The chemical and enzymatic oxidation of hematohemin IX. Identification of hematobiliverdin IXalpha as the sole product of the enzymatic oxidation

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Abstract
Oxidative cleavage of hematohemin IX in pyridine solution in the presence of ascorbic acid (coupled oxidation), followed by esterification of the products with boron trifluoride/methanol produced the four possible hematobiliverdin esters in 11.1% overall yield. Transetherifications took place simultaneously with the esterification reaction and resulted in the formation of the dimethyl ester of hematobiliverdin IX.GAMMA. 8a,13a-dimethyl ether (1.8%), the dimethyl ester of hematobiliverdin IX.beta. 13a,18a-dimethyl ether (1.9%), the dimethyl ester of hematobiliverdin IX.delta. 8 a-monomethyl ether (1.4%), and the dimethyl ester of hematobiliverdin IX.alpha. 18 a-monomethyl ether (0.4%). The latter was the sole product obtained after the enzymatic oxidation of hematohemin with heme oxygenase, after esterification of the reaction product with boron trifluoride/methanol. When the esterification step was omitted hematobiliverdin IX.alpha. was obtained from the enzymatic oxidation. The strurctures of the hematobiliverdin derivatives were secured by their NMR and mass spectra data. Saponification of the dimethyl esters afforded the hematobiliverdin methyl ethers, which were excellent substrates of biliverdin reductase and were readily reduced to the corresponding bilirubins. Hematobiliverdin IX.alpha. was also a good substrate of biliverdin reductase. It is concluded that the enzymatic oxidation of hematohemin IX by heme oxygenase is .alpha.-selective, while biliverdin reductase shows no selectivity in the reduction of the four hematobiliverdin isomers.

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