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Query: UNIPROT:P06889 (Mol)
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Penicillium marneffei is a thermally dimorphic opportunistic human pathogen with a saprophytic filamentous hyphal form at 25 degrees C and a pathogenic unicellular yeast form at 37 degrees C. During infection. P. marneffei yeast cells exist intracellularly in macrophages. To cope with nutrient deprivation during the infection process, a number of pathogens employ the glyoxylate cycle to utilize fatty acids as carbon sources. The genes which constitute this pathway have been implicated in pathogenesis. To investigate acetate and fatty acid utilization, the acuD gene encoding a key glyoxylate cycle enzyme (isocitrate lyase) was cloned. The acuD gene is regulated by both carbon source and temperature in P. marneffei, being strongly induced at 37 degrees C even in the presence of a repressing carbon source such as glucose. When introduced into the non-pathogenic monomorphic fungus Aspergillus nidulans, the P. marneffei acuD promoter only responds to carbon source. Similarly, when the A. nidulans acuD promoter is introduced into P. marneffei it only responds to carbon source suggesting that P. marneffei possesses both cis elements and trans-acting factors to control acuD by temperature. The Zn(II)2Cys6 DNA binding motif transcriptional activator FacB was cloned and is responsible for carbon source-, but not temperature-, dependent induction of acuD. The expression of acuD at 37 degrees C is induced by AbaA, a key regulator of morphogenesis in P. marneffei, but deletion of abaA does not completely eliminate temperature-dependent induction, suggesting that acuD and the glyoxylate cycle are regulated by a complex network of factors in P. marneffei which may contribute to its pathogenicity.
Mol Microbiol 2006 Dec
PMID:Developmental regulation of the glyoxylate cycle in the human pathogen Penicillium marneffei. 1742 90

Corynebacterium glutamicum grows on a variety of carbohydrates and organic acids as single or combined sources of carbon and energy. Here we show the ability of C. glutamicum to grow on ethanol with growth rates up to 0.24 h(-1) and biomass yields up to 0.47 g dry weight (g ethanol)(-1). Mutants of C. glutamicum deficient in phosphotransacetylase (PTA), isocitrate lyase (ICL) and malate synthase (MS) were unable to grow on ethanol, indicating that acetate activation and the glyoxylate cycle are essential for utilization of this substrate. In accordance, the expression profile of ethanol-grown C. glutamicum cells compared to that of glucose-grown cells revealed an increased expression of genes encoding acetate kinase (AK), PTA, ICL and MS. Furthermore, the specific activities of these four enzymes as well as those of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) were found to be high in ethanol-grown and low in glucose-grown cells. Growth of C. glutamicum on a mixture of glucose and ethanol led to a biphasic growth behavior, which was due to the sequential utilization of glucose before ethanol. Accordingly, the specific activities of ADH, ALDH, AK, PTA, ICL and MS in cells grown in medium containing both substrates were as low as in glucose-grown cells in the first growth phase, but increased 5- to 100-fold during the second growth phase. The results indicate that ethanol catabolism in C. glutamicum is subject to carbon source-dependent regulation, i.e., to a carbon catabolite control.
J Mol Microbiol Biotechnol 2008
PMID:Ethanol catabolism in Corynebacterium glutamicum. 1769 3

The Aspergillus niger genome contains four genes that encode proteins exhibiting greater than 30% amino acid sequence identity to the confirmed oxaloacetate acetyl hydrolase (OAH), an enzyme that belongs to the phosphoenolpyruvate mutase/isocitrate lyase superfamily. Previous studies have shown that a mutant A. niger strain lacking the OAH gene does not produce oxalate. To identify the function of the protein sharing the highest amino acid sequence identity with the OAH (An07g08390, Swiss-Prot entry Q2L887, 57% identity), we produced the protein in Escherichia coli and purified it for structural and functional studies. A focused substrate screen was used to determine the catalytic function of An07g08390 as (2R,3S)-dimethylmalate lyase (DMML): k(cat)=19.2 s(-1) and K(m)=220 microM. DMML also possesses significant OAH activity (k(cat)=0.5 s(-1) and K(m) =220 microM). DNA array analysis showed that unlike the A. niger oah gene, the DMML encoding gene is subject to catabolite repression. DMML is a key enzyme in bacterial nicotinate catabolism, catalyzing the last of nine enzymatic steps. This pathway does not have a known fungal counterpart. BLAST analysis of the A. niger genome for the presence of a similar pathway revealed the presence of homologs to only some of the pathway enzymes. This and the finding that A. niger does not thrive on nicotinamide as a sole carbon source suggest that the fungal DMML functions in a presently unknown metabolic pathway. The crystal structure of A. niger DMML (in complex with Mg(2+) and in complex with Mg(2+) and a substrate analog: the gem-diol of 3,3-difluoro-oxaloacetate) was determined for the purpose of identifying structural determinants of substrate recognition and catalysis. Structure-guided site-directed mutants were prepared and evaluated to test the contributions made by key active-site residues. In this article, we report the results in the broader context of the lyase branch of the phosphoenolpyruvate mutase/isocitrate lyase superfamily to provide insight into the evolution of functional diversity.
J Mol Biol 2009 Feb 20
PMID:Structure and function of 2,3-dimethylmalate lyase, a PEP mutase/isocitrate lyase superfamily member. 1913 76

The vascular wilt pathogen Fusarium oxysporum f. sp. lycopersici efficiently invades roots and colonizes vascular tissues of its host tomato. For these processes, the F-box protein Frp1 is required. The Fusarium oxysporum Deltafrp1 mutant was characterized in detail to uncover the cause of its colonization defect. Using growth assays, we could attribute poor root colonization to reduced assimilation of organic acids, amino acids (except proline), or polysaccharides, singly or in combination. External root colonization by the Deltafrp1 mutant is restored by the addition of 0.1% glucose or proline but infection still does not occur. This is due to the inability of the Deltafrp1 mutant to penetrate the roots, as demonstrated by the lack of expression of SIX1 in the Deltafrp1 strain, which is a gene exclusively expressed inside roots, and loss of cell wall-degrading enzyme (CWDE) gene expression. Many of the metabolic defects of the Deltafrp1 strain can be attributed to reduced expression of the ICL1 (isocitrate lyase) gene. Strikingly, an Deltaicl1 mutant is still fully pathogenic and capable of external root colonization. We conclude that the inability of the Deltafrp1 strain to colonize and invade roots is not primarily due to metabolic defects but can be attributed to reduced expression of several CWDE genes.
Mol Plant Microbe Interact 2009 May
PMID:Impaired colonization and infection of tomato roots by the Deltafrp1 mutant of Fusarium oxysporum correlates with reduced CWDE gene expression. 1934 69

We developed a metabolism-based systems biology framework to model drug-induced growth inhibition of Mycobacterium tuberculosis in murine macrophage cells. We used it to simulate ex vivo bacterial growth inhibition due to 3-nitropropionate (3-NP) and calculated the corresponding time- and drug concentration-dependent dose-response curves. 3-NP targets the isocitrate lyase 1 (ICL1) and ICL2 enzymes in the glyoxylate shunt, an essential component in carbon metabolism of many important prokaryotic organisms. We used the framework to in silico mimic drugging additional enzymes in combination with 3-NP to understand how synergy can arise among metabolic enzyme targets. In particular, we focused on exploring additional targets among the central carbon metabolism pathways and ascertaining the impact of jointly inhibiting these targets and the ICL1/ICL2 enzymes. Thus, additionally inhibiting the malate synthase (MS) enzyme in the glyoxylate shunt did not produce synergistic effects, whereas additional inhibition of the glycerol-3-phosphate dehydrogenase (G3PD) enzyme showed a reduction in bacterial growth beyond what each single inhibition could achieve. Whereas the ICL1/ICL2-MS pair essentially works on the same branch of the metabolic pathway processing lipids as carbon sources (the glyoxylate shunt), the ICL1/ICL2-G3PD pair inhibition targets different branches among the lipid utilization pathways. This allowed the ICL1/ICL2-G3PD drug combination to synergistically inhibit carbon processing and ultimately affect cellular growth. Our previously developed model for in vitro conditions failed to capture these effects, highlighting the importance of constructing accurate representations of the experimental ex vivo macrophage system.
Mol Biosyst 2011 Sep
PMID:Modeling synergistic drug inhibition of Mycobacterium tuberculosis growth in murine macrophages. 2171 81

Bradyrhizobium japonicum, a nitrogen-fixing bacterium in soil, establishes a symbiotic relationship with the leguminous soybean plant. Despite a mutualistic association between the two partners, the host plant produces an oxidative burst to protect itself from the invasion of rhizobial cells. We investigated the effects of H(2)O(2)-mediated oxidative stress on B. japonicum gene expression in both prolonged exposure (PE) and fulminant shock (FS) conditions. In total, 439 and 650 genes were differentially expressed for the PE and FS conditions, respectively, at a twofold cut-off with q < 0.05. A number of genes within the transport and binding proteins category were upregulated during PE and a majority of those genes are involved in ABC transporter systems. Many genes encoding ? factors, global stress response proteins, the FixK(2) transcription factor, and its regulatory targets were found to be upregulated in the FS condition. Surprisingly, catalase and peroxidase genes which are typically expressed in other bacteria under oxidative stress were not differentially expressed in either condition. The isocitrate lyase gene (aceA) was induced by fulminant H(2)O(2) shock, as was evident at both the transcriptional and translational levels. Interestingly, there was no significant effect of H(2)O(2) on exopolysaccharide production at the given experimental conditions.
Mol Plant Microbe Interact 2011 Dec
PMID:Whole-genome expression profiling of Bradyrhizobium japonicum in response to hydrogen peroxide. 2186 47

We studied the role of isocitrate lyase in the interaction between Mycobacterium bovis BCG and mice. ApoB100-only LDLR-/- (B6;129S-ApoBtm2SgyLdlrtm1Her/J) mice were inoculated with M. bovis BCG harbouring plasmids carrying the gene for isocitrate lyase. The presence of ~29 times more copies of this gene resulted in a higher bacterial yield in the spleens and lungs of the infected mice. The spleen was 3-4 times heavier, and in the spleen the bacteria survived over 10 days longer than did the bacteria with the control plasmid. Propionate was less toxic for bacteria carrying icl plasmids in vitro. This recombinant BCG can be a possible vaccine candidate.
Mol Biol Rep 2013 Aug
PMID:Isocitrate lyase encoding plasmids in BCG cause increased survival in ApoB100-only LDLR-/- mice. 2365 2

A cDNA library was constructed to mRNA enriched for isocitrate-lyase mRNA from castor-bean (Ricinus communis var. zanzibarensis) endosperms. Nine clones for isocitrate lyase (EC 4.1.3.1) were identified. The insert of 2.2 kb from clone ICL4 was sequenced and proved to contain the entire coding region, 1731 bp, for isocitrate lyase. The amino acid sequence of isocitrate lyase was deduced from the nucleic acid sequence. By analogy with muscle aldolase a lysine residue that possibly takes part in the binding of the substrate was identified. The 3' untranslated region contained three putative polyadenylation addition signals and two direct repeats.
Plant Mol Biol 1987 Nov
PMID:Nucleic acid (cDNA) and amino acid sequences of isocitrate lyase from castor bean. 2430 9

Actinomycetes undergo a dramatic reorganization of metabolic and cellular machinery during a brief period of growth arrest ("metabolic switch") preceding mycelia differentiation and the onset of secondary metabolite biosynthesis. This study explores the role of phosphorylation in coordinating the metabolic switch in the industrial actinomycete Saccharopolyspora erythraea. A total of 109 phosphopeptides from 88 proteins were detected across a 150-h fermentation using open-profile two-dimensional LC-MS proteomics and TiO(2) enrichment. Quantitative analysis of the phosphopeptides and their unphosphorylated cognates was possible for 20 pairs that also displayed constant total protein expression. Enzymes from central carbon metabolism such as putative acetyl-coenzyme A carboxylase, isocitrate lyase, and 2-oxoglutarate dehydrogenase changed dramatically in the degree of phosphorylation during the stationary phase, suggesting metabolic rearrangement for the reutilization of substrates and the production of polyketide precursors. In addition, an enzyme involved in cellular response to environmental stress, trypsin-like serine protease (SACE_6340/NC_009142_6216), decreased in phosphorylation during the growth arrest stage. More important, enzymes related to the regulation of protein synthesis underwent rapid phosphorylation changes during this stage. Whereas the degree of phosphorylation of ribonuclease Rne/Rng (SACE_1406/NC_009142_1388) increased during the metabolic switch, that of two ribosomal proteins, S6 (SACE_7351/NC_009142_7233) and S32 (SACE_6101/NC_009142_5981), dramatically decreased during this stage of the fermentation, supporting the hypothesis that ribosome subpopulations differentially regulate translation before and after the metabolic switch. Overall, we show the great potential of phosphoproteomic studies to explain microbial physiology and specifically provide evidence of dynamic protein phosphorylation events across the developmental cycle of actinomycetes.
Mol Cell Proteomics 2014 May
PMID:Temporal dynamics of the Saccharopolyspora erythraea phosphoproteome. 2461 62

In a previous report, the pepper receptor-like kinase 1 (CaRLK1) gene was shown to be responsible for negatively regulating plant cell death caused by pathogens via accumulation of superoxide anions. Here, we examined whether this gene also plays a role in regulating cell death under abiotic stress. The total concentrations of free amino acids in CaRLK1-overexpressed cells (RLKox) increased by twofold compared with those of the wild-type Nicotiana tabacum BY-2 cells. Additionally, alanine and pyruvate concentrations increased by approximately threefold. These accumulations were associated with both the expression levels of the isocitrate lyase (ICL) and malate synthase genes and their specific activities, which were preferentially up-regulated in the RLKox cells. The expression levels of ethylene biosynthetic genes (ACC synthase and ACC oxidase) were suppressed, but those of both the metallothionein and lesion simulating disease 1 genes increased in the RLKox cells during submergence-induced hypoxia. The specific activity of catalase, which is involved in protecting ICL from reactive oxygen species, was also induced threefold in the RLKox cells. The primary roots of the transgenic plants that were exposed to hypoxic conditions grew at similar rates to those in normal conditions. We propose that CaRLK1 maintains a persistent hypoxia-resistant phenotype.
Plant Mol Biol 2014 Oct
PMID:Ectopic expression of CaRLK1 enhances hypoxia tolerance with increasing alanine production in Nicotiana spp. 2503 Feb 25


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