Crystal structure of heme A synthase from Bacillus subtilis

Satomi Niwa, Kazuki Takeda, Masayuki Kosugi, Erika Tsutsumi, Tatsushi Mogi, and Kunio Miki
PNAS November 20, 2018 115 (47) 11953-11957; published ahead of print November 5, 2018 https://doi.org/10.1073/pnas.1813346115

  1. Edited by Johann Deisenhofer, University of Texas Southwestern Medical Center, Dallas, TX, and approved October 8, 2018 (received for review August 3, 2018)

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Significance

In aerobic organisms, the terminal enzymes of the respiratory chain such as cytochrome c oxidase receive electrons and reduce molecular oxygen to water. Heme A is an essential cofactor for these oxidases and constitutes the redox-active sites and the proton-transfer pathways. Heme A is synthesized by heme A synthase (HAS). The molecular architecture and reaction mechanism is unknown. In this work, we determined the crystal structure of HAS from Bacillus subtilis in the apo form at high resolution. The structure in the holo form was also constructed using the crystal structure. These structures provide some clues for the heme A biosynthetic process, including substrate binding manner and catalytic residues.

Abstract

Heme A is an essential cofactor for respiratory terminal oxidases and vital for respiration in aerobic organisms. The final step of heme A biosynthesis is formylation of the C-8 methyl group of heme molecule by heme A synthase (HAS). HAS is a heme-containing integral membrane protein, and its structure and reaction mechanisms have remained unknown. Thus, little is known about HAS despite of its importance. Here we report the crystal structure of HAS from Bacillus subtilis at 2.2-Å resolution. The N- and C-terminal halves of HAS consist of four-helix bundles and they align in a pseudo twofold symmetry manner. Each bundle contains a pair of histidine residues and forms a heme-binding domain. The C-half domain binds a cofactor-heme molecule, while the N-half domain is vacant. Many water molecules are found in the transmembrane region and around the substrate-binding site, and some of them interact with the main chain of transmembrane helix. Comparison of these two domain structures enables us to construct a substrate-heme binding state structure. This structure implies that a completely conserved glutamate, Glu57 in B. subtilis, is the catalytic residue for the formylation reaction. These results provide valuable suggestions of the substrate-heme binding mechanism. Our results present significant insight into the heme A biosynthesis.

Footnotes

  • ↵1To whom correspondence should be addressed. Email: miki{at}kuchem.kyoto-u.ac.jp.

  • Author contributions: K.T., T.M., and K.M. designed research; S.N., K.T., M.K., and E.T. performed research; S.N. and K.T. analyzed data; and S.N., K.T., T.M., and K.M. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.wwpdb.org (PDB ID code 6A2J for native dataset and 6IED for S-anomalous dataset).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1813346115/-/DCSupplemental.

Published under the PNAS license.

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Crystal structure of heme A synthase from Bacillus subtilis
Satomi Niwa, Kazuki Takeda, Masayuki Kosugi, Erika Tsutsumi, Tatsushi Mogi, Kunio Miki
Proceedings of the National Academy of Sciences Nov 2018, 115 (47) 11953-11957; DOI: 10.1073/pnas.1813346115
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