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The mechanism of haem catabolism. Bilirubin formation in living rats by [18O]oxygen labelling.

ABSTRACT: 1. The pathway of haem breakdown in living rats was studied by using 18O in the oxygen that the animals consumed. By cannulation of the common bile duct and collection of bile, labelled bilirubin was isolated and its mass spectrum determined. One set of results was obtained for a rat to which haemoglobin had been intravenously administered and another set obtained for a rat that was not given exogenous haem. Isomerization of bilirubin IXalpha to the XIIIalpha and IIIalpha isomers did not occur to any significant extent. The 18O-labelling pattern obtained in the bilirubin was consistent with a Two-Molecule Mechanism, whereby the terminal lactam oxygen atoms of bilirubin are derived from different oxygen molecules. The consequences of this mechanism are discussed in terms of the possible intermediates of the catabolic pathway. 2. 18O-labelled bilirubin appeared in the bile in less than 10 min after exposure of the animals to labelled oxygen. This result suggests that all of the chemical transformations involving production of biliverdin, reduction to bilirubin and conjugation of the bilirubin are fast processes. 3. The quantitative recovery of label obtained in the experiments suggests that there is little or no exchange of newly synthesized bilirubin with existing bilirubin pools in the animal.

SUBMITTER: Brown SB

PROVIDER: S-EPMC1183896 | biostudies-other | 1978 Feb

REPOSITORIES: biostudies-other

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Project description:Work on the electronic structures of metal-oxo complexes began in Copenhagen over 50 years ago. This work led to the prediction that tetragonal multiply bonded transition metal-oxos would not be stable beyond the iron-ruthenium-osmium oxo wall in the periodic table and that triply bonded metal-oxos could not be protonated, even in the strongest Brønsted acids. In this theory, only double bonded metal-oxos could attract protons, with basicities being a function of the electron donating ability of ancillary ligands. Such correlations of electronic structure with reactivity have gained importance in recent years, most notably owing to the widespread recognition that high-valent iron-oxos are intermediates in biological reactions critical to life on Earth. In this Account, we focus attention on the oxygenations of inert organic substrates by cytochromes P450, as these reactions involve multiply bonded iron-oxos. We emphasize that P450 iron-oxos are strong oxidants, so strong that they would destroy nearby amino acids if substrates are not oxygenated rapidly; it is our view that these high-valent iron-oxos are such dangerous reactive oxygen species that Nature surely found ways to disable them. Looking more deeply into this matter, mainly by examining many thousands of structures in the Protein Data Bank, we have found that P450s and other enzymes that require oxygen for function have chains of tyrosines and tryptophans that extend from active-site regions to protein surfaces. Tyrosines are near the heme active sites in bacterial P450s, whereas tryptophan is closest in most human enzymes. High-valent iron-oxo survival times taken from hole hopping maps range from a few nanoseconds to milliseconds, depending on the distance of the closest Trp or Tyr residue to the heme. In our proposed mechanism, multistep hole tunneling (hopping) through Tyr/Trp chains guides the damaging oxidizing hole to the protein surface, where it can be quenched by soluble protein or small molecule reductants. As the Earth's oxygenic atmosphere is believed to have developed about 2.5 billion years ago, the increase in occurrence frequency of tyrosine and tryptophan since the last universal evolutionary ancestor may be in part a consequence of enzyme protective functions that developed to cope with the environmental toxin, O2.

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The mechanism of haem catabolism. Bilirubin formation in living rats by [18O]oxygen labelling.

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