Dual role of a single multienzyme complex in the oxidative decarboxylation of pyruvate and branched-chain 2-oxo acids in <i>Bacillus subtilis</i>

Lowe, Peter N.; Hodgson, Jeffery A.; Perham, Richard N.

doi:10.1042/bj2150133

Cited by 68 publications

(44 citation statements)

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“…Apicomplexans have repurposed another member of this family -the branched-chain ketoacid dehydrogenase (BCKDH) complex, usually responsible for branched-chain amino acid (BCAA) degradationfor mitochondrial conversion of pyruvate to acetyl-CoA [46]. BCKDH had been hypothesized to have PDH activity in Apicomplexa because (i) BCKDH has some PDH activity in other organisms [48][49][50],[ 1 6 _ T D $ D I F F ] and (ii) other enzymes of the BCAA degradation pathway and associated detoxification steps by the methyl-citrate cycle are lacking in Plasmodium spp., resulting in the apparent 'orphan' status of this enzyme [4,6,9,47]. Genetic ablation of the functional subunit of BCKDH (E1/) in P. berghei leads to abrogation of gametocyte maturation and ookinete production, and an almost complete halt in oocyst development, consistent with increased TCA function during this differentiation ( Figure 1) [46].…”

Section: Apicomplexan Mitochondrial Enzymes: Old Dogs New Tricksmentioning

confidence: 99%

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: Apicomplexan Mitochondrial Enzymes: Old Dogs New Tricksmentioning

confidence: 99%

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Jacot

Waller

Soldati‐Favre

et al. 2016

Trends in Parasitology

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“…P. gingivalis could be included in rare eubacterial species having 2-oxoglutarate oxidoreductase, such as Helicobacter pylori (17,20). In most eubacteria, corresponding oxoacid oxidoreductases are known as NAD-dependent dehydrogenases (25,32,52).…”

Section: Discussionmentioning

confidence: 99%

Metabolic Pathways for Cytotoxic End Product Formation from Glutamate- and Aspartate-Containing Peptides by Porphyromonas gingivalis

2000

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Metabolic pathways involved in the formation of cytotoxic end products by Porphyromonas gingivalis were studied. The washed cells of P. gingivalis ATCC 33277 utilized peptides but not single amino acids. Since glutamate and aspartate moieties in the peptides were consumed most intensively, a dipeptide of glutamate or aspartate was then tested as a metabolic substrate of P. gingivalis. P. gingivalis cells metabolized glutamylglutamate to butyrate, propionate, acetate, and ammonia, and they metabolized aspartylaspartate to butyrate, succinate, acetate, and ammonia. Based on the detection of metabolic enzymes in the cell extracts and stoichiometric calculations (carbon recovery and oxidation/reduction ratio) during dipeptide degradation, the following metabolic pathways were proposed. Incorporated glutamylglutamate and aspartylaspartate are hydrolyzed to glutamate and aspartate, respectively, by dipeptidase. Glutamate is deaminated and oxidized to succinyl-coenzyme Porphyromonas gingivalis (formerly Bacteroides gingivalis), a black-pigmented gram-negative anaerobe, is frequently detected in the lesions of several types of periodontitis (37-39, 57), and its isolation frequency increases in active sites of periodontitis (50). These observations suggest the strong relation of this bacterium with periodontal diseases.P. gingivalis has several periodontal pathogenic factors, including membrane-associated proteases, immunoactive cellular compounds, and cytotoxic metabolic end products (19, 31). The main cytotoxic end products, butyrate, propionate, and ammonia, have been found to easily penetrate into periodontal tissue, due to their low molecular weights (59), and subsequently to disturb host cell activity and host defense systems at millimolar concentrations (3, 10-12, 24, 40, 42, 49), the concentration levels found in the P. gingivalis culture supernatant and the gingival crevicular fluid of periodontally diseased subjects (7, 41). Among metabolic end products of P. gingivalis, butyrate is considered the most cytotoxic (42). However, only little information is available about the mechanism of cytotoxic end product formation by P. gingivalis.Several attempts have been made to elucidate the metabolic system of P. gingivalis. Shah and Williams (47) demonstrated that P. gingivalis is capable of degrading aspartate and asparagine to succinate, although P. gingivalis usually produces little succinate (18). Joe et al. (22) reported that this bacterium has glutamate dehydrogenase as an enzyme for glutamate degradation. However, most researchers have concluded that P. gingivalis utilizes mainly peptides instead of single amino acids as sources of energy and cell materials (35,46,48,55,60,62). For example, a chemically defined medium for P. gingivalis must be supplemented with a peptide or a protein such as Trypticase (46, 62) or bovine serum albumin (35). Thus, due to the complicated amino acid composition of peptides or proteins, it had been difficult to determine the amino acid metabolic pathway of P. gingivalis. In additio...

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“…The B. subtilis PDH has been previously isolated and shown to contain four subunits with very similar sizes to those of the S complex (32). The B. subtilis PDH complex also possesses BCDH activity (41).…”

Section: Methodsmentioning

confidence: 99%

“…One of these proteins (64 kilodaltons [kDa]) appeared to be located between the membrane and the attached ribosomes, since it was protected against trypsin or proteinase K, unless the membrane fraction was first treated with EDTA, which detaches ribosomes (15,34). Antiserum raised against the 64-kDa protein immunoprecipitated three additional proteins of 41,36, and 60 kDa. This set of four proteins was termed the S complex (secretory-complex).…”

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confidence: 99%

Secretory S complex of Bacillus subtilis: sequence analysis and identity to pyruvate dehydrogenase

Hemilä¹,

Palva²,

Paulín³

et al. 1990

J Bacteriol

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We have cloned the operon coding for the Bacillus subtilis S complex, which has been proposed to be a component in protein secretion machinery. A lambda gtlO library of B. subtilis was screened with antiserum directed against the Staphylococcus aureus membrane-bound ribosome protein complex, which is homologous to the B. subtilis S complex. Two positive overlapping lambda clones were sequenced. The S-complex operon weights of 46,000, 41,000, 71,000, and 60,000 (2). This set of four proteins was designated the membrane-bound ribosome protein (MBRP) complex. These four proteins were found in roughly stoichiometrical amounts in the complex, although the 60-kDa protein appeared to be loosely bound to it (2, 3). The MBRP complex was found both on membrane and in the cytoplasm. The membrane-bound fraction of the MBRP complex appeared to be mostly bound to ribosomes, since it was protected against trypsin (3). Thus, the MBRP complex seems to be shielded by ribosomes similarly to the B. subtilis 64-kDa protein.

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Dual role of a single multienzyme complex in the oxidative decarboxylation of pyruvate and branched-chain 2-oxo acids in Bacillus subtilis

Cited by 68 publications

References 20 publications

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Metabolic Pathways for Cytotoxic End Product Formation from Glutamate- and Aspartate-Containing Peptides by Porphyromonas gingivalis

Secretory S complex of Bacillus subtilis: sequence analysis and identity to pyruvate dehydrogenase

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