Essential Amino Acid Residues Controlling the Unique Regioselectivity of Heme Oxygenase in Pseudomonas aeruginosa

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Abstract
Heme oxygenase (HO), an amphipathic microsomal protein, catalyzes the oxygen-dependent degradation of heme (iron-protoporphyrinIX) to α-biliverdin, CO, and free iron ion. Interestingly, all of HO regiospecifically oxidize the α-meso position of the heme to form α-biliverdin isomer while nonenzymatic heme degradation forms all four possible α-, β-, γ-, δ-biliverdin isomers at nearly identical yield. Recently, an interesting example has been found in HO (PigA) of the Gram-negative bacterium Pseudomonas aeruginosa, which does not produce α-biliverdin at all, but forms the mixture of β- and γ-biliverdins at a ratio of 3:7. While studying the mechanism of the unique regioselectivty of PigA, we found essential amino acid residues, Lys34, Lys132, and Phe189, controlling the unique regioselectivity of PigA. In this communication, we show that Lys34 and Lys132 are essential amino acid residues to hold the rotated heme in the active site of PigA via hydrogen-bonding interaction with the heme propionate and that Phe189 controls the product ratio of β- and δ-biliverdins via steric interaction with heme substituents. These interactions place the β- or δ-meso position of the heme at the oxidation site of PigA, leading to the unique regioselectivity.