University of Leicester
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Structural basis of pyrrole polymerization in human porphobilinogen deaminase

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journal contribution
posted on 2019-03-07, 10:03 authored by P Pluta, P Roversi, G Bernardo-Seisdedos, AL Rojas, JB Cooper, S Gu, RW Pickersgill, O Millet
Human porphobilinogen deaminase (PBGD), the third enzyme in the heme pathway, catalyzes four times a single reaction to convert porphobilinogen into hydroxymethylbilane. Remarkably, PBGD employs a single active site during the process, with a distinct yet chemically equivalent bond formed each time. The four intermediate complexes of the enzyme have been biochemically validated and they can be isolated but they have never been structurally characterized other than the apo- and holo-enzyme bound to the cofactor. We present crystal structures for two human PBGD intermediates: PBGD loaded with the cofactor and with the reaction intermediate containing two additional substrate pyrrole rings. These results, combined with SAXS and NMR experiments, allow us to propose a mechanism for the reaction progression that requires less structural rearrangements than previously suggested: the enzyme slides a flexible loop over the growing-product active site cavity. The structures and the mechanism proposed for this essential reaction explain how a set of missense mutations result in acute intermittent porphyria.


Support was provided from The Department of Industry, Tourism and Trade of the Government of the Autonomous Community of the Basque Country (Elkartek BG2015) and from the Ministry of Science and Technology MINECO (CTQ2015-68756-R) to OM, from the European Molecular Biology Organization (EMBO ASTF 46-2015) to PP and OM and the BBSRC award (BB/IO13334/1) to SG & RWP. PR is the recipient of a Leicester LISCB-Welcome Trust ISSF award, grant reference 204801/Z/16/Z.



Biochim Biophys Acta Gen Subj, 2018, 1862 (9), pp. 1948-1955

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/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology


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Biochim Biophys Acta Gen Subj





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