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Published in Anton Sebastian, A Dictionary of the History of Medicine, 2018
Kornberg, Sir Hans Leo (b 1928) German-born British biochemist who worked mainly on microbial metabolism. He discovered the glyoxylate cycle of fatty acid metabolism used by plants, fungi and microorganisms. He was elected FRS in 1965, knighted in 1978 and has been Chairman of the Royal Commission on Environmental Pollution and a trustee of both the Nuffield and Wellcome trusts.
Distribution and Biological Functions of Pyruvate Carboxylase in Nature
Published in D. B. Keech, J. C. Wallace, Pyruvate Carboxylase, 2018
Genetic techniques have not yet been employed to demonstrate the essential function of this anaplerotic enzyme in these organisms, but in general, its activity, as a function of growth time, exhibits a pattern that is typical of an anabolic enzyme.240 Furthermore, higher levels of activity are associated with an increased production of biomass.240 Similarly, reduced levels of pyruvate carboxylase activity in Candida tropicalis, brought about by culturing this yeast on biotin-deficient, glucose-containing media, were also associated with a marked (55%) reduction in growth.591 Biotin deficiency in Candida tropicalis also resulted in reduced activity of another biotin-containing enzyme, acetyl-CoA carboxylase, as well as a massive (8- to 13-fold) increase in the activity of isocitrate lyase, a key enzyme of the glyoxylate cycle. However, while the effect of biotin deficiency on cell growth and isocitrate lyase activity was evident in cultures utilizing the three hexoses tested (viz., glucose, fructose, and mannose), it was not seen in cells cultured on n-alkane. This contrast, together with the three-fold elevation of pyruvate concentration and a similar drop in oxaloacetate level in biotindeficient cells, suggests an important role for the anaplerotic activity of pyruvate carboxylase vis-a-vis the activity of the glyoxylate cycle, an alternative source of C4-compounds.
Penicillium and Talaromyces
Published in Dongyou Liu, Laboratory Models for Foodborne Infections, 2017
Elena Bermúdez, Félix Núñez, Josué Delgado, Miguel A. Asensio
It seems that T. marneffei possesses the ability to evade a normally functioning immune system until in vivo conditions, due to immunosuppression, are favorable to dissemination throughout the host.18 Upon switching to 37°C, T. marneffei undergoes a process termed arthroconidiation. Conidia germinate with the onset of extensive hyphal branching. Fragmentation occurs to generate single, uninucleated yeast cells that divide by fission. Switching from yeast growth at 37°C to hyphal growth at 25°C requires the polarized growth of yeast cells, septation, and branching, to form the characteristic multinucleate hyphal mycelium. Genes responsible for growth, morphogenesis, and development of T. marneffei have been characterized.19 Conidial germination and temperature adaptation require both HHK and heterotrimeric G-protein-Ras signaling, as well as the establishment of actin-mediated polarized growth through a Rho GTPase. In addition, the p21-activated kinase pathway is involved in sensing the environment inside a host cell by T. marneffei, being central to eliciting the appropriate morphogenetic response to the host environment.20 Systems for detecting and responding to changes in carbon sources also play a major role in adaptation to the host niche and are essential factors for persistence in a mammalian host. Many of the genes whose expression is upregulated during the mold-to-yeast transition are related to those genes involved in energy metabolism. The temperature-dependent regulation of isocitrate lyase, a key component of the glyoxylate cycle, activates the glyoxylate cycle for utilization of poor carbon sources.16
The relationship between cigarette smoking and the tongue microbiome in an East Asian population
Published in Journal of Oral Microbiology, 2020
Noriaki Sato, Masanori Kakuta, Eiichiro Uchino, Takanori Hasegawa, Ryosuke Kojima, Wataru Kobayashi, Kaori Sawada, Yoshihiro Tamura, Itoyo Tokuda, Seiya Imoto, Shigeyuki Nakaji, Koichi Murashita, Motoko Yanagita, Yasushi Okuno
A metagenomic analysis was conducted to determine the functional consequences of different microbiota compositions using the PICRUSt2 algorithm. The mean ± SD of the overall weighted NSTI values was 0.063 ± 0.034. Among the 395 MetaCyc pathways predicted by the Enzyme Commission number abundance, 290 pathways existing in more than 15% of the participants were tested; 189 pathways were significantly different when comparing never smokers to current smokers. Among these pathways were those involved in denitrification, sulfate reduction, the tricarboxylic acid (TCA) cycle, glyoxylate cycle, aerobic respiration, 2-methylcitrate cycle, and several compound biosynthesis pathways such as ubiquinol, menaquinol, L-arginine or L-ornithine. One pathway (mycolyl-arabinogalactan-peptidoglycan complex biosynthesis) was significantly different between former and never smokers. The results of differential abundance analyses for pathways are summarized in Table S4.
Drug targets in dormant Mycobacterium tuberculosis: can the conquest against tuberculosis become a reality?
Published in Infectious Diseases, 2018
Vivek Kumar Gupta, M. Madhan Kumar, Dharmendra Singh, Deepa Bisht, Shweta Sharma
Dormant bacilli face depletion of oxygen and nutrients which are the main factors responsible for NRP stage of Mtb. The stress environment causes a massive metabolic shunt and down regulates tricarboxylic acid (TCA) cycle enzymes [21]. In this carbon deficient environment, Mtb cannot use TCA cycle for generation of energy. So, at this stage carbon conserving glyoxylate cycle is up regulated in order to continue generating energy from an alternative carbon source namely lipids. The ICL is a glyoxylate cycle enzyme which converts isocitrate to succinate and glyoxylate, followed by the addition of acetyl-CoA to glyoxylate to form malate by malate synthase. ICL plays an important role in the survival of latent Mtb during chronic stage of infection [22]. The glyoxylate pathway is absent in host and has been identified as potential and selective drug target in dormant bacilli.
The piperazine scaffold for novel drug discovery efforts: the evidence to date
Published in Expert Opinion on Drug Discovery, 2022
Maria Novella Romanelli, Dina Manetti, Laura Braconi, Silvia Dei, Alessio Gabellini, Elisabetta Teodori
Quinolones are widely used antibacterial drugs, which often contain a piperazine ring. In recent times, the free NH moiety of quinolones such as ciprofloxacin, norfloxacin, and others has been exploited for the synthesis of hybrids with improved activity especially toward resistant strains. This strategy, which takes advantage of the piperazine ring as a linker, has recently been reviewed [91]. As an example, we can report the approach of Sriram et al. who attached a 5-nitro-2,6-dioxohexahydro-4-pyrimidinecarboxamido residue to various anilines and arylpiperazines, including norfloxacin, gatifloxacin, and ciprofloxacin. The compounds were evaluated for in vitro activity against Mycobacterium tuberculosis (MTB) H37Rv, MDR MTB, and Mycobacterium smegmatis (MC2) [92]. The quinolone derivatives were the most active compounds in the series, with minimum inhibitory concentration (MIC) <1 μM against MTB and MDR-MTB. Gyrase inhibitory properties were not measured, but since these compounds showed activity against dormant MTB, the authors tested their ability to inhibit the isocitrate lyase (ICL) enzyme of MTB. ICL is an important enzyme in the glyoxylate cycle during carbohydrate starvation; in MTB, it catalyses the cleavage of isocitrate to glyoxylate and succinate, allowing the organism to survive on acetate or fatty acids [93]. The quinolone hybrids showed 36–46% inhibition against MTB ICL at 10 μM; 60 (Figure 8) was the most active compound in vitro with MICs of <0.17 and 0.17 μM against MTB and MDR-TB, respectively, and showing higher potency with respect to isoniazid and rifampicin.