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Possible Acetylation of Tobramycin CoA Complex by Mycobacterium Tuberculosis

spinqualitylabelsall models Structure of HMG-CoA reductase (PDB entry 1dq8) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D The study where this molecule was obtained is named "Aminoglycoside 2'-N-acetyltransferase from Mycobacterium tuberculosis-Complex with Coenzyme A and Tobramycin". The study suggested a reason for Tobramycin resistance. The resistance may be due to the possible acetylation of mycobacteria by Tobramycin. When Tobramycin acetylates it loses its function. The reason for the acetylation is not fully understood but a possible explanation may be that the mycobacteria needs to be acetylated so that a key biosynthetic intermediate, Mycothiol can be activated. Mycothiol is a major reducing agent in the myobacteria. If this occurs it may participate in the regulation of cellular redox potential. A redox reaction or reduction-oxidation reaction is a chemical reaction that changes the oxidation state of the atom. An example of this would be the oxidation of a carbon atom to CO2. Oxidation is the loss of electrons or a gain in the oxidation state of the atom or molecule. A reduction is the gain of electrons or the decrease in oxidation state. Tobramycin Tobramycin is an antibiotic part of the aminoglycoside family. Aminoglycosides produce antibacterial effects by inhibiting protein synthesis and compromising the cell wall structure. It was derived from Streptomyces tenebrarius. Tobramycin is targets a variety of bacteria particularly gram(-) species. Some of the more common side effects are ototoxicity and nephrotoxicity. Ototoxic is hearing loss and nephrotoxic is casuing kidney damage. The kidney damage is due to Tobramycin reabsorption through the renal tubules. Tobramycin trade name is Tobrex. It is a pregnancy category D, making it not the best choice for patients who are pregnant. Tobramycin can be given intravenously, intramuscularly, as an inhalation or ophthalmicly. The chemical formula for Tobramycin is C18H37N5O9 and the molecular mass is 467.515 g/mol. Hydrogen Bonds Hydrogen Bonds are attractive interactions (dipole-dipole) between an electronegative atom and hydrogen. The hydrogen bonds in this picture are displayed as yellow dashed lines. This bond always involves a hydrogen atom. A hydrogen bond is stronger then a van-der-waals interaction but weaker then an ionic or covalent bond. The hydrogen bonds in this display are between the alpha helices and beta sheets. An ionic bond is an attraction between two molecules of opposite charge. Covalent bonds, the strongest type of bond, involves the sharing of electrons between two molecules. Secondary Structures This molecule represents the alpha helices and beta strands. The alpha helices are represented with pink arrows and the beta strands are represented with yellow arrows. This molecule has approximately four alpha helices and two beta strands. The structure of the alpha and beta sheets in this structure represents the GNAT fold. The GNAT fold is almost completely catalyzed by CoA- dependent transfer of an acyl group to an exposed amino acid group. This interaction is the basis for the study. This shows how the acetylation of Mycothiol is occurring and why. Ligands The ligands displayed in the molecule to the right are Coenzyme A, Tobramycin and 3'-Phosphate-Adenosine-5'-Diphosphate. Coenzyme A (CoA) is a coenzyme that synthesizes and oxidizes fatty acids. Pap's IUPAC name is [(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonooxyoxolan-2-yl]methylphosphono hydrogen phosphate. The ligands are held together by the hydrogen bonds created by alpha and beta sheets. The Protein in this molecule is represented as a dimer. A dimer is a chemical structure formed from two subunits. The dimer is constructed by connecting two subunits along their axis so that all four modules contribute to the structure. Protein Binding This molecule displays the protein bound to the ligand CoA. The red molecules represent an anionic or negatively charged interaction. The dark blue molecules emphasize the cationic or positively charged interactions. The cationic and anionic interactions are contributed to arginine, aspartic acid, or glycine amino acids. The light blue molecules represent histidine, which is a basic amino acid. The difference in the charges displayed here contribute to the stability of the molecule. Since the charges are different it allows the molecules to be attracted to the opposite charge holding the molecule in a stable position. Active Site The active site of a molecule can be described as a pocket where interaction between structures causes a desired effect. This is a good representation of the active site. The active site is where the substrate, in this case tobramycin, binds to CoA and the mycobacterium to cause an antibacterial effect. It the study described this is where the acetylation of the mycothiol should be occurring. Amino Acids Amino acids are the building blocks of proteins. There are 20 common amino acids. The contain and amine group (-NH2), a carboxylic acid group (-COOH) and a functional group specific to each amino acid. The functional group determines how the amino acid is classified. They are categorized as either, polar, non-polar, acidic or basic. There are 8 different amino acids present in the Tobramycin-CoA molecule. CoA has a combination of 7 amino acids bound to it. The amino acids are two Arginine (basic amino acid), one Glycine (polar amino acid), and four Valine (non-polar amino acid). PAP has four amino acids bound to it, two Histidine and two tryptophan (non-polar amino acid). Tobramycin also has four amino acids bound to it, two aspartic acid (acidic amino acid)), Serine (polar amino acid) and tryptophan (non-polar amino acid). CoA Amino Acids In this representation it displays the interaction between CoA and Arginine. Arginine is displayed as the pink molecule and CoA is displayed as the orange and red molecule. Arginine is classified as a basic, nonessential amino acid. Nonessential meaning the human body can synthesize it. Val96 and CoA are clearly displayed in this representation. Valine is a nonpolar amino acid. Unlike Arginine, Valine is an essential amino acid. PAP Amino Acids This shows His 54 and PAP interaction.Histidine is the smallest amino acid. I is also classified as an essential amino acid. The other Amino acid bound to PAP is Typ90. Tryptophan is an essential amino acid. Tryptophan is a precursor to serotonin which is a key neurotransmitter in the gastrointestinal tract, platelets, and the central nervous system (CNS).