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Class Id ribonucleotide reductase utilizes a Mn2(IV,III) cofactor and undergoes large conformational changes on metal loading
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Fysikalisk kemi.
Vise andre og tillknytning
2019 (engelsk)Inngår i: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 24, nr 6, s. 863-877Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Outside of the photosynthetic machinery, high-valent manganese cofactors are rare in biology. It was proposed that a recently discovered subclass of ribonucleotide reductase (RNR), class Id, is dependent on a Mn2(IV,III) cofactor for catalysis. Class I RNRs consist of a substrate-binding component (NrdA) and a metal-containing radical-generating component (NrdB). Herein we utilize a combination of EPR spectroscopy and enzyme assays to underscore the enzymatic relevance of the Mn2(IV,III) cofactor in class Id NrdB from Facklamia ignava. Once formed, the Mn2(IV,III) cofactor confers enzyme activity that correlates well with cofactor quantity. Moreover, we present the X-ray structure of the apo- and aerobically Mn-loaded forms of the homologous class Id NrdB from Leeuwenhoekiella blandensis, revealing a dimanganese centre typical of the subclass, with a tyrosine residue maintained at distance from the metal centre and a lysine residue projected towards the metals. Structural comparison of the apo- and metal-loaded forms of the protein reveals a refolding of the loop containing the conserved lysine and an unusual shift in the orientation of helices within a monomer, leading to the opening of a channel towards the metal site. Such major conformational changes have not been observed in NrdB proteins before. Finally, in vitro reconstitution experiments reveal that the high-valent manganese cofactor is not formed spontaneously from oxygen, but can be generated from at least two different reduced oxygen species, i.e. H2O2 and superoxide (O 2 ·− ). Considering the observed differences in the efficiency of these two activating reagents, we propose that the physiologically relevant mechanism involves superoxide.

sted, utgiver, år, opplag, sider
2019. Vol. 24, nr 6, s. 863-877
Emneord [en]
Ribonucleotide reductase, Dimanganese cofactor, Radicals, Electron paramagnetic resonance, X-ray crystallography, Phylogeny
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-392170DOI: 10.1007/s00775-019-01697-8ISI: 000487094500011PubMedID: 31414238OAI: oai:DiVA.org:uu-392170DiVA, id: diva2:1347126
Forskningsfinansiär
EU, European Research Council, 714102Swedish Research Council, 621-2014-5670Swedish Research Council, 2016-04855Swedish Research Council, 2016-01920Swedish Cancer Society, 2018/820Magnus Bergvall FoundationWenner-Gren FoundationsTilgjengelig fra: 2019-08-30 Laget: 2019-08-30 Sist oppdatert: 2019-10-30bibliografisk kontrollert

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