Molecular basis for metabolite channeling in a ring opening enzyme of the phenylacetate degradation pathway

Nitish Sathyanarayanan, Giuseppe Cannone, Lokesh Gakhar, Nainesh Katagihallimath, Ramanathan Sowdhamini, Subramanian Ramaswamy () and Kutti R. Vinothkumar ()
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Nitish Sathyanarayanan: Institute for Stem Cell Science and Regenerative Medicine
Giuseppe Cannone: Medical Research Council Laboratory of Molecular Biology
Lokesh Gakhar: University of Iowa
Nainesh Katagihallimath: Institute for Stem Cell Science and Regenerative Medicine
Ramanathan Sowdhamini: National Centre for Biological Sciences TIFR
Subramanian Ramaswamy: Institute for Stem Cell Science and Regenerative Medicine
Kutti R. Vinothkumar: National Centre for Biological Sciences TIFR

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Substrate channeling is a mechanism for the internal transfer of hydrophobic, unstable or toxic intermediates from the active site of one enzyme to another. Such transfer has previously been described to be mediated by a hydrophobic tunnel, the use of electrostatic highways or pivoting and by conformational changes. The enzyme PaaZ is used by many bacteria to degrade environmental pollutants. PaaZ is a bifunctional enzyme that catalyzes the ring opening of oxepin-CoA and converts it to 3-oxo-5,6-dehydrosuberyl-CoA. Here we report the structures of PaaZ determined by electron cryomicroscopy with and without bound ligands. The structures reveal that three domain-swapped dimers of the enzyme form a trilobed structure. A combination of small-angle X-ray scattering (SAXS), computational studies, mutagenesis and microbial growth experiments suggests that the key intermediate is transferred from one active site to the other by a mechanism of electrostatic pivoting of the CoA moiety, mediated by a set of conserved positively charged residues.

Date: 2019
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DOI: 10.1038/s41467-019-11931-1

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