Jul 102013
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Felix Spenkuch

Institute of Pharmacy and Biochemistry Johannes Gutenberg-Universit&#228t, Mainz, Germany

JUnQ, 3, 2, OQ, 17-20, 2013 (Received 28.04.2013, accepted 22.06.2013, published online 10.07.2013)

In the central dogma of molecular biology DNA (deoxynucleic acid) is transcribed into RNA (ribonucleic acid) which in turn makes the protein. 60 years after the creation of this dogma, however, it is clear that RNA is much more than the transient copy of DNA. A special subgroup of RNA molecules also transfers the aminoacids to the protein making machinery, thereby requiring a delicate balance of conformational uniformity and flexibility. In addition, RNA carries out many regulatory functions and is, in particular, the catalytic component of the proteinmaking machinery of the ribosome. It is understood today that RNA has to be heavily and specifically modified to carry out all these complex functions: The four building blocks known at the beginning of RNA research (adenosine, cytidine, guanosine, and uridine) are extended to 160 to date, numbers growing. Pseudouridine (&#968), the so called ‘fifth nucleoside’, is a C-C-glycosidic isomer of uridine and is as abundant as the four canonical bases. While its function is only partly understood, the mechanism of its formation by the action of enzymes called &#968-synthases, is even more nebulous. This article sums up information obtained by using the mechanistic probe 5-fluorouridine (5FU) on &#968-synthases: Three mechanisms were proposed to date of which none is solidly proven or disproven. Recent results show, however, that 5-fluorouridine may not form a reaction intermediate of usual &#968-formation, as expected, but may react by a totally different mechanism. Could new mechanistic probes and simulations help to elucidate the mechanism of these marvelous enzymes?

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