A full conformational space analysis of bilirubin (original) (raw)
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Bioorganic & Medicinal Chemistry, 1998
The in vivo metabolism of a bilirubin analog substituted with a propionic acid chain in C 8 (5) showed that it is excreted in bile conjugated with glucuronic acid, while a positional isomer substituted with a propionate in C 7 (6) is excreted in bile without conjugation. A conformational analysis employing an optimized Monte Carlo method and a mixed Monte Carlo/stochastic dynamics reveals that isomer 5 adopts a`ridge tile' conformation, stabilized by the presence of three intramolecular hydrogen bonds. On the contrary, isomer 6 exhibits a more closed structure, where impairment in the formation of at least one of the hydrogen bonds occurs. These theoretical predictions agree well with 1 H NMR, UVvis, and TLC data. #
Russian Journal of Physical Chemistry A, 2011
Quantum chemical calculations of the structural characteristics of the bilirubin molecule and its anion are performed. Intramolecular hydrogen bonds are studied using NBO analysis. It is shown that hydro gen bonds in the bilirubin molecule are nonequivalent, and the bond formed by the keto oxygen of the pyrrole ring and the hydrogen of the carboxyl group belonging to the propionate residue is energetically more favor able. Structural characteristics of the molecular and ion forms of bilirubin in aqueous solution are studied by molecular dynamics simulation. It is found that intermolecular hydrogen bonds with water molecules are formed due to oxygen atoms of the carboxyl group and the keto group of bilirubin, and the probability of their formation by anions is much higher than that for molecules.
Ab initio relative stability of a few conformers of bilirubinin vacuo and in aqueous solution (PCM)
International Journal of Quantum Chemistry, 1998
The conformational properties of bilirubin present a considerable interest from the medical and biological points of view, because of the toxic pigment peculiar solubility features. Therefore, ab initio geometry optimizations at the 3-21GrSCF level were carried out on a few model-built structures of bilirubin, after substituting the methyl groups on the heteroaromatic rings with H atoms. The structures obtained show a varied network of H bonds, ranging from 0 to 6 H bonds for the lowest-energy conformer in vacuo. This conformer assumes a ''ridge-tile'' shape previously found in w Ž .x both MMrMD simulations D. A. Lightner et al., J. Am. Chem. Soc. 114, 10123 1992 w and semiempirical calculations W. H. Shelver et al., Int. J. Quantum Chem. 44, 141 Ž .
Toward an amphiphilic bilirubin: the crystal structure of a bilirubin E-isomer
The Journal of Organic Chemistry, 2008
A new bilirubinoid analog (1) with two methoxy β-substituents on the lactam ring of each dipyrrinone was synthesized and examined spectroscopically. It is more soluble in CH 3 OH and CHCl 3 than bilirubin, which is insoluble in CH 3 OH but soluble in CHCl 3 . The solubility of 1 is ...
Hepatology, 1993
This workshop, conceived in December 1986 when it was realized that an update on the interdisciplinary field of "bilirubinology" was long overdue, was designed to bring together leaders in the field to discuss, in depth, new data and controversial aspects of bilirubin chemistry, transport and metabolism, as well as animal models and treatment of hyperbilirubinemia. This brief summary cannot fully convey the constructive and stimulating atmosphere of the 16 presentations, 18 posters and lively discussion by the 72 participants. CHEMISTRY Falk and Lightner opened the conference by describing the structure of unconjugated bilirubin (UCB) (1-3), a linear tetrapyrrole with two relatively planar dipyrromethenone halves joined to the central C10 methylene group, giving the molecule a configuration like a two-bladed propeller (Fig. 1, top). Variations are possible in the positions of endovinyl and exovinyl groups (111, IX and XI11 isomers) (l), the location of the two ethylcarboxyl sidechains (a, p, y and 6 isomers) (4), the ionization of the two carboxyls (diacid monoanion and dianion) (3), the lactam-lactim tautomerization of the two end-pyrrolenone (A + D) rings (1) and the configurational (geometrical) Z, E isomerization of the double bonds at C4,5 and C15,16 (4). For each of the above structural or geometrical isomers, the configuration may be altered by varying the angles of rotation (+1 and $2) of the two propeller blades around the single bonds joining them to the central methylene, and the angle (8) between the blades (Fig. 1, bottom) (2). As a result, UCB has more than 2,000 possible isomer-conformer variations. Esterification of one or both of the carboxyl groups and aggregation of the individual species provide further possible modifi-This report was supported by research grants from the National Institutes of Health, USPHS (2-ROl-DK-32130), US. Veterans Administration Merit Review Award, the Alexander von Humboldt Foundation and from the Ministero Pubblica Istruzione, Italy.
Journal of Molecular Biology, 1995
Crystal structure determinations of two orthorhombic (P2 1 2 1 2 1) crystal modifications of the biliverdin apomyoglobin complex are described. The Chemie two structures were determined by X-ray diffraction at 100 K to a resolution Karl-Franzens-Universität of 1.5 Å and 1.4 Å. Both crystal forms were grown by hanging-drop A-8010 Graz, Austria techniques, using phosphate as precipitant. The structures were solved by 2 Institut fü r Chemie, Johannes molecular replacement and refined to final R-values of 19.4% and 21.2%. Kepler Universität, A-4040 Both structures are very similar with respect to the binding site and the Linz, Austria conformation of the biliverdin chromophore, which occurs in a (P) helical conformation. It is located within the heme pocket, very close in position and orientation to the heme binding site in myoglobin. Two water molecules not present in the crystal structure of myoglobin are sequestered within the heme pocket in the biliverdin-apomyoglobin complex, and they are engaged in hydrogen bonding to the biliverdin and to the protein. Comparison with structural results from an earlier NMR study of the same complex shows good agreement.
Bioorganic & Medicinal Chemistry, 2003
The cyclic 2,18-bridged biliverdin (2) is excreted in rat bile without reduction to the corresponding bilirubin. Conformational analysis, employing an optimized Monte Carlo method and a mixed Monte Carlo/stochastic dynamics, reveals that biliverdin IXa (1) and the cyclic analogue 2 adopt 'lock washer' conformations, stabilized by the presence of intramolecular hydrogen bonds between N 23 ...H 22 N and, to a lesser extent, between N 23 ...H 24 N. Although 2 is very similar in overall shape to 1, the former adopts a 'locked lock washer' conformation unable to undergo fluctuations, thus possibly hampering a proper recognition by biliverdin reductase. #
Crystallographic Analysis of Human Serum Albumin Complexed with 4Z,15E-Bilirubin-IXα
Journal of Molecular Biology, 2008
Bilirubin, an insoluble yellow-orange pigment derived from heme catabolism, accumulates to toxic levels in individuals with impaired or immature liver function. The resulting jaundice may be managed with phototherapy to isomerize the biosynthetic 4Z,15Z-bilirubin-IXα to more soluble and excretable isomers, such as 4Z,15E-bilirubin. Bilirubin and its configurational isomers are transported to the liver by human serum albumin (HSA) but their precise binding location(s) on the protein have yet to be determined. To investigate the molecular details of their interaction, we co-crystallised bilirubin with HSA. Strikingly, the crystal structuredetermined to 2.42 Å resolution-revealed the 4Z,15E-bilirubin-IXα isomer bound to an L-shaped pocket in sub-domain IB. We also determined the cocrystal structure of HSA complexed with fusidic acid, an antibiotic that competitively displaces bilirubin from the protein, and showed that it binds to the same pocket. These results provide the first crystal structure of a natural bilirubin pigment bound to serum albumin, challenge some of the present conceptions about HSA-bilirubin interactions, and provide a sound structural framework for finally resolving the long-standing question of where 4Z,15Z-bilirubin-IXα binds to the protein.
The Journal of Chemical Physics, 2013
The pKa, the negative logarithm of the acid dissociation equilibrium constant, of the carboxylic acid groups of unconjugated bilirubin in water is a discussed issue because there are quite different experimental values reported. Using quantum mechanical calculations we have studied the conformational behavior of unconjugated bilirubin species (in gas phase and in solution modeled implicitly and explicitly) to provide evidence that may clarify pKa values because of its pathophysiological relevance. Our results show that rotation of carboxylate group, which is not restricted, settles it in a suitable place to establish stronger interactions that stabilizes the monoanion and the dianion to be properly solvated, demonstrating that the rationalization used to justify the high pKa values of unconjugated bilirubin is inappropriate. Furthermore, low unconjugated bilirubin (UCB) pKa values were estimated from a linear regression analysis.