Capture of long‐missing heme oxygenases that degrade both heme b and heme c

Abstract

Heme serves as a crucial cofactor for hemoproteins and as an iron reservoir; yet, its accumulation is toxic, necessitating efficient degradation pathways. While the catabolism of free heme b is well characterized, the enzymes that disrupt its counterpart covalently tethered to a peptide (heme c ) have remained elusive. Here, through a pipeline of multiple in silico analyses, we predict a distinct Core‐only type of heme oxygenases (HOs) within the HugZ superfamily to have the potential to degrade both heme b and peptide‐tethered heme c . Biochemical and physiological characterization confirms that representative Core‐only‐type HOs confer balanced dual‐substrate specificity. In contrast, the C‐extension and N‐fusion‐type HOs degrade heme b, but not heme c, because the entry of heme c into the active pocket is blocked by their extra domains. Moreover, we show that the degradation of heme c by the Core‐only‐type HOs requires proteolytic digestion of heme c ‐carrying proteins by a protease such as DegQ, which occurs in the periplasm. Overall, this work provides an integrated evolutionary, structural, biochemical, and physiological framework that defines a novel strategy for heme recycling and adaptive metabolic flexibility in bacteria.