ABSTRACT
A novel phosphate transfer process involving the non-enzymatic transfer of a phosphate group from inositol pyrophosphates to serine residues in proteins has been recently reported. Semi-empirical calculations at the PM3/SM5.2 level were undertaken to explore the effect of inositol pyrophosphate structure and overall charge on the thermodynamics of this phosphate transfer.
Subject(s)
Inositol Phosphates/metabolism , Models, Biological , Phosphates/metabolism , Animals , Biological Transport , Diphosphates/chemistry , Diphosphates/metabolism , Inositol/chemistry , Inositol/metabolism , Inositol Phosphates/chemistry , PhosphorylationABSTRACT
Intracellular thiols are essential biomolecules, which play several critical roles in living organisms including controlling intracellular redox potential and acting as cofactors for several vital detoxification enzymes including S-transferases and formaldehyde dehydrogenases. The tripeptide gamma-L-glutamyl-L-cysteinylglycine, more commonly known as glutathione, is well known as the major intracellular thiol in eukaryotes and in some bacteria. However, glutathione is absent in the Actinomycetales bacteria such as Mycobacteria and Streptomyces and is believed to be replaced by 1-D-myo-inosityl-2-(N-acetyl-L-cysteinyl)amido-2-deoxy-alpha-D-glucopyranoside, mycothiol, in these organisms. Although much is known about the chemistry and biochemistry of glutathione, currently much less is known concerning mycothiol and its properties. The structure of mycothiol is composed of a glycoside linkage between myo-inositol and D-glucosamine with an N-acetyl-L-cysteine linked to the 2'-amino group of the d-glucosamine moiety. Mycothiol is currently of intense interest due to its essential role in the cellular physiology of Mycobacteria, such as Mycobacterium tuberculosis, and its possible role in antimycobacterial drug resistance. A detailed investigation of its chemistry is therefore essential in ameliorating our knowledge of this key glycothiol, and in shedding additional light on its biochemical role in these pathogenic organisms. This report presents a detailed conformational analysis of mycothiol utilizing a variety of force fields and stochastic search protocols. Cluster analyses of energetically low lying conformations have indicated the presence of several key conformations that are populated in the gas phase and with implicit water solvation. These conformations are compared to recent NMR studies on a derivative of mycothiol. This information should be an important contribution to our basic understanding of the chemistry of this glycothiol and critical in the design of novel inhibitors of pathogen enzymes that require it.
Subject(s)
Disaccharides/chemistry , Intracellular Fluid/chemistry , Mycobacterium/chemistry , Pyrazoles/chemistry , Sulfhydryl Compounds/chemistry , Carbohydrate Conformation , Cysteine , Glycopeptides , InositolABSTRACT
The presence of thiols in living systems is critical for the maintenance of cellular redox potentials and protein thiol-disulfide ratios, as well as for the protection of cells from reactive oxygen species. In addition to the well-studied tripeptide glutathione (gamma-Glu-Cys-Gly), a number of compounds have been identified that contribute to these essential cellular roles. This review provides a survey of the chemistry and biochemistry of several critically important and naturally occurring intracellular thiols such as coenzyme M, trypanothione, mycothiol, ergothioneine, and the ovothiols. Coenzyme M is a key thiol required for methane production in methogenic bacteria. Trypanothione and mycothiol are very important to the biochemistry of a number of human pathogens, and the enzymes utilizing these thiols have been recognized as important novel drug targets. Ergothioneine, although synthesized by fungi and the Actinomycetales bacteria, is present at significant physiological levels in humans and may contribute to single electron redox reactions in cells. The ovothiols appear to function as important modulators of reactive oxygen toxicity and appear to serve as small molecule mimics of glutathione peroxidase, a key enzyme in the detoxification of reactive oxygen species.
Subject(s)
Glutathione/analogs & derivatives , Mesna/metabolism , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/metabolism , Drug Design , Furans/chemistry , Glutathione/metabolism , Glutathione Peroxidase/metabolism , Humans , Marine Biology , Molecular Structure , Oxidation-ReductionABSTRACT
Intracellular naturally occurring aromatic thiols such as ergothioneine and the ovothiols have been shown to play a variety of roles in cellular function. A detailed ab initio electronic structure analysis of these thiols is reported evaluating the thermodynamics of the reactions of these intracellular thiols with alkyl thiols, HO*, H2O2, ascorbate and their disulfides.
