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Heme redox potentials hold the key to reactivity differences between nitric oxide reductase and heme-copper oxidase.

Abstract：

:Despite high structural homology between NO reductases (NORs) and heme-copper oxidases (HCOs), factors governing their reaction specificity remain to be understood. Using a myoglobin-based model of NOR (FeBMb) and tuning its heme redox potentials (E°') to cover the native NOR range, through manipulating hydrogen bonding to the proximal histidine ligand and replacing heme b with monoformyl (MF-) or diformyl (DF-) hemes, we herein demonstrate that the E°' holds the key to reactivity differences between NOR and HCO. Detailed electrochemical, kinetic, and vibrational spectroscopic studies, in tandem with density functional theory calculations, demonstrate a strong influence of heme E°' on NO reduction. Decreasing E°' from +148 to -130 mV significantly impacts electronic properties of the NOR mimics, resulting in 180- and 633-fold enhancements in NO association and heme-nitrosyl decay rates, respectively. Our results indicate that NORs exhibit finely tuned E°' that maximizes their enzymatic efficiency and helps achieve a balance between opposite factors: fast NO binding and decay of dinitrosyl species facilitated by low E°' and fast electron transfer facilitated by high E°'. Only when E°' is optimally tuned in FeBMb(MF-heme) for NO binding, heme-nitrosyl decay, and electron transfer does the protein achieve multiple (>35) turnovers, previously not achieved by synthetic or enzyme-based NOR models. This also explains a long-standing question in bioenergetics of selective cross-reactivity in HCOs. Only HCOs with heme E°' in a similar range as NORs (between -59 and 200 mV) exhibit NOR reactivity. Thus, our work demonstrates efficient tuning of E°' in various metalloproteins for their optimal functionality.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Bhagi-Damodaran A,Reed JH,Zhu Q,Shi Y,Hosseinzadeh P,Sandoval BA,Harnden KA,Wang S,Sponholtz MR,Mirts EN,Dwaraknath S,Zhang Y,Moënne-Loccoz P,Lu Y

doi

10.1073/pnas.1720298115

subject

Has Abstract

pub_date

2018-06-12 00:00:00

pages

6195-6200

issue

eissn

0027-8424

issn

1091-6490

pii

1720298115

journal_volume

115

pub_type

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Heme redox potentials hold the key to reactivity differences between nitric oxide reductase and heme-copper oxidase.