Abstract:
:Adenosyltransferases (ATRs) catalyze the synthesis of the reactive cobalt-carbon bond found in coenzyme B(12) or 5'-deoxyadenosylcobalamin (AdoCbl), which serves as a cofactor for a number of isomerases. The reaction involves a reductive adenosylation of cob(II)alamin in which an electron delivered by a reductase reduces cob(II)alamin to cob(I)alamin, which attacks the 5'-carbon of ATP to form AdoCbl and inorganic triphosphate. Of the three classes of ATRs found in nature, the PduO type, which is also the only one found in mammals, is the most extensively studied. The crystal structures of a number of PduO-type ATRs are available and reveal a trimeric organization with the active sites located at the subunit interfaces. We have previously demonstrated that the ATR from Methylobacterium extorquens, which supports methylmalonyl-CoA mutase activity, serves dual functions; i.e., it tailors the active AdoCbl form of the cofactor and then transfers it directly to the dependent mutase (Padovani et al. (2008) Nat. Chem. Biol. 4, 194). Only two of the three active sites in ATR are simultaneously occupied by AdoCbl. In this study, we demonstrate that binding of the substrate ATP to ATR that is fully loaded with AdoCbl leads to the ejection of 1 equivalent of the cofactor into solution. In the presence of methylmalonyl-CoA mutase and ATP, AdoCbl is transferred from ATR to the acceptor protein in a process that exhibits an approximately 3.5-fold lower K(act) for ATP compared to the one in which cofactor is released into solution. Furthermore, ATP favorably influences cofactor transfer in the forward direction by reducing the ratio of apo-methylmalonyl-CoA mutase/holo-ATR required for delivery of 1 equivalent of AdoCbl, from 4 to 1. These results lead us to propose a rotary mechanism for ATR function in which, at any given time, only two of its active sites are used for AdoCbl synthesis and where binding of ATP to the vacant site leads to the transfer of the high value AdoCbl product to the acceptor mutase.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Padovani D,Banerjee Rdoi
10.1021/bi900454ssubject
Has Abstractpub_date
2009-06-16 00:00:00pages
5350-7issue
23eissn
0006-2960issn
1520-4995journal_volume
48pub_type
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