Structural basis of pyrrole polymerization in human porphobilinogen deaminase.

Autor: Pluta P; Protein Stability and Inherited Disease Laboratory, CIC bioGUNE, Derio, Bizkaia 48160, Spain., Roversi P; Oxford Glycobiology Institute, Dept. of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester LE1 7RH, England, UK., Bernardo-Seisdedos G; Protein Stability and Inherited Disease Laboratory, CIC bioGUNE, Derio, Bizkaia 48160, Spain., Rojas AL; Structural Biology Unit, CIC bioGUNE, Derio, Bizkaia 48160, Spain., Cooper JB; Department of Biological Sciences, Birkbeck, London WC1E 7HX, UK; Division of Medicine, University College London, London WC1E 6BT, UK., Gu S; School of Biological and Chemical Sciences, Chemistry & Biochemistry Department, Queen Mary University of London, Mile End Road, London E1 4NS, UK., Pickersgill RW; School of Biological and Chemical Sciences, Chemistry & Biochemistry Department, Queen Mary University of London, Mile End Road, London E1 4NS, UK., Millet O; Protein Stability and Inherited Disease Laboratory, CIC bioGUNE, Derio, Bizkaia 48160, Spain. Electronic address: omillet@cicbiogune.es.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. General subjects [Biochim Biophys Acta Gen Subj] 2018 Sep; Vol. 1862 (9), pp. 1948-1955. Date of Electronic Publication: 2018 Jun 15.
DOI: 10.1016/j.bbagen.2018.06.013
Abstrakt: 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.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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