title: A new way to degrade heme: the Mycobacterium tuberculosis enzyme MhuD catalyzes heme degradation without generating CO.
abstract: MhuD is an oxygen-dependent heme-degrading enzyme from Mycobacterium tuberculosis with high sequence similarity (∼45%) to Staphylococcus aureus IsdG and IsdI. Spectroscopic and mutagenesis studies indicate that the catalytically active 1:1 heme-MhuD complex has an active site structure similar to those of IsdG and IsdI, including the nonplanarity (ruffling) of the heme group bound to the enzyme. Distinct from the canonical heme degradation, we have found that the MhuD catalysis does not generate CO. Product analyses by electrospray ionization-MS and NMR show that MhuD cleaves heme at the α-meso position but retains the meso-carbon atom at the cleavage site, which is removed by canonical heme oxygenases. The novel tetrapyrrole product of MhuD, termed "mycobilin," has an aldehyde group at the cleavage site and a carbonyl group at either the β-meso or the δ-meso position. Consequently, MhuD catalysis does not involve verdoheme, the key intermediate of ring cleavage by canonical heme oxygenase enzymes. Ruffled heme is apparently responsible for the heme degradation mechanism unique to MhuD. In addition, MhuD heme degradation without CO liberation is biologically significant as one of the signals of M. tuberculosis transition to dormancy is mediated by the production of host CO.
authors: Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Katahira, Aoba, Sendai 980-8577, Japan.
authors: Shusuke
authors: S
authors: Nambu
authors: Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Katahira, Aoba, Sendai 980-8577, Japan.
authors: Toshitaka
authors: T
authors: Matsui
authors: Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697; Department of Pharmaceutical Sciences, University of California, Irvine, California 92697.
authors: Celia W
authors: CW
authors: Goulding
authors: Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Katahira, Aoba, Sendai 980-8577, Japan.
authors: Satoshi
authors: S
authors: Takahashi
authors: Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Katahira, Aoba, Sendai 980-8577, Japan. Electronic address: mis2@tagen.tohoku.ac.jp.
authors: Masao
authors: M
authors: Ikeda-Saito
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D002248:Carbon Monoxide / Q000737:chemistry; D020134:Catalytic Domain; D015964:Gene Expression Regulation, Bacterial; D006418:Heme / Q000737:chemistry*; D006419:Heme Oxygenase (Decyclizing) / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008956:Models, Chemical; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010105:Oxygenases / Q000737:chemistry / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013059:Spectrum Analysis, Raman / Q000379:methods
chemical_list: D001426:Bacterial Proteins; D006418:Heme; D002248:Carbon Monoxide; D010105:Oxygenases; C482079:IsdG protein, Staphylococcus aureus; D006419:Heme Oxygenase (Decyclizing); D009251:NADPH-Ferrihemoprotein Reductase