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Structural Basis for Adenosylcobalamin Activation in AdoCbl-Dependent Ribonucleotide Reductases
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
2010 (Engelska)Ingår i: ACS chemical biology, ISSN 1554-8929, Vol. 5, nr 10, s. 933-942Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Class II ribonucleotide reductases (RNR) catalyze the formation of an essential thiyl radical by homolytic cleavage of the Co-C bond in their adenosylcobalamin (AdoCbl) cofactor. Several mechanisms for the dramatic acceleration of Co-C bond cleavage in AdoCbl-dependent enzymes have been advanced, but no consensus yet exists. We present the structure of the class II RNR from Thermo toga maritima in three complexes: (i) with allosteric effector dTTP, substrate GDP, and AdoCbl; (ii) with dTTP and AdoCbl; (iii) with dTTP, GDP, and adenosine. Comparison of these structures gives the deepest structural insights so far into the mechanism of radical generation and transfer for AdoCbl-dependent RNR. AdoCbl binds to the active site pocket, shielding the substrate, transient 5'-deoxyadenosyl radical and nascent thiyl radical from solution. The e-propionamide side chain of AdoCbl forms hydrogen bonds directly to the alpha-phosphate group of the substrate. This interaction appears to cause a "locking-in" of the cofactor, and it is the first observation of a direct cofactor-substrate interaction in an AdoCbl-dependent enzyme. The structures support an ordered sequential reaction mechanism with release or relaxation of AdoCbl on each catalytic cycle. A conformational change of the AdoCbl adenosyl ribose is required to allow hydrogen transfer to the catalytic thiol group. Previously proposed Mechanisms for radical transfer in B12-dependent enzymes cannot fully explain the transfer in class II RNR, suggesting that it may form a separate class that differs from the well characterized eliminases and mutases.

Ort, förlag, år, upplaga, sidor
2010. Vol. 5, nr 10, s. 933-942
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URN: urn:nbn:se:su:diva-51743DOI: 10.1021/cb1000845ISI: 000282924500004OAI: oai:DiVA.org:su-51743DiVA, id: diva2:386090
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authorCount :3Tillgänglig från: 2011-01-12 Skapad: 2011-01-12 Senast uppdaterad: 2011-01-12Bibliografiskt granskad

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