scholarly journals Prenylquinones in Human Parasitic Protozoa: Biosynthesis, Physiological Functions, and Potential as Chemotherapeutic Targets

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3721
Author(s):  
Ignasi Verdaguer ◽  
Camila Zafra ◽  
Marcell Crispim ◽  
Rodrigo Sussmann ◽  
Emília Kimura ◽  
...  
Keyword(s):  
Drug Targets ◽  
Shikimate Pathway ◽  
Mitochondrial Respiratory Chain ◽  
Side Chain ◽  
Head Group ◽  
Parasitic Protozoa ◽  
Amino Acid Degradation ◽  
Phylogenetic Origin ◽  
Metabolic Reactions ◽  
Vertebrate Hosts

Human parasitic protozoa cause a large number of diseases worldwide and, for some of these diseases, there are no effective treatments to date, and drug resistance has been observed. For these reasons, the discovery of new etiological treatments is necessary. In this sense, parasitic metabolic pathways that are absent in vertebrate hosts would be interesting research candidates for the identification of new drug targets. Most likely due to the protozoa variability, uncertain phylogenetic origin, endosymbiotic events, and evolutionary pressure for adaptation to adverse environments, a surprising variety of prenylquinones can be found within these organisms. These compounds are involved in essential metabolic reactions in organisms, for example, prevention of lipoperoxidation, participation in the mitochondrial respiratory chain or as enzymatic cofactors. This review will describe several prenylquinones that have been previously characterized in human pathogenic protozoa. Among all existing prenylquinones, this review is focused on ubiquinone, menaquinone, tocopherols, chlorobiumquinone, and thermoplasmaquinone. This review will also discuss the biosynthesis of prenylquinones, starting from the isoprenic side chains to the aromatic head group precursors. The isoprenic side chain biosynthesis maybe come from mevalonate or non-mevalonate pathways as well as leucine dependent pathways for isoprenoid biosynthesis. Finally, the isoprenic chains elongation and prenylquinone aromatic precursors origins from amino acid degradation or the shikimate pathway is reviewed. The phylogenetic distribution and what is known about the biological functions of these compounds among species will be described, as will the therapeutic strategies associated with prenylquinone metabolism in protozoan parasites.

scholarly journals New aspects of microbial vitamin K2 production by expanding the product spectrum

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Zimeng Zhang ◽  
Linxia Liu ◽  
Chuan Liu ◽  
Yumei Sun ◽  
Dawei Zhang
Keyword(s):  
Metabolic Engineering ◽  
Small Molecules ◽  
Shikimate Pathway ◽  
Vitamin K2 ◽  
Side Chain ◽  
Head Group ◽  
Depth Information ◽  
Product Spectrum ◽  
Different Types ◽  
Membrane Engineering

AbstractVitamin K2 (menaquinone, MK) is an essential lipid-soluble vitamin with critical roles in blood coagulation and bone metabolism. Chemically, the term vitamin K2 encompasses a group of small molecules that contain a common naphthoquinone head group and a polyisoprenyl side chain of variable length. Among them, menaquinone-7 (MK-7) is the most potent form. Here, the biosynthetic pathways of vitamin K2 and different types of MK produced by microorganisms are briefly introduced. Further, we provide a new aspect of MK-7 production, which shares a common naphthoquinone ring and polyisoprene biosynthesis pathway, by analyzing strategies for expanding the product spectrum. We review the findings of metabolic engineering strategies targeting the shikimate pathway, polyisoprene pathway, and menaquinone pathway, as well as membrane engineering, which provide comprehensive insights for enhancing the yield of MK-7. Finally, the current limitations and perspectives of microbial menaquinone production are also discussed. This article provides in-depth information on metabolic engineering strategies for vitamin K2 production by expanding the product spectrum.

scholarly journals Fluorenone imidazolium salts as novel de Vries materials

RSC Advances ◽  
2020 ◽  
Vol 10 (40) ◽  
pp. 23999-24016
Author(s):  
Korinna Bader ◽  
Carsten Müller ◽  
Yann Molard ◽  
Angelika Baro ◽  
Philipp Ehni ◽  
...  
Keyword(s):  
Central Core ◽  
Side Chain ◽  
Head Group ◽  
Imidazolium Salts ◽  
De Vries

ILCs consisting of cationic head group–spacer–fluorenone central core–side chain show de Vries-like behaviour.

Structural investigation of inhibitor designs targeting 3-dehydroquinate dehydratase from the shikimate pathway of Mycobacterium tuberculosis

2011 ◽  
Vol 436 (3) ◽  
pp. 729-739 ◽  
Author(s):  
Marcio V. B. Dias ◽  
William C. Snee ◽  
Karen M. Bromfield ◽  
Richard J. Payne ◽  
Satheesh K. Palaninathan ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Structural Investigation ◽  
Catalytic Mechanism ◽  
Shikimate Pathway ◽  
Structural Rearrangement ◽  
Competitive Inhibitors ◽  
Structural Insights ◽  
Potential Drug Targets

The shikimate pathway is essential in Mycobacterium tuberculosis and its absence from humans makes the enzymes of this pathway potential drug targets. In the present paper, we provide structural insights into ligand and inhibitor binding to 3-dehydroquinate dehydratase (dehydroquinase) from M. tuberculosis (MtDHQase), the third enzyme of the shikimate pathway. The enzyme has been crystallized in complex with its reaction product, 3-dehydroshikimate, and with six different competitive inhibitors. The inhibitor 2,3-anhydroquinate mimics the flattened enol/enolate reaction intermediate and serves as an anchor molecule for four of the inhibitors investigated. MtDHQase also forms a complex with citrazinic acid, a planar analogue of the reaction product. The structure of MtDHQase in complex with a 2,3-anhydroquinate moiety attached to a biaryl group shows that this group extends to an active-site subpocket inducing significant structural rearrangement. The flexible extensions of inhibitors designed to form π-stacking interactions with the catalytic Tyr24 have been investigated. The high-resolution crystal structures of the MtDHQase complexes provide structural evidence for the role of the loop residues 19–24 in MtDHQase ligand binding and catalytic mechanism and provide a rationale for the design and efficacy of inhibitors.

Electron Transport from QA to Thymoquinone in a Synechococcus Oxygen-Evolving Photosystem II Preparation: Role of QB and Binding Affinity of Thymoquinone to the QB Site

1993 ◽  
Vol 48 (3-4) ◽  
pp. 174-178 ◽  
Author(s):  
Kazuhiko Satoh ◽  
Yasuhiro Kashino ◽  
Hiroyuki Koike
Keyword(s):  
Binding Affinity ◽  
Turnover Rate ◽  
Side Chain ◽  
Head Group ◽  
Binding Affinities ◽  
Ps Ii ◽  
Thermophilic Cyanobacteria ◽  
High Concentrations ◽  
Oxygen Evolving

Abstract We have recently shown that binding affinities of benzoquinones can be estimated by two methods in photosystem (PS) II particles (K. Satoh et al., Biochim. Biophys. Acta 1102, 45-52 (1992)). Using these methods we calculated the binding affinity of thymoquinone (2-methyl-5-isopropyl-p-benzoquinone) to the QB site and studied how the quinone accepts electrons in oxygen-evolving PS II particles isolated from the thermophilic cyanobacteria, Synechococcus elongatus and S. vulcanus. The results are as follows: (1) The binding constant of thymoqui­ none to the QB site determined by several methods was around 0.33 mᴍ . (2) At low thymoquinone concentrations the quinone was supposed to accept electrons via QB-plastoquinone, whereas at high concentrations the quinone seemed to bind to the QB site and accept an electron directly from Q-A. Lower rates of photoreduction of the quinone at high concentrations were attributed to a slower turnover rate of the quinone at the QB site than that of endogenous plastoquinone. (3) A model for the function of plastoquinone at the QB site, which can explain all the results, was presented. According to this model, the plastoquinone molecule at the QB site is not replaced by another plastoquinone molecule. Instead, it transfers electrons to pool plastoquinone molecules by turning over its head group but remaining its long side chain bound to the PS II complexes.

Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets

2001 ◽  
Vol 17 (11) ◽  
pp. 532-537 ◽  
Author(s):  
Graham H. Coombs ◽  
Daniel E. Goldberg ◽  
Michael Klemba ◽  
Colin Berry ◽  
John Kay ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Targets ◽  
Parasitic Protozoa ◽  
Aspartic Proteases

Effective dispersants for concentrated, nonaqueous suspensions

1992 ◽  
Vol 7 (10) ◽  
pp. 2884-2893 ◽  
Author(s):  
I. Sushumna ◽  
R.K. Gupta ◽  
E. Ruckenstein
Keyword(s):  
Main Chain ◽  
Side Chain ◽  
Solid Loading ◽  
Head Group ◽  
Side Chains ◽  
Concentrated Suspensions ◽  
Fatty Esters ◽  
Solids Loading ◽  
High Solids Loading ◽  
Order Of Magnitude

With the aim of identifying effective dispersants that would yield stable, high solids loading (≥60 vol.%) suspensions of oxides, carbides, or nitrides in nonaqueous carriers such as paraffinic oils, a number of dispersants were evaluated, using in most cases A16SG grade alumina from Alcoa as the filler. Among those evaluated were some common dispersants, such as menhaden fish oil and oleic acid, and commercial dispersants not commonly used in ceramic processing, such as polymeric fatty esters and petroleum sulfonates. More importantly, a few dispersants were synthesized and evaluated. The latter dispersants contained straight or cyclic (benzenic) side chains located far from the head group on 18 carbon main-chain fatty acid molecules. Among these, the dispersants with a 5–10 carbon side chain or with a benzenic side chain yielded very fluid suspensions (≥60 vol.%) compared to those with long polymeric or oligomeric side chains, or with no side chains, or the commercial dispersants; in some cases, for the same solid loading, the suspension viscosities were an order of magnitude lower with the synthesized side chain dispersants. These results indicate that molecules with an optimum side chain length located sufficiently far from the head group and an optimum backbone (main chain) constitute the most effective dispersants for concentrated suspensions. By combining the advantages provided by wider particle size distributions and by these effective dispersants, suspensions highly concentrated (up to 74 vol.%), and yet processable and “flowing” paste-like have been prepared.

scholarly journals Tyrosine Metabolism in Blowfly Larvae at Pupation

1964 ◽  
Vol 17 (3) ◽  
pp. 803 ◽  
Author(s):  
RH Hackman KN Saxen
Keyword(s):  
Direct Evidence ◽  
Side Chain ◽  
Cross Linking ◽  
Cuticular Protein ◽  
Oxidative Deamination ◽  
Tyrosine Metabolism ◽  
Metabolic Reactions

In insects tyrosine has been regarded as participating in metabolic reactions which lead, not only to its incorporation in various proteins, but also to sclerotization of the cuticle (i.e. quinone cross-linking of cuticular protein). Three different meta-bolic pathways have been suggested, all of which lack direct evidence to support them. The suggested pathways are (i) oxidative deamination leading to the formation of o-quinones, (ii) non-specific hydroxylation and elimination of the side-chain leading to the formation of p-quinones, and (iii) conversion to N-acetyldopamine which is the phenolic precursor of the sclerotizing quinone. For a review of these theories see Pryor (1962) and Hackman (1964).

scholarly journals Molecular determinants for agonist recognition and discrimination in P2X2 receptors

2019 ◽  
Vol 151 (7) ◽  
pp. 898-911 ◽  
Author(s):  
Federica Gasparri ◽  
Jesper Wengel ◽  
Thomas Grutter ◽  
Stephan A. Pless
Keyword(s):  
Drug Targets ◽  
P2x Receptors ◽  
Carbonyl Oxygen ◽  
Site Directed Mutagenesis ◽  
Side Chain ◽  
Ligand Recognition ◽  
Directed Mutagenesis ◽  
Backbone Carbonyl ◽  
Molecular Determinants ◽  
Atp Analogues

P2X receptors (P2XRs) are trimeric ligand-gated ion channels that open a cation-selective pore in response to ATP binding. P2XRs contribute to synaptic transmission and are involved in pain and inflammation, thus representing valuable drug targets. Recent crystal structures have confirmed the findings of previous studies with regards to the amino acid chains involved in ligand recognition, but they have also suggested that backbone carbonyl atoms contribute to ATP recognition and discrimination. Here we use a combination of site-directed mutagenesis, amide-to-ester substitutions, and a range of ATP analogues with subtle alterations to either base or sugar component to investigate the contributions of backbone carbonyl atoms toward ligand recognition and discrimination in rat P2X2Rs. Our findings demonstrate that while the Lys69 backbone carbonyl makes an important contribution to ligand recognition, the discrimination between different ligands is mediated by both the side chain and the backbone carbonyl oxygen of Thr184. Together, our data demonstrate how conserved elements in P2X2Rs recognize and discriminate agonists.

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