5M6R

Human porphobilinogen deaminase in complex with reaction intermediate

Summary for 5M6R

• Entry DOI: 10.2210/pdb5m6r/pdb
• Descriptor: Porphobilinogen deaminase, 3-[4-(2-hydroxy-2-oxoethyl)-5-[[4-(2-hydroxy-2-oxoethyl)-5-[[4-(2-hydroxy-2-oxoethyl)-5-[[4-(2-hydroxy-2-oxoethyl)-3-(3-hydroxy-3-oxopropyl)-5-methyl-1~{H}-pyrrol-2-yl]methyl]-3-(3-hydroxy-3-oxopropyl)-1~{H}-pyrrol-2-yl]methyl]-3-(3-hydroxy-3-oxopropyl)-1~{H}-pyrrol-2-yl]methyl]-1~{H}-pyrrol-3-yl]propanoic acid, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: porphobilinogen deaminase, heme biosynthesis, porphyria, hmbs, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 87638.27

Authors

Pluta, P.,Millet, O.,Roversi, P.,Rojas, A.L.,Gu, S. (deposition date: 2016-10-25, release date: 2017-11-15, Last modification date: 2024-11-13)

Primary citation

Pluta, P.,Roversi, P.,Bernardo-Seisdedos, G.,Rojas, A.L.,Cooper, J.B.,Gu, S.,Pickersgill, R.W.,Millet, O.
Structural basis of pyrrole polymerization in human porphobilinogen deaminase.
Biochim Biophys Acta Gen Subj, 1862:1948-1955, 2018

PubMed Abstract: 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.

PubMed: 29908816
DOI: 10.1016/j.bbagen.2018.06.013

Experimental method

X-RAY DIFFRACTION (2.73 Å)