Page 8 - IPA_1_2022
P. 8


        The key to a powerful

        antibiotic’s formation now clear

              powerful class of antibiotics   methylation -- adding a methyl     rather than ‘radical chemistry,’”
              called carbapenems can         group. In this case, TokK helps     said Booker. “But here we found
        A cumvent antibiotic                 facilitate the addition of three    that TokK, and we think many other
        resistance thanks to a particular    methyl groups to the antibiotic,    cobalamin-dependent radical SAM
        chain of atoms in their structure.   building the side chain that is so   enzymes, use radical chemistry.
        Now, a team of researchers from      critical in this antibiotic.        It turns out that cobalamin is
        Penn State and Johns Hopkins                                             much more versatile than we had
        University have imaged an enzyme     The researchers found that, like    previously appreciated.”
        involved in the creation of this chain   most radical SAM enzymes,
        to better understand how it forms    TokK first uses one if its iron-    This improved understanding
        -- and perhaps replicate the process   sulfur clusters to convert a SAM   of how the side chain in
        to improve future antibiotics. A paper   molecule into a “free radical,”   carbapenems is created could
        describing the process appears Feb.   which propels the reaction         provide important insight for how
        2 in the journal Nature.             forward. The radical then takes     to replicate this process and
                                             a hydrogen atom from the under-     potentially improve antibiotics.
        Carbapenems are naturally occurring   construction antibiotic. TokK then
        potent, broad-spectrum antibiotics   donates a methyl group from a       “Multiple methylations by a
        that belong to a larger group called   part of its structure called methyl-  radical SAM enzyme are unusual,
        beta-lactam antibiotics that also    cobalamin to the vacant spot on     although not unprecedented,
        includes penicillin. Carbapenems     the antibiotic where the hydrogen   and have created a ‘library’ of
        are often used as a last resort to   was removed. This methylation       two- and three-carbon variants of
        treat bacterial infections, including   process is repeated three times,   the carbapenem core in nature,”
        hospital-acquired and ventilator-    ultimately producing the side chain   said Craig Townsend, Alsoph H.
        associated bacterial pneumonia       with three methyl groups.           Corwin Professor of Chemistry at
        -- an increasing problem during                                          Johns Hopkins and an author of
        the COVID-19 pandemic. Certain       “TokK acts like a scaffold in this   the paper. “Two methyl groups may
        carbapenems have a side chain that   process, bringing together the      be optimal for antibiotic activity,
        includes two or three methyl groups   methyl-cobalamin, a SAM molecule,   but one wonders if engineering of
        -- a carbon atom and three hydrogen   and the antibiotic into an ideal   TokK to incorporate four or more of
        atoms -- that help them thwart       position for transfer of the methyl   these groups could lead to further
        antibiotic resistance.               group to occur,” said Hayley Knox, a   improvements in the running battle
                                             graduate student at Penn State and   against bacterial resistance.”
        “In many cases, bacteria can evolve   an author of the paper. “The second
        resistance to beta-lactam antibiotics   methyl group is actually attached   This work was funded by the
        by degrading a structure in the      much more quickly than we would     National Institutes of Health, the
        antibiotic called the ‘beta-lactam   expect based on the energetics.     Penn State Eberly College of
        ring,’ which renders it ineffective,”   We think that this is because the   Science, and the Howard Hughes
        said Squire Booker, a biochemist     components are already so well      Medical Institute.
        at Penn State, investigator with the   aligned from the first step.”
        Howard Hughes Medical Institute,                                         Story Source:
        and an author of the paper. “But the   Cobalamin, also known as vitamin   Materials provided by Penn State.
        addition of the methyl groups in the   B12, helps facilitate a variety of   Original written by Gail McCormick.
        side chain prevents this degradation,   enzyme-driven reactions. However,   Note: Content may be edited for
        making carbapenems powerful          this type of “radical chemistry” is   style and length.
        clinical tools. In this study, we    uncommon in known reactions
        imaged a protein called TokK that we   where cobalamin is involved,      Journal Reference:
        know facilitates the synthesis of the   suggesting that cobalamin may play   1 Hayley L. Knox, Erica K. Sinner,
        side chain in order to reconstruct the   a different role than anticipated in   Craig A. Townsend, Amie K.
        initial chemical steps in this process.”  many reactions.                Boal, Squire J. Booker. Structure
                                                                                 of a B12-dependent radical
        TokK is a type of radical SAM        “Typically, we think of             SAM enzyme in carbapenem
        (S-adenosylmethionine) enzyme        methylcobalamin as being involved   biosynthesis. Nature, 2022; DOI:
        that is involved in the process of   in what we call ‘polar chemistry’   10.1038/s41586-021-04392-4

   3   4   5   6   7   8   9   10   11   12   13