function [51]. Based on protein homology, we identified CobB (PGN_004) with 58% exact and 73% positive identity to the CobB protein from Bacteroides thetaiotaomicron (Accession number NP_811887).…”

Section: Rr Rprymentioning

confidence: 99%

Two-component signal transduction systems in oral bacteria

Mattos-Graner

Duncan²

2017

Journal of Oral Microbiology

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We present an overview of how members of the oral microbiota respond to their environment by regulating gene expression through two-component signal transduction systems (TCSs) to support conditions compatible with homeostasis in oral biofilms or drive the equilibrium toward dysbiosis in response to environmental changes. Using studies on the sub-gingival Gram-negative anaerobe Porphyromonas gingivalis and Gram-positive streptococci as examples, we focus on the molecular mechanisms involved in activation of TCS and species specificities of TCS regulons.

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Section: Rr Rprymentioning

confidence: 99%

Two-component signal transduction systems in oral bacteria

Mattos-Graner

Duncan²

2017

Journal of Oral Microbiology

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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%

“…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]. Both of these are acetylated in T. gondii [90], but deacetylation may be important in regulating the gluconeogenic activity that is vital for normal cell growth [91].…”

Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

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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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“…Succinylation of Enzymes Involved in Central MetabolismIncreasing evidences show that lysine succinylation may play a regulatory role in metabolic pathways, similar with lysine acetylation (4,67). We investigated the succinylation of metabolic enzymes in Mtb by mapping succinylated proteins to KEGG metabolic pathways (supplemental Table S8).…”

Section: Sequence Recognition Motifs and Local Structural Properties-mentioning

confidence: 99%

Succinylome Analysis Reveals the Involvement of Lysine Succinylation in Metabolism in Pathogenic Mycobacterium tuberculosis*

Yang

Wang

Chen

et al. 2015

Molecular & Cellular Proteomics

122

139

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Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, remains one of the most prevalent human pathogens and a major cause of mortality worldwide. Metabolic network is a central mediator and defining feature of the pathogenicity of Mtb. Increasing evidence suggests that lysine succinylation dynamically regulates enzymes in carbon metabolism in both bacteria and human cells; however, its extent and function in Mtb remain unexplored. Here, we performed a global succinylome analysis of the virulent Mtb strain H37Rv by using high accuracy nano-LC-MS/MS in combination with the enrichment of succinylated peptides from digested cell lysates and subsequent peptide identification. In total, 1545 lysine succinylation sites on 626 proteins were identified in this pathogen. The identified succinylated proteins are involved in various biological processes and a large proportion of the succinylation sites are present on proteins in the central metabolism pathway. Site-specific mutations showed that succinylation is a negative regulatory modification on the enzymatic activity of acetylCoA synthetase. Molecular dynamics simulations demonstrated that succinylation affects the conformational stability of acetyl-CoA synthetase, which is critical for its enzymatic activity. Further functional studies showed that CobB, a sirtuin-like deacetylase in Mtb, functions as a desuccinylase of acetyl-CoA synthetase in in vitro assays. Together, our findings reveal widespread roles for lysine succinylation in regulating metabolism and diverse processes in Mtb. Our data provide a rich resource for functional analyses of lysine succinylation and facilitate the dissection of metabolic networks in this life-threatening pathogen.

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Acetylation of Metabolic Enzymes Coordinates Carbon Source Utilization and Metabolic Flux

Cited by 915 publications

References 16 publications

Two-component signal transduction systems in oral bacteria

Two-component signal transduction systems in oral bacteria

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Succinylome Analysis Reveals the Involvement of Lysine Succinylation in Metabolism in Pathogenic Mycobacterium tuberculosis*

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