Heme degradation in Mycobacterium tuberculosis

Abstract

Bacterial pathogens must acquire host iron for their survival and proliferation. Because of limited availability of free iron in the host, they have evolved to overcome this restriction by employing a family of heme oxygenase enzymes that mediate the oxidative cleavage of heme into biliverdin, carbon monoxide, and iron by three step monooxygenation reaction. However, MhuD, a heme degradation enzyme of Mycobacterium tuberculosis, the etiological agent of tuberculosis, accomplishes this task without generating carbon monoxide, which induces the M. tuberculosis latent state. This unusual heme degradation reaction proceeds through sequential mono- and di-oxygenation events within the single active center of MhuD, a mechanism unprecedented in oxygenase enzyme catalysis. Like canonical heme oxygenase, the initial MhuD monooxygenation converts heme to meso-hydroxyheme, which subsequently reacts with O2 at an unusual position to completely suppress monooxygenation but to allow ring cleavage through dioxygenation. This mechanistic change, due to heavy deformation of hydroxyheme, rationally explains the unique heme catabolites of MhuD. Coexistence of mechanistically distinct functions is a newly identified strategy to expand the physiological outcome of enzymes.