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First atomic structure of a bacterial bd-type oxidase

April 2016. Microorganisms have evolved a number of enzymes to reduce oxygen and prevent oxidative stress. Cytochrome bd oxidases serve this role and also confer tolerance to nitric oxide, thus contributing to the virulence of pathogenic bacteria. This class of oxidases is a particularly promising target for anti-microbial drugs but until now eluded high-resolution crystallography. A team of scientists led by Hartmut Michel at the Max Planck Institute of Biophysics in Frankfurt now succeeded in determining the three-dimensional structure of cytochrome bd oxidase from a thermophilic bacterium.

The study, published on 29 April 2016 by the journal Science, found that the overall structure and triangular arrangement of the heme cofactors bear little structural resemblance to those of other membrane-spanning oxidases. The crystal structure, derived from crystals diffracting anisotropically to 3.1 to 4 Å resolutions, shows that the bd oxidase from G. thermodenitrificans has 19 helices that span the bacterial cytoplasmic membrane. CydA and CydB have nine helices each and the 19th helix is the small peptide called CydS. The CydA and CydB protein subunits share the same fold, most likely as a result of gene duplication of a single ancestral gene that encoded a homodimeric oxidase. However, the three hemes are associated only with CydA, which also harbors the site of quinol oxidation. CydS is a single transmembrane helix of 33 amino acid residues and may stabilize the b558 heme next to the quinol oxidation site. Surprisingly, the three hemes are found in a triangular arrangement and not in the form of a linear chain. 


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Most biological oxygen consumption is carried out by membrane-integrated oxidases, which fall into three main classes. The cytochrome bd oxidases are present in certain bacteria and archaea. More widespread are the  heme-copper oxidases (HCOs), which are present in humans and other eukaryotes as well as bacteria. A third class, the cyanide-resistant alternative oxidases (AOXs) are found in certain plants, fungi and bacteria. Atomic structures of oxidases from the HCO and AOX classes are available, but despite decades of research, no cytochrome bd structure had been forthcoming until the breakthrough reported here.

Cytochrome bd oxidases have a distinctive heme composition consisting of two hemes b and one heme d. They possess a high oxygen affinity and thus play a role in protection against oxidative stress and the colonization of O2-poor environments by pathogenic bacteria. Cytochrome bd oxidases rapidly dissociate gaseous inhibitory nitrogen ligands and confer tolerance under nitric oxide stress conditions, an ability crucial for the viability of pathogenic bacteria upon host infection. Pathogenic bacteria with bd-type oxidases include for example Salmonella and the causative agents of tuberculosis and brucellosis.


Hartmut Michel
Department of Molecular Membrane Biology
Max Planck Institute of Biophysics
Max-von-Laue-Straße 3
60438 Frankfurt/Main, Germany


Schara Safarian, Chitra Rajendran, Hannelore Müller, Julia Preu, Julian D. Langer, Sergey Ovchinnikov, Taichiro Hirose, Tomoichirou Kusumoto, Junshi Sakamoto, Hartmut Michel. 2016. Structure of a bd oxidase indicates similar mechanisms for membrane-integrated oxygen reductases. Science published 29 Apr 2016, p.583-586. Link