Gene/Protein Disease Symptom Drug Enzyme Compound
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The hyperthermophilic, sulfate-reducing archaeon Archaeoglobus fulgidus strain 7324, rather than the type strain VC16, was found to grow on starch and sulfate as energy and carbon source. Fermentation products and enzyme activities were determined in starch-grown cells and compared to those of cells grown on lactate and sulfate. During exponential growth on starch, 1 mol of glucose-equivalent was incompletely oxidized with sulfate to approximately 2 mol acetate, 2 mol CO2 and 1 mol H2S. Starch-grown cells did not contain measurable amounts of the deazaflavin factor F420 (<0.03 nmol/mg protein) and thus did not show the F420-specific green-blue fluorescence. In contrast, lactate (1 mol) was completely oxidized with sulfate to 3 mol CO2 by strain 7324, and lactate-grown cells contained high amounts of F420 (0.6 nmol/mg protein). In extracts of starch-grown cells, the following enzymes of a modified Embden-Meyerhof pathway were detected: ADP-dependent hexokinase (ADP-HK), phosphoglucose isomerase, ADP-dependent 6-phosphofructokinase (ADP-PFK), fructose-1,6-phosphate aldolase, glyceraldehyde-3-phosphate:ferredoxin oxidoreductase (GAP:FdOR), phosphoglycerate mutase, enolase, and pyruvate kinase (PK). Specific activities of ADP-HK, ADP-PFK, GAP:FdOR, and PK were significantly higher in starch-grown cells than in lactate-grown cells, indicating induction of these enzymes during starch catabolism. Pyruvate conversion to acetate involved pyruvate:ferredoxin oxidoreductase and ADP-forming acetyl-CoA synthetase. The findings indicate that the archaeal sulfate reducer A. fulgidus strain 7324 converts starch to acetate via a modified Embden-Meyerhof pathway and acetyl-CoA synthetase (ADP-forming). This is the first report of growth of a sulfate reducer on starch, i.e. on a polymeric sugar.
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PMID:Sugar utilization in the hyperthermophilic, sulfate-reducing archaeon Archaeoglobus fulgidus strain 7324: starch degradation to acetate and CO2 via a modified Embden-Meyerhof pathway and acetyl-CoA synthetase (ADP-forming). 1170 74

Several low virulent Candida albicans mutant strains: CM1613 (deleted in the Mitogen Activated Protein (MAP) Kinase MKC1), CNC13 (deleted in the MAP-kinase HOG1) and the morphological mutant 92' were used as vaccines employing a murine model of systemic candidiasis. In this vaccination trial, only the CNC13 strain was able to induce protection against a subsequent infection with a lethal dose of the wild-type strain. The protection induced by CNC13 vaccinated animals resulted in 60-70% percent of survival. These results demonstrate that collaboration between cellular and humoral responses, induced by the CNC13 mutant, elicited a long lasting and effective protection. Using a proteomic approach (two-dimensional gel electrophoresis followed by Western blotting), twenty-five C. albicans immunogenic proteins were detected and identified by matrix-assisted laser desorption/ionization and/or tandem mass spectrometry. We were able to define an antibody pattern in the sera from the nonvaccinating strains (92' and CM1613), which was different from the profile detected in the sera from surviving animals (vaccinated with the CNC13 mutant). The utility of this proteomic approach has allowed us to identify antigens that induce protective IgG2a antibody isotype in the sera from vaccinated animals: enolase (Eno1p), pyruvate kinase (Cdc19p), pyruvate decarboxylase (Pdc11p), a component from the 40S ribosomal subunit (Bel1p), triosephosphate isomerase (Tpi1p), DL-glycerol phosphatase (Rhr2p), fructose-bisphosphate aldolase (Fba1p) and two new protective antigens: IMP dehydrogenase (Imh3p), and acetyl-CoA synthetase (Acs2p). The antigenic proteins that promote protective antibodies described in this work are excellent candidates for a future fungal vaccine; their heterologous expression and vaccine design is currently underway.
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PMID:Low virulent strains of Candida albicans: unravelling the antigens for a future vaccine. 1537 49

Enolase is a component of the glycolysis pathway and a "moonlighting" protein, with important roles in diverse cellular processes that are not related to its function in glycolysis. However, small molecule tools to probe enolase function have been restricted to crystallography or enzymology. In this study, we report the discovery of the small molecule "ENOblock", which is the first, nonsubstrate analogue that directly binds to enolase and inhibits its activity. ENOblock was isolated by small molecule screening in a cancer cell assay to detect cytotoxic agents that function in hypoxic conditions, which has previously been shown to induce drug resistance. Further analysis revealed that ENOblock can inhibit cancer cell metastasis in vivo. Moreover, an unexpected role for enolase in glucose homeostasis was revealed by in vivo analysis. Thus, ENOblock is the first reported enolase inhibitor that is suitable for biological assays. This new chemical tool may also be suitable for further study as a cancer and diabetes drug candidate.
ACS Chem Biol 2013
PMID:A unique small molecule inhibitor of enolase clarifies its role in fundamental biological processes. 2354 95

Nuclear receptor related 1 (NURR1) is an essential protein for maintenance of dopaminergic neurons in adult midbrain of which deficiency leads to Parkinson's disease. To enhance the NURR1 production of neural cells, various approaches are under investigation. Here we report that NURR1 is highly expressed in stem cells by exposure to an L-polarized blue light emitting diode (LED). Compared to stem cells cultured in the absence of a LED, under polarized green and red LEDs, the stem cells exposed to a polarized blue LED significantly enhanced neuronal biomarkers such as neurofilament M (NFM) and neuron specific enolase (NSE) at both mRNA and protein levels. In particular, NURR1 was selectively enhanced by the stem cells exposed to the L-polarized blue LED. Stem cells exposed to the L-polarized blue LED increased mitochondrial ATP and intracellular calcium ions, which support neuronal differentiation of the stem cells. This study suggests that chiro-optical treatments by using polarized light with a specific wavelength can be used for engineering of stem cells with enhanced specific biochemicals, which may open a new method for a specific disease.
ACS Chem Neurosci 2017 07 19
PMID:Chiro-Optical Modulation for NURR1 Production from Stem Cells. 2845 58

Isozymes are enzymes with similar sequences that catalyze the same reaction in a given species. In Saccharomyces cerevisiae, most isozymes have major isoforms with high expression levels and minor isoforms with little expression under normal growth conditions. In a proteomic study aimed at identifying yeast protein regulated by rapamycin, we found an interesting phenomenon, that, for several metabolic enzymes, the major isozymes are downregulated while the minor isozymes are upregulated. Through enzymological and biochemical studies, we demonstrate that a rapamycin-upregulated enolase isozyme (ENO1) favors gluconeogenesis and a rapamycin-upregulated alcohol dehydrogenase isozyme (ALD4) promotes the reduction of NAD+ to NADH (instead of NADP+ to NADPH). Gene deletion study in yeast showed that the ENO1 and ALD4 are important for yeast survival under less-favorable growth conditions. Therefore, our study highlights the different metabolic needs of cells under different conditions and how nature chooses different isozymes to fit the metabolic needs.
ACS Chem Biol 2018 11 16
PMID:Selective Usage of Isozymes for Stress Response. 3034 89

Yeast enolase serves as a prototype for metalloenzymes with labile, catalytic active site metal ions and is important for glycolysis and fermentation processes. Herein, microsecond molecular dynamics simulations of the protein-substrate and protein-product complexes are conducted to elucidate the mechanism of the opening of catalytically important active site loops. These simulations indicate that conversion of substrate to product is accompanied by diminished metal coordination and hydrogen-bonding interactions, as well as enhanced loop flexibility. Moreover, free energy simulations show that the loop opening is endergonic when substrate is bound but exergonic when product is bound. Thus, the conversion to product weakens the association of the loop with the ligand and binding site, thereby facilitating the loop opening after catalysis and enabling product release. These insights about active site loop motions in enzyme catalysis may be useful in guiding enzyme design efforts.
ACS Catal 2019 Oct 04
PMID:Substrate-to-Product Conversion Facilitates Active Site Loop Opening in Yeast Enolase: A Molecular Dynamics Study. 3185 82

Glycolysis inhibition remains aspirational in cancer therapy. We recently described a promising phosphonate inhibitor of enolase for cancers harboring homozygous deletions of ENO1. Here, we describe the application of a nitroheterocycle phosphonoamidate pro-drug pair to capitalize on tumor hypoxia. This bioreducible prodrug exhibits greater-than 2-fold potency under hypoxic conditions compared to normoxia and exhibits robust stability in biological fluids. Our work provides strong in vitro proof-of-concept for using bioreduction as a pro-drug delivery strategy in the context of enolase inhibition.
ACS Med Chem Lett 2020 Jul 09
PMID:Bioreducible Phosphonoamidate Pro-drug Inhibitor of Enolase: Proof of Concept Study. 3267 58

Recently, growing attention has been paid to the changes of brain biomarkers following the epilepsy. However, establishing specific epilepsy-related biomarkers has been impeded due to contradictory findings. This study systematically reviewed the evidence on brain biomarkers in epilepsy and determined reliable biomarkers in epileptic patients. A comprehensive systematic search of online databases was performed to find eligible studies up to August 2019. The quality of studies methodologically was assessed using the Newcastle-Ottawa Scale score. Among the several biomarkers, S100 calcium binding protein B (S100B) and neuron specific enolase (NSE) have been qualified for meta-analysis of the association between epilepsy and the brain biomarkers. Inverse-variance weights method was used to calculate pooled standardized mean difference (SMD) estimate with 95% CI, and random effects meta-analysis was conducted taking into account conceptual heterogeneity. Sensitivity analysis and publication bias assessment was performed using Stata. Of 29 studies that were qualified for further analysis, only 22 studies were eligible to quantify by meta-analysis. Significant increase of serum S100B levels (SMD = 0.80; 95% CI 0.18 to 1.42) but not NSE (SMD = 0.45; 95% CI -0.09 to 1.00) has been found in epileptic patients compared with healthy controls. Subgroup meta-analysis by age demonstrated that S100B could be found in pediatric (SMD = 1.15; 95% CI 0.03 to 2.27) not adult patients (SMD = 0.43; 95% CI -0.12 to 0.98). Findings of this meta-analysis indicate that serum level of S100B is significantly increased in epileptic patients, suggesting the elevation and release of the brain biomarkers from brain to blood following epileptic seizures.
ACS Chem Neurosci 2020 Nov 04
PMID:Elevated Blood-Based Brain Biomarker Levels in Patients with Epileptic Seizures: A Systematic Review and Meta-analysis. 3314 22