Structure–function characterization of the mono- and diheme forms of MhuD, a noncanonical heme oxygenase from Mycobacterium tuberculosis

Abstract

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Chemistry and Biology of Coenzyme F420 in Tuberculosis treatment

“…Mycobacterium tuberculosis (MTB) infection causes acute oxidative stress and increases the expression of HO-1, which may in turn facilitate MTB survival and growth due to increased iron availability. [75][76][77] MhuD is a noncanonical heme oxygenase (HO) from M. tuberculosis (Mtb) that catalyzes unique heme degradation chemistry distinct from canonical HOs, generating mycobilin products without releasing carbon monoxide. [75][76][77] Its crucial role in the Mtb heme uptake pathway has identified MhuD as an auspicious drug target.…”

“…[75][76][77] MhuD is a noncanonical heme oxygenase (HO) from M. tuberculosis (Mtb) that catalyzes unique heme degradation chemistry distinct from canonical HOs, generating mycobilin products without releasing carbon monoxide. [75][76][77] Its crucial role in the Mtb heme uptake pathway has identified MhuD as an auspicious drug target. MhuD is capable of binding either one or two hemes within a single active site.…”

“…MhuD is capable of binding either one or two hemes within a single active site. [75][76][77] The characterization of Rv2074 from Mycobacterium tuberculosis has been reported, which belongs to a structurally and mechanistically distinct family of F420H2-dependent BVRs (F-BVRs) that are exclusively found in Actinobacteria. 76 Bilirubin is a potent antioxidant that is produced from the reduction of biliverdin by a novel F420H2 -dependent biliverdin reductase in M. tuberculosis.…”

Heme acquisition and tolerance in Gram-positive model bacteria: An orchestrated balance

“…MhuD of M. tuberculosis can bind one or two molecules of heme at the same active site, whereas IsdG/I just binds a single heme at an active site [ 73 ]. Both diheme-MhuD and monoheme-MhuD complexes are enzymatically active and are able to degrade heme [ 78 ]. IsdG-like proteins have also been identified in S. epidermidis [ 79 ], B. anthracis [ 80 ], and L. monocytogenes [ 81 ].…”

Differentiating the roles of Mycobacterium tuberculosis substrate binding proteins, FecB and FecB2, in iron uptake

“…Both FecB and FecB2 constructs with hexa-histidine (His) tags have high nanomolar to micromolar affinities to heme, 1.20 ± 0.10 μM and 0.87 ± 0.06 μM, respectively (S5 Fig and Table 2). Previous studies have shown that His tags can interfere with heme binding studies [50][51][52], thus we determined the affinity of heme to FecB and FecB2 in the absence of a His tag (Figs 4 and S5). For FecB, the affinity for heme was similar in the presence or absence of the His tag.…”