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The tetrahydrobiopterin radical interacting with high- and low-spin heme in neuronal nitric oxide synthase - A new indicator of the extent of NOS coupling
University of Alabama, AL 35487 USA; Northwestern University, IL 60208 USA.
Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering. University of Alabama, AL 35487 USA.
University of Alabama, AL 35487 USA.
University of Alabama, AL 35487 USA.
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2016 (English)In: FREE RADICAL BIOLOGY AND MEDICINE, ISSN 0891-5849, Vol. 101, 367-377 p.Article in journal (Refereed) Published
Abstract [en]

Reaction intermediates trapped during the single-turnover reaction of the neuronal ferrous nitric oxide synthase oxygenase domain (Fe(II)nNOS(OX)) show four EPR spectra of free radicals. Fully-coupled nNOSOX with cofactor (tetrahydrobiopterin, BH4) and substrate (L-arginine) forms the typical BH4 cation radical with an EPR spectrum similar to 4.0 mT wide and hyperfine tensors similar to reports for a biopterin cation radical in inducible NOSOX (iNOS(OX)). With excess thiol, nNOSox lacking BH4 and L-arg is known to produce superoxide. In contrast, we find that nNOSOX with BH4 but no L-arg forms two radicals with rather different, fast (similar to 250 mu s at 5 K) and slower (similar to 500 mu s at 20 K), electron spin relaxation rates and a combined similar to 7.0 mT wide EPR spectrum. Rapid freeze-quench CW- and pulsed-EPR measurements are used to identify these radicals and their origin. These two species are the same radical with identical nuclear hyperfine couplings, but with spin-spin couplings to high-spin (4.0 mT component) or low-spin (7.0 mT component) Fe(III) heme. Uncoupled reactions of nNOS leave the enzyme in states that can be chemically reduced to sustain unregulated production of NO and reactive oxygen species in ischemia-reperfusion injury. The broad EPR signal is a convenient indicator of uncoupled nNOS reactions producing low-spin Fe(III) heme.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC , 2016. Vol. 101, 367-377 p.
Keyword [en]
Nitric oxide synthase; Tetrahydrobiopterin radical; EPR; ENDOR; ESEEM
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-134088DOI: 10.1016/j.freeradbiomed.2016.10.503ISI: 000390701300033PubMedID: 27989753OAI: oai:DiVA.org:liu-134088DiVA: diva2:1067841
Note

Funding Agencies|National Institutes of Health, United States [HL095820]

Available from: 2017-01-23 Created: 2017-01-22 Last updated: 2017-01-23

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